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............................ New Concepts in Diabetes and Its Treatment

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New Concepts in Diabetes and Its Treatment

Editors

Francesco Belfiore, Catania Carl Erik Mogensen, Aarhus

22 figures and 60 tables, 2000

............................ Francesco Belfiore, MD Institute of Internal Medicine University of Catania, Ospedale Garibaldi

Carl Erik Mogensen, MD Medical Department M (Diabetes and Endocrinology), Kommunehospitalet University Hospital in Aarhus

Library of Congress Cataloging-in-Publication Data New concepts in diabetes and its treatment / editors, F. Belfiore, Carl Erik Mogensen. p. cm. Includes bibliographical references and indexes. ISBN 3–8055–6907–6 (hardcover : alk. paper) 1. Diabetes. I. Belfiore, Francesco. II. Mogensen, Carl Erik. [DNLM: 1. Diabetes Mellitus – therapy. 2. Diabetes Mellitus – complications. WK 815 N5315 2000] RC660.N396 2000 616.462–dc21 99–057726 CIP

Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Ó Copyright 2000 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–6907–6

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Contents

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Introduction Belfiore, F. (Catania); Mogensen, C.E. (Aarhus)

Chapter I 3

Etiological Classification, Pathophysiology and Diagnosis Belfiore, F.; Iannello, S. (Catania)

Chapter II 20 Insulin Secretion and Its Pharmacological Stimulation Belfiore, F.; Iannello, S. (Catania)

Chapter III 38 Insulin Resistance and Its Relevance to Treatment Belfiore, F.; Iannello, S. (Catania)

Chapter IV 56 Diet and Modification of Nutrient Absorption Iannello, S. (Catania)

Chapter V 72 Insulin Treatment in Type 1 and Type 2 Diabetes: Practical Goals and

Algorithms Belfiore, F.; Iannello, S. (Catania)

Chapter VI 90 Overview of Diabetes Management: ‘Combined’ Treatment and

Therapeutic Additions Belfiore, F.; Iannello, S. (Catania)

Chapter VII 103 Clinical Emergencies in Diabetes. 1: Diabetic Ketoacidosis and

Hyperosmolar Nonketotic Syndrome Belfiore, F.; Iannello, S. (Catania)

Chapter VIII 111 Clinical Emergencies in Diabetes. 2: Hypoglycemia Belfiore, F.; Iannello, S. (Catania)

Chapter IX 125 Mechanisms of Diabetic Complications (Nephropathy) as Related to

Perspectives of Treatment Cooper, M.E. (West Heidelberg, Vic.)

Chapter X 135 Diabetic Retinopathy Bek, T. (Aarhus)

Chapter XI 152 Nephropathy and Hypertension in Diabetic Patients Mogensen, C.E. (Aarhus)

Chapter XII 174 Lipid Abnormalities and Lipid Lowering in Diabetes Belfiore, F.; Iannello, S. (Catania)

Chapter XIII 186 Cardiovascular Disease and Diabetes Zuanetti, G. (Milan)

Chapter XIV 199 Diabetic Neuropathy Boulton, A.J.M.; Malik, R.A. (Manchester)

Contents

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Chapter XV 208 Foot Problems in Diabetes Shaw, J.E.; Boulton, A.J.M. (Manchester)

Chapter XVI 218 Erectile Dysfunction in Diabetes and Its Treatment Tagliabue, M.; Molinatti, G.M. (Turin)

Chapter XVII 229 Multifactorial Intervention in Type 2 Diabetes mellitus Gæde, P.; Pedersen, O. (Copenhagen)

Chapter XVIII 241 Managing Diabetes and Pregnancy Kitzmiller, J.L. (San Jose, Calif.)

253 Author Index 254 Subject Index

Contents

VII

Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 1–2

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Introduction

Diabetes mellitus and its complications are clinical conditions of growing importance both from the clinical as well as epidemiological standpoint. The relevance of diabetes at clinical and individual level is given by its lifethreatening acute complications and, especially, by its chronic complications affecting several organs and systems, with increased risk for ocular, renal, cardiac, cerebral, nervous and peripheral vascular diseases. The high prevalence of diabetes in many developed countries or in special ethnic groups, entailing premature disability and mortality, points to its relevance at population level. It is, therefore, mandatory for both the specialist and the practitioner to be acquainted with the pathophysiological mechanisms, clinical manifestations and, above all, therapy of diabetes mellitus. Recent data showing that control of hyperglycemia may prevent the onset or slow down the progression of complications point to the importance of an appropriate and efficacious treatment. Indeed, the aim of this book is to serve as a tool to provide physicians with the latest views on diagnostic aspects and pathophysiological mechanisms as a premise to go deep into the various facets of the modern management of diabetes. This book begins with introductory chapters on classification and clinical aspects, after which an account is given of insulin secretion as modulated by sulfonylureas and of insulin resistance (in its genetic and acquired components) as modified by diet and the new lipase-inhibitory drug or by metformin (and perhaps troglitazone agents). Insulin therapy of both type 1 and, when required, type 2 diabetes is adequately covered. This is followed by an integrated view of metabolic control, including combined therapy and self-monitoring, in the light of the lesson from DCCT (Diabetes Control and Complications Trial) and UK-PDS (United Kingdom Prospective Diabetes Study).

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The mechanisms of complications are treated as an introduction to the understanding of possible therapeutic strategies. Then retinopathy, nephropathy, hypertension and cardiovascular disease are considered in their clinical aspects and therapeutic interventions. Extensive space is devoted to the various neuropathic manifestations, including erectile dysfunction, as well as to the foot problems. Final chapters highlight the need for multifactorial treatment and the clinical and therapeutic problems of diabetic pregnancy. The international panel of authors has made any effort to condense this rich content into a relatively short text and to present it in a clear and smoothto-read form. While more extensive information may be found in larger treatises (see Suggested Reading, below), we hope that this medium-size book will be useful to all physicians interested in the management of diabetic patients by providing them with a simple yet updated source of information concerning the New Concepts in Diabetes and Its Treatment. Francesco Belfiore Carl Erik Mogensen

Suggested Reading Alberti KGMM, Zimmet P, DeFronzo RA: International Textbook of Diabetes mellitus, ed 2. Chichester, Wiley, 1999. Belfiore F (ed): Frontiers in Diabetes. Basel, Karger, vol 8/1987, vol 9/1990, vol 10/1990, vol 11/1992, vol 12/1993, vol 14/1998. Bray G, Bouchard C, James WPT (eds): Handbook of Obesity. New York, Dekker, 1997. Kakn CR, Weir GC (eds): Joslin’s Diabetes mellitus, ed 13. Malvern, Lea & Febiger, 1994. Mogensen CE (ed): The Kidney and Hypertension in Diabetes mellitus, ed 5. Boston, Kluwer Academic, 2000. Pickup JC, Williams G (eds): Textbook of Diabetes, ed 2. Oxford, Blackwell, 1997. Porte D Jr, Sherwin RS (eds): Ellenberg and Rifkin’s Diabetes mellitus, ed 4, Amsterdam, Elsevier, 1990, and ed 5, Old Tappan/NJ, Appleton & Lange, 1996.

Introduction

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Chapter I

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Etiological Classification, Pathophysiology and Diagnosis F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Introduction According to the classical definition, diabetes mellitus is a disorder resulting from both genetic predisposition and favoring environmental factors, and is characterized by alterations in the metabolism of carbohydrate, fat and protein, which are caused by a relative or absolute deficiency of insulin secretion and different levels of insulin resistance. In the patients with long-standing diabetes, late complications develop consisting of alterations and failure of various organs (especially the noninsulin-sensitive ones) including the eyes (retinopathy with vision loss), kidneys (nephropathy leading to renal failure), nerves (peripheral and autonomic neuropathy), heart and blood vessels (precocious and severe cardiovascular, cerebrovascular and peripheral vascular atherosclerosis). Diabetes mellitus includes etiologically and clinically different diseases that have hyperglycemia in common, representing a syndrome rather than a single disease. Until 1997, the classification and diagnosis of diabetes were based on the criteria developed by an international work group, sponsored by the National Diabetes Data Group (NDDG) of the American National Institute of Health, and published in 1979. The World Health Organization (WHO) Expert Committee on Diabetes in 1980 and the WHO Study Group on Diabetes mellitus in 1985 adopted the recommendations of the NDDG with slight alterations. In 1995, an International Expert Committee was established (sponsored by the American Diabetes Association) with the aim to review the scientific literature since 1979 and to decide the adequate changes in the classification and diagnostic criteria of diabetes. The committee work culminated in a document

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published in 1997, divided into four sections (definition and description of diabetes, classification of diabetes, diagnostic criteria and testing for diabetes), which we summarize in this chapter.

Definition and Description of Diabetes mellitus The basis of the metabolic alterations in diabetes is the reduction (to a various degree) of insulin action on insulin-sensitive tissues, due to deficiency of insulin secretion or to insulin resistance or both. The majority of cases of diabetes mellitus falls into two major forms: type 1 and type 2 diabetes.

Type 1 Diabetes Immune-Mediated Type 1 Diabetes Type 1 diabetes (previously also named insulin-dependent diabetes mellitus – IDDM – or juvenile-onset diabetes) is an immune-mediated form of diabetes, which accounts for approximately 5–10% of all diabetics in the Western world. It occurs mainly in healthy nonobese children or young adults but may also affect subjects at any age, and results from an absolute deficiency of insulin secretion (evidenced by low or undetectable levels of plasma Cpeptide), caused by a cellular-mediated autoimmune destruction of pancreatic b-cells. Although the affected subjects are usually nonobese, the presence of obesity is not incompatible with the diagnosis of type 1 diabetes. The course may be rapid in children and young adults, slower in older patients. Adult patients can retain for some time a residual b-cell function while children and adolescents often show early the effects of severe insulin lack, with a diabetes appearing abruptly over days or weeks and rapidly progressing to acute lifethreatening complication (ketoacidotic coma), which may be the first manifestation of the disease, particularly in presence of precipitating factors such as infections or other stress. Genetic Predisposition. Type 1 diabetes is favored by a not yet fully understood genetic predisposition, linked to the HLA system. Pedigree studies of type 1 diabetes families have shown a low prevalence of direct vertical transmission. However, the risk to develop the disease for children who are first-degree relatives of type 1 diabetic patients is between 5 and 10%, the risk being increased when there is haploidentity with the affected sibling and even more when there is HLA identity. It has also been observed that the risk is 5-fold higher for children of a diabetic father compared to children of a diabetic mother (sexual imprinting). Candidate genes for type 1 diabetes have been

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suggested to occur in chromosomes 2, 6, 11 and 15. However, the major gene seems to be located at the HLA locus in the chromosome 6. Indeed, it is now largely accepted that type 1 diabetes is strongly associated to HLA system, especially with the class II molecules which encode for the D allele. Patients who express the DR3 or DR4 alleles or those who are heterozygous (DR3/ DR4) are especially susceptible to type 1 diabetes. Class I alleles (B8, B15) also seem to be associated to type 1 diabetes as they show linkage disequilibrium, i.e. show nonrandom association with the D alleles. Recently, great importance has been attributed to the DQ locus. It has been shown that DQb1*0301 and DQb1*0302 segregate with DR4 and that DQb1*0201 segregates with DR3. Presence of DQb1*0201 and DQb1*0302 or, especially, the heterozygous state DQb1*0201/0302 entails high risk. On the other hand, DQb1*0502 and DQb1*0602 are associated with the DR2 haplotypes and would be protective. Immunologic Mechanisms. Class II molecules are expressed by macrophages, endothelial cells and lymphocytes, and are required for the presentation of an antigen to the regulatory T cells, which become activated, thus triggering the immune response. In other words, the favoring HLA haplotypes indicated above permit the interaction of environmental factors (such as certain viral infections or chemical agents) with specific cell membrane components (the HLA molecules), which results in the presentation of the antigen to the regulatory T lymphocytes, thus triggering an autoimmune mechanism. Several viral infections have been suggested as favoring type 1 diabetes, including Coxsackievirus infections, infectious mononucleosis, mumps, congenital rubella, hepatitis and encephalomyocarditis. Some toxins have also been implicated. Consumption of cow’s milk during the early life may be an important environmental factor associated with type 1 diabetes development and, because the role of bovine albumin in the induction of b-cell autoimmunity have not been confirmed, b-casein has been suggested as the responsible protein. Virus, toxins, or other factors may directly damage b-cells or favor apoptosis (programmed cell death), or may expose cryptic antigen to the immune system, or may act through molecular mimicry (exogenous molecules similar in amino acid sequence to some endogenous molecules), or they may induce expression of class II molecules in the b-cells (which therefore would become antigenpresenting cells, able to trigger the autoimmune response). An alternative hypothesis which does not rely on exogenous antigen postulates a defective removal of autoreactive T cells, which normally are destroyed in the thymus in the early life. In contrast to the most common form of type 1 diabetes, linked to environmental factors (formerly called type IA), in approximately 10% of all cases of type 1 diabetes (more frequently in females, with HLADR3, from 30 to50 years of age), the disease is a primary autoimmune disorder (previously called type IB) and is associated to other endocrine and nonendo-

Etiological Classification, Pathophysiology and Diagnosis

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crine autoimmune diseases (Grave’s disease, Hashimoto’s thyroiditis, Addison’s disease, primary gonadal failure, vitiligo, pernicious anemia, connective tissue disease, celiac disease, myasthenia gravis, etc.). This primary autoimmune pathogenesis seems to be confirmed by a persistence of islet cell autoantibodies (ICAs) forever. In 85–90% of patients, diabetes is early associated with one or more serological genetic markers such as ICAs, IAAs (insulin autoantibodies), GAD65 (autoantibodies to glutamic acid decarboxylase) and IA-2 or IA-2b (autoantibodies to tyrosine phosphatase). These autoantibodies disappear over the course of a few years in the majority of patients, and may be the result rather than the cause of the autoimmune process. Clinical Picture. Manifest type 1 diabetes is characterized by symptoms linked to the marked hyperglycemia, such as polyuria (due to the osmotic effect of glucose), polydipsia (to compensate for the water lost with polyuria), polyphagia (to compensate for the energetic substrate glucose lost in the urine), weight loss and fatigue (due to loss of glucose in urine and to dehydration), and blurred vision (due to lens osmotic disturbances). These patients are insulindependent for their survival and prone to ketosis; impairment of growth, susceptibility to certain infections, hypertension, lipoprotein metabolism alterations, periodontal disease and psychosocial dysfunctions are frequent. Idiopathic Type 1 Diabetes The idiopathic diabetes includes some forms of type 1 diabetes (common in individuals of African and Asian origin) due to unknown etiology, with strong genetic inheritance (not HLA-associated), without markers of autoimmunity. There is severe deficit of insulin secretion and tendency to ketoacidosis, with absolute requirement of insulin therapy. Pathophysiology of Type 1 Diabetes The pathophysiological changes occurring in type 1 diabetes as a consequence of the severe insulin deficiency may be better understood by comparing the normal picture of the main metabolic pathways, as summarized in figure 1, with the abnormal situation present in type 1 diabetes, outlined in figure 2 (see also chapter III on Insulin Resistance). In type 1 diabetes, the deficit of insulin and the prevalence of counterregulatory hormones, primarily glucagon, leads to the activation of glycogenolysis and gluconeogenesis in liver, with ensuing enhanced hepatic glucose output (HGO). In addition, the deficiency in insulin action results in reduced glucose utilization in peripheral insulin sensitive tissues (primarily muscle) as well as in activation of lipolysis in the adipose tissue (insulin normally exerts an antilipolytic effect), with enhanced release of FFA. The latter, although they cannot be directly converted into glucose in man, favor gluconeogenesis in the liver. Combination of enhanced HGO and reduced glucose utiliza-

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Fig. 1. Scheme showing the main metabolic pathways of intermediate metabolism in the three insulin-sensitive tissues (liver, muscle and adipose tissue) participating in the metabolic homeostasis. Note that most metabolic pathways are opposed to each other to form couples composed of a ‘forward pathway’ and a ‘backward pathway’, thus allowing substrate cycling. Examples are: glycogen synthesis and glycogenolysis (steps 1 and 2 in liver, 11 and 12 in muscle), glycolysis and gluconeogenesis (steps 5 and 6), triglyceride synthesis and hydrolysis (lipolysis) (steps 17 and 18 in adipose tissue; 26 and 27 in liver), protein synthesis and proteolysis (steps 13 and 14), etc. Some cycles are ‘inter-tissular’, linking liver and muscle, such as the Cori cycle (expanded to include alanine in addition to lactate and pyruvate), composed of steps 10, 6, 3, 8 and 9, pertaining to carbohydrate metabolism, as well as the cycle linking liver and adipose tissue (steps 19, 22, 26, 28 and 29), pertaining to lipid metabolism. In the normal state, blood glucose is kept at the normal level through a balance between hepatic glucose production (step 3) and glucose utilization by peripheral tissues, mainly the muscle (step 8). VLDL and triglycerides are kept normal through a balance between hepatic production (step 28) and peripheral degradation by LPL, primarily at adipose tissue level (step 29). Ketones are not present because Ac-CoA is entirely oxidized to CO2 (or utilized for the synthesis of FFA – step 24).

tion results in hyperglycemia. In addition, FFA exert anti-insulin effects at the muscle level, through the mechanism of the glucose-FFA cycle (Randle’s cycle), which may cause resistance to the therapeutically administered insulin (see the chapter on Insulin Resistance). It should also be considered that hyperglycemia itself favors glucose utilization (glucose effectiveness), perhaps by acting on noninsulin-dependent glucose transporters (GLUT1 in gut, GLUT2 in liver and GLUT3 in brain), and that in type 1 diabetes this glucose effect may be reduced, i.e. there may be ‘glucose resistance’.


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Fig. 2. Scheme of the main metabolic pathways (similar to that outlined in figure 1) and of their changes in activity rate occurring in states of severe insulin deficiency, such as decompensated type 1 diabetes (thick or thin arrows indicate increased or decreased activity, respectively). Note the prevalence of the catabolic pathways over the anabolic ones: glycogenolysis over glycogen synthesis (steps 2 and 1 in liver, steps 12 and 11 in muscle), gluconeogenesis over glycolysis (steps 6 and 5), triglyceride hydrolysis or lipolysis over triglyceride synthesis (steps 17 and 18), proteolysis over proteosynthesis (steps 14 and 13), etc. Concerning the ‘inter-tissural’ cycles, note the prevalence of hepatic glucose production (step 3) over glucose utilization (step 8), leading to glucose accumulation in blood (unnumbered arrow starting from glucose). The enhanced hepatic glucose production (step 3), effected by the enzyme glucose-6-Pase, utilizes glucose-6-P in part derived from glycogen (step 2) but mainly formed through the gluconeogenic process (step 6) which in turn utilizes the gluconeogenic precursors (pyruvate, lactate and alanine) coming from the muscle (step 10), where they are mainly produced from amino acids (step 15) derived from the enhanced proteolysis (step 14). Note the overall process of conversion of protein to glucose (steps 14, 15, 10, 6 and 3), and consider that some amount of the glucose-6-P formed through the gluconeogenic process may be converted into glycogen (this latter conversion being favored by cortisol). With regard to the FFA-VLDL cycle, linking liver and adipose tissue, note the enhanced FFA release from adipose tissue (step 19), the enhanced afflux of FFA to muscle (step 20), where they are oxidized (step 21) and oppose the oxidation of glucose-derived pyruvate (glucose-FFA cycle, see the text), thus inducing insulin resistance. Note also the hyperafflux of FFA to the liver, where they may be reesterified to triglycerides (step 26) or b-oxidized to Ac-CoA (step 23). The triglycerides so formed may be deposited in the hepatocytes (steatosis) or may be incorporated into VLDL which are secreted into the circulation (step 28), leading to the marked hypertriglyceridemia of the decompensated diabetes. The large amount of Ac-CoA produced by b-oxidation of FFA cannot be entirely oxidized in the Krebs cycle (also for the relative deficiency of oxalacetate, which is diverted towards gluconeogenesis) and is converted into ketone bodies (step 25) leading the ketoacidosis. Thus, in the diabetic state, blood glucose is elevated because hepatic glucose production (step 3) prevails over glucose utilization

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Type 2 Diabetes Type 2 diabetes (previously also named non-insulin-dependent diabetes mellitus – NIDDM – or adult-onset diabetes) occurs in approximately 90–95% of diabetic people in the Western world, resulting from insulin resistance and insufficient compensatory insulin secretion. The disease has an insidious onset and remains asymptomatic and undiagnosed for a long period, even if the moderate hyperglycemia is able to induce severe diabetic late complications. Type 2 diabetes is strongly favored by genetic predisposition. However, although it shows familial aggregation as well as a high concordance (80%) in monozygotic twins, its mode of inheritance is not fully understood. It may well be a polygenic disease. In any case, the risk of offspring and siblings of type 2 diabetic patients to develop the disease is relatively elevated. In addition to the genetic predisposition, favoring environmental factors are involved, such as excessive caloric intake, obesity with increased body fat in the abdominal (visceral) site, sedentary habit, etc. The insulin levels may be normal or even increased (especially in presence of obesity) for a long time, but may decrease in the late stage of the disease. The abnormal carbohydrate metabolism can be early identified measuring fasting glycemia (FPG) or performing an oral glucose tolerance test (OGTT). This type of diabetes is noninsulin-dependent for survival and is nonketosis prone. Hyperglycemia is usually improved or corrected by diet, weight loss and oral hypoglycemic drugs. In type 2 diabetics an acute life-threatening complication, the nonketotic hyperosmolar coma, can develop whereas ketoacidosis seldom occurs spontaneously, although it may arise during stress, infections or other illnesses. Pathophysiology of Type 2 Diabetes This disease is due to a varying combination of insulin resistance and reduction (especially in the late stage of the disease) in insulin secretion (see chapter II on Insulin Secretion and chapter III on Insulin Resistance). The metabolic alterations are less pronounced than those in type 1 diabetes, outlined in figure 2 (see also chapter III on Insulin Resistance). Due to insulin resistance (and to enhanced counterregulatory hormones), there is increased HGO (which contributes primarily to fasting hyperglycemia) and reduced peripheral glucose utilization. There is also elevation of plasma FFA (resulting from activation of lipolysis and/or the often enhanced fat mass due to coexisting by peripheral tissues, mainly the muscle (step 8). VLDL and triglycerides are increased because hepatic production (step 28) prevails over peripheral degradation by LPL, primarily at the adipose tissue level (step 29). Ketones are formed at high rate (step 25) because the large amount of Ac-CoA cannot be entirely oxidized to CO2.


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obesity), which in turn contributes to insulin resistance through the mechanism of the glucose-FFA cycle. As mentioned above (under Type 1 Diabetes), hyperglycemia itself favors glucose utilization (glucose effectiveness). This mechanism may be impaired in type 2 diabetes, i.e. ‘glucose resistance’ may be present. It has been observed that in obesity and type 2 diabetes (as well as in acromegaly and Cushing’s disease), in the postabsorptive period, noninsulinmediated glucose uptake is a major determinant of glucose disposal and is similar in the different pathologies studied. On the other hand, although absolute rates of basal insulin-mediated glucose uptake are reduced in insulinresistant states, they do not achieve statistical value compared with control subjects because of compensatory hyperinsulinemia.

Other Specific Types of Diabetes Various, less common, types of diabetes are known to occur, in which the secretory defect is based upon different mechanisms. Genetic Defects of b-Cell Function The maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of noninsulin-dependent diabetes, characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance. There is no HLA association nor evidence of cell-mediated autoimmunity. It has been estimated that 2–5% of patients with type 2 diabetes may have this form of diabetes mellitus. However, the frequency of MODY is probably underestimated. Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic b-cell dysfunction, rather than insulin resistance, is the primary defect in this disorder. To date, three MODY genes have been identified. MODY-1. Studies in an affected family showed that the gene responsible for MODY-1 is tightly linked to the adenosine deaminase gene on chromosome 20q. Further research has shown that responsible for MODY-1 is a mutation in the gene-encoding hepatocyte nuclear factor (HNF)-4a, a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1a expression. MODY-2. This form is due to mutations in glucokinase (GK – see chapter II for the functional meaning of GK in b-cells) and is associated with defects in insulin secretion, reduction in hepatic glycogen synthesis and in the net accumulation of hepatic glycogen as well as increased hepatic gluconeogenesis following meals, resulting in impaired glucose tolerance or diabetes mellitus

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characterized by mild chronic hyperglycemia. The hyperglycemia due to GK deficiency is often mild (fewer than 50% of subjects have overt diabetes) and is evident during the early years of life. Despite the long duration of hyperglycemia, GK-deficient subjects have a low prevalence of micro- and macrovascular complications of diabetes. Obesity, arterial hypertension and dyslipidemia are also uncommon in this form of diabetes. MODY-3. In several families, this form of MODY was found to be linked with microsatellite markers on chromosome 12q. The disease was estimated to be linked to this chromosome region in approximately 50% of families in a heterogeneity analysis. It is the most common form of MODY. Affected patients exhibit major hyperglycemia with a severe insulin secretory defect, suggesting that the causal gene is implicated in pancreatic b-cell function. MODY-3 was further shown to be due to mutations in the gene-encoding HNF-1a (which is encoded by the gene TCF1). HNF-1a is a transcription factor that helps in the tissuespecific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene. Familial Hyperinsulinemia. The high-affinity sulfonylurea receptor, a novel member of the ATP-binding cassette superfamily, is one component of the ATP-sensitive K+ channel. The protein is critical for regulation of insulin secretion from pancreatic b-cells, and mutations in the receptor (or in the KATP channels) have been linked to familial hyperinsulinemia, a disorder characterized by unregulated insulin release despite severe hypoglycemia. Other forms may be due to mutation in the GK gene, leading to a hyperresponsive enzyme. Other. In addition, a diabetes type associated with deafness may be linked to point mutations in mitochondrial DNA, and still other forms with less clearly defined defects are known to occur. In about 50% of cases of MODY, the genetic background is uncertain. It should be stressed that the role of the above genes (responsible for b-cell dysfunction) in the susceptibility to the more common late-onset form of type 2 diabetes remains uncertain. Genetic studies seem to exclude any function as major susceptibility genes, although they might play a minor role in a polygenic context or a major role in particular populations. Rare Genetic Defects of Insulin Action These are a heterogeneous group of rare conditions which includes: (a) syndromes associated with acanthosis nigricans, which is a brown to almost black hyperpigmentation of the skin, most often located in the neck, axilla, groin or other areas, less rare in Blacks or in subjects of Hispanic origin. The affected patients show high insulin levels. Some cases are due to mutation in the insulin receptor resulting in diminished tyrosine-kinase activity (type A syndrome). Others are due to antibodies to the insulin receptors which prevent insulin


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binding (type B syndrome). Interestingly, some cases have been reported in which antibodies to the receptor exert an agonistic effect, producing hypoglycemia. (b) Generalized or partial (face and trunk) lipodystrophies, which may be congenital or acquired, are characterized by fat depletion, and result from decrease in the number or affinity of the receptor for insulin or from postreceptor defects. Patients show high insulin levels, hyperglycemia (without ketoacidosis for the scarcity of fat), hypertriglyceridemia (with eruptive xanthomas), enlargement of liver, spleen, heart, and hypertrophy of external genitalia. Lymphadenopathy and hirsutism may also occur as well as varicose veins, mental retardation and kidney involvement. In the congenital form, there is also muscle hypertrophy. (c) Leprechaunism syndrome, due to mutation in insulin receptors (which may be altered in both the a and b subunits and whose expression in the cell membrane is markedly reduced), and consisting of insulin resistance associated with severe growth retardation, elfin appearance of the face, hirsutism, absence of subcutaneous fat and thickened skin. (d) Other rare conditions such as the Werner’s syndrome, the Alstro¨m syndrome, the Rabson-Mendenhall syndrome (which may be associated with acanthosis nigricans), the pineal hypertrophy syndrome, and the ataxia telangiectasia syndrome. Diseases of the Exocrine Pancreas Any disease process affecting the pancreas may involve the islets and produce diabetes (table 1). May we recall the fibrocalculous pancreatopathy, that occurs in India, Africa and West Indies with a frequency similar to that of type 2 diabetes. This form involves young people with malnutrition and pancreatic calculi, and is characterized by severe hyperglycemia and insulin dependence but not by proneness to ketosis, as a moderate insulin secretion is retained.

Gestational Diabetes mellitus (GDM) GDM is defined as any degree of glucose intolerance with onset during pregnancy. It should be distinguished by the mild deterioration of glucose tolerance which may occur also during normal pregnancy (particularly in the 3rd trimester). The prevalence of GDM can range from 2 to 3% of pregnancies, depending on the different racial/ethnic subpopulations studied. A known diabetic woman who becomes pregnant is not classified as GDM. The GDM is a serious problem and its recognition is important to prevent the associated perinatal morbidity or mortality and the maternal complications (cesarean delivery and chronic hypertension). GDM usually returns to a normal glucose tolerance state after delivery, but 60% of affected women can develop diabetes within 15

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Table 1. Etiologic classification of diabetes mellitus 1. Type 1 diabetes A. Immune-mediated B. Idiopathic 2. Type 2 diabetes 3. Other specific types A. Genetic defects of b-cell function (MODY-1, MODY-2, MODY-3, mitochondrial DNA, and others) B. Genetic defects in insulin action (type A insulin resistance, leprechaunism, Rabson-Mendenhall syndrome, lipoatrophic diabetes, and others) C. Diseases of the exocrine pancreas (pancreatitis, pancreatectomy, trauma, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, and others) D. Endocrinopathies (acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma, and others) E. Drug- or chemical-induced diabetes (vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, b-adrenergic agonists, thiazides, dilantin, a-interferon, and others) F. Infections (congenital rubella, cytomegalovirus, and others) G. Uncommon forms of immune-mediated diabetes (‘stiff-man’ syndrome, anti-insulin receptor antibodies, and others) H. Other genetic syndromes sometimes associated with diabetes (Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome, Wolfram’s syndrome, Friedreich’s ataxia, Huntington’s chorea, Lawrence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome, and others) 4. Gestational diabetes mellitus (GDM)

years after parturition. About 6 weeks after the delivery, the GDM woman should be reclassified as diabetic or glucose intolerant or normoglycemic.

Comment In the previous NDDG/WHO classification, diabetes mellitus was divided into 5 distinct types: IDDM, NIDDM, GDM (gestational diabetes), malnutrition-related diabetes and other types, and the category of IGT (impaired glucose tolerance) was included, in which plasma glycemia during an OGTT was above normal but not diabetic. The 1997 Expert Committee changed the NDDG/ WHO classification, including only 4 clinical classes: (1) type 1 diabetes, (2) type 2 diabetes, (3) other specific types and (4) GDM (table 1). The most important changes introduced include the following: (a) Elimination of the terms ‘insulindependent’ or ‘noninsulin-dependent’ diabetes mellitus and ‘IDDM’ or


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‘NIDDM’ (which are confusing as they classified the patient according to treatment rather than etiology). (b) Preservation of the terms ‘type 1’ or ‘type 2’ diabetes (with Arabic numerals) and elimination of the confusing terms ‘type I’ or ‘type II’ diabetes (with Roman numerals); patients with no evidence of autoimmunity are classified as being affected by type 1 idiopathic diabetes. (c) Type 1 diabetes does not include those forms of b-cell destruction due to nonautoimmune-specific causes. (d) Type 2 diabetes includes the most common form characterized by insulin resistance and insulin secretory defect. (e) The class previously named malnutrition-related diabetes mellitus has been eliminated. (f ) The IGT stage has been retained, and the stage of IFG was added. (g) GDM, as defined by WHO and NDDG, was retained.

Diagnostic Criteria for Diabetes mellitus A precocious diagnosis of diabetes is important to prevent or attenuate late diabetic complication, and depends upon the adequate use and interpretation of laboratory tests (especially in absence of specific symptoms). Many different diagnostic schemes have been in use. Recently, on the basis of the available data, the diagnostic criteria previously recommended by NDDG or WHO were modified. According to the revised criteria by the Expert Committee [1997], the ‘normal values’ and the ‘diagnostic values’ for diabetes (which do not coincide with the goals of therapy) are as follows (values given in the text refer to venous plasma glucose which is the preferred measurement; equivalents for whole blood and capillary glucose estimations, according to the IDF guidelines [1999] to type 2 diabetes, are indicated in footnotes). Normal Values. The upper limit of normal venous plasma values has been set at 110 mg/dl (6.1 mmol/l) for FPG and at 140 mg/dl (7.8 mmol/l) for the 2-hour value after glucose load (OGTT). Diagnostic Values. (a) FPG q126 mg/dl (or 7.0 mmol/l)1 after a fasting of at least 8 h, confirmed on a subsequent day, to rule out a labeling or technical error; (b) 2-hour value during OGTT q200 mg/dl (or q11.1 mmol/l)2, confirmed in a repeated test to make the final diagnosis; (c) symptoms of diabetes and a casual value q200 mg/dl (or 11.1 mmol/l) at any time of day. For epidemiological studies, diabetes prevalence and incidence should be estimated by a FPG q126 mg/dl. The value of FPG was changed from the Same value for capillary plasma glucose; q110 mg/dl (?6.0 mmol/l) for venous or capillary whole blood glucose. 2 q220 mg/dl (q12.2 mmol/l) for capillary plasma glucose; q180 mg/dl (q10.0 mmol/l) for venous whole blood glucose; q200 mg/dl (q11.0 mmol/l) for capillary whole blood glucose. 1

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previous value (q140 mg/dl) to current value (q126 mg/dl), because (1) the cutpoint of FPG q140 mg/dl defines a greater degree of hyperglycemia than did the cutpoint of the 2-hour value q200 mg/dl, and (2) this degree of hyperglycemia usually reflects a serious abnormality associated with serious chronic diabetic complications. The 2-hour value q200 mg/dl has been retained for the diagnosis of diabetes because it was well accepted, and enormous clinical and epidemiological data are based on this cutpoint value. The criteria for diagnosis of diabetes in an asymptomatic child should be stricter than those for the adults to avoid overdiagnosis of diabetes, and it should be considered that normal children commonly present OGTT values lower than adults. The diagnostic values for GDM as proposed by O’Sullivan and Mahan [1993], revised by NDDG and adopted by ADA and the American College of Obstetricians and Gynecologists (ACOG), are set lower than those for nonpregnant adults. A screening test is indicated between 24 and 28 weeks of gestation in asymptomatic female patients at risk, and a value 1 h after a 50 g of glucose load q140 mg/dl (or 7.8 mmol/l) can identify the individuals at risk for GDM in whom a full diagnostic 3-hour OGTT with 100 g of glucose should be performed. GDM occurs with an FPG q105 mg/dl (or 5.8 mmol/l) and a 2-hour value during OGTT q165 mg/dl (or 9.2 mmol/l). An intermediate metabolic state was introduced, which is characterized by glucose levels above those considered as normal but below those accepted for the diagnosis of diabetes mellitus. Referring to the fasting state, this condition was named impaired fasting glycemia or IFG (FPG q110 but p126 mg/dl or q6.0 but p7.0 mmol/l )3. Referring to the postload state, it was named impaired glucose tolerance or IGT (2-hour postload value in OGTT q140 mg/dl but p200 mg/dl or q7.8 but p11.1 mmol/l)4, without spontaneous hyperglycemia). IFG or IGT are not clinical entities but rather risk factors for future type 2 diabetes and cardiovascular disease, being associated with the metabolic syndrome or insulin resistance syndrome, characterized by abdominal or visceral obesity, hypertension, dyslipidemia (hypertriglyceridemia and low HDL value) and hyperuricemia. Conversion of IGT to type 2 diabetes takes years or decades and occurs in about 10–50% of IGT patients. Thus, IGT may not progress to overt diabetes and may revert to normoglycemia, especially in obese patients after dietary treatment and weight reduction. Same value for capillary plasma glucose; q100 but p110 mg/dl (q5.5 but p6.0 mmol/l) for venous or capillary whole blood glucose. 4 q160 but p220 mg/dl (q8.9 but p12.2 mmol/l) for capillary plasma glucose; q120 but p180 mg/dl (q6.7 but p10.0 mmol/l) for venous whole blood glucose; q140 but p200 mg/dl (q7.8 but p11.1 mmol/l) for capillary whole blood glucose. 3


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Table 2. Subjects in whom OGTT should be performed First-degree relative of type 2 diabetic patients (especially if monozygotic twin of a diabetic patient or offspring of two diabetic parents) Subjects with abnormal or borderline glycemic values (FPG q110 mg/dl but p126 mg/dl) during screening test for diabetes Pregnant women with suspected GDM Obese subjects (especially when a family history of diabetes is present) Individuals with a family history of MODY Members of racial or ethnic groups with high prevalence of diabetes (American Indians or Pacific Islanders, African-Americans, Hispanics, etc.) Patients with unexplained neuropathy or coronary disease or peripheral vascular disease or retinopathy or nephropathy (especially under 50 years of age) Patients with hyperglycemia or glycosuria found during acute illness, stress situations, surgical procedures, steroid administration, etc.

Oral Glucose Tolerance Test The OGTT is not recommended for routine clinical use (being a nonspecific test) and should be standardized for both procedure and interpretation, while the use of FPG is encouraged as a simple, convenient, accurate, acceptable to patients and low cost test for diagnosing diabetes. FPG and 2-hour OGTT values are equivalent for the diagnosis of diabetes (even if not perfectly correlated with each other), and actually the FPG alone is preferable for its better reproducibility (6% variation) whereas OGTT, repeated in adults during a 2to 6-week interval, presents an intraindividual coefficient of variation of 17% for the 2-hour value. OGTT remains, however, the most sensitive and practical test for the early recognition of asymptomatic diabetes without high FPG value, and it is an invaluable tool in research studies. If the OGTT is used, the test procedures recommended are that of WHO. The indications of OGTT are outlined in table 2. The following variables may affect the OGTT results: Technical Variables. Venous versus capillary blood: In adults venous blood from an antecubital vein is usually employed, obtained with minimum stasis. In the capillary blood, glucose approximates that of arterial blood, and is higher than in venous blood by 2–3 mg/dl in the fasting state and by 20–70 mg/dl during OGTT. Plasma or serum versus whole blood : Plasma or serum is generally employed, providing more stable values. In these materials glucose concentration is 15% higher than in whole blood. The blood sample should be immediately refrigerated to prevent glycolysis of glucose by blood cells (fluoride cannot be

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used when glucose is measured by enzymatic methods), which would result in artifactual low glucose values. Methods for determining glycemia: The most commonly used methods are the glucose-specific enzymatic methods. The use of strips, read with glucose reflectance meter, is not recommended for diagnostic purpose (for its great variability) whereas it is useful for blood glucose self-monitoring during diabetes treatment. Glucose dose and concentration: In the past, glucose doses for OGTT varied from 50 to 100 g. To avoid nausea and to achieve a better standardization the use of an oral flavored solution of 75 g glucose dissolved in 300 ml of water for adults is now recommended. In children, 1.75 g/kg ideal body weight (up to a maximum of 75 g) should be used. During pregnancy, the OGTT is performed utilizing 100 g of glucose. The glucose solution should be consumed over 5 min. Timing of samples for OGTT: Blood samples are obtained in the fasting state and after 30, 60, 90, 120 min according to NDDG for testing individual patients. According to WHO, only 0- and 120-min samples should be used, which makes the test more suitable for testing large population groups or for epidemiological studies. During pregnancy, a 180-min sample should also be obtained. For the diagnosis of reactive hypoglycemia, the OGTT should be prolonged to 5 h. Time of day: There is a diurnal variation in glucose tolerance (which deteriorates in the afternoon); thus, a standard OGTT should be obtained in the morning, after a fasting of 10–14 h. Host Variables. Preceding diet: A diet containing 250 g of carbohydrate is recommended for at least 3 days before the test. In subjects on reduced diets, a diet containing at least 200 g of carbohydrates should be taken for 1 week before the OGTT. Coffee or smoking are avoided before and during the test. Physical activity: OGTT should not be performed in patients at bed rest, hospitalized or immobilized (conditions which may reduce glucose tolerance). A moderate walking during the test is permitted, but physical exercise should be avoided. Acute or chronic illness: OGTT should not be performed in patients affected by acute infections, acute cardiovascular and cerebrovascular diseases, active endocrinopathies, hepatic or renal diseases, or in subjects under stress or treated with some drugs such as glucocorticoids, estrogens, salicylates, thiazides, nicotinic acid, dilantin, etc. Age: Glucose tolerance deteriorates with advancing age (because of decreased or delayed insulin secretion, reduced insulin sensitivity, increase of insulin antagonists, physical inactivity, obesity and other associated diseases, etc.). In the elderly, the 2-hour glycemic level would increase by 10 mg/dl for each decade over 50 years.


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Other Tests Oral cortisone-glucose tolerance test is not a diagnostic test but is used for research purpose. The intravenous glucose tolerance test (or IVGTT) should be used as a diagnostic test only for patients with gastrointestinal disorders interfering with absorption of glucose. It is less physiological than OGTT, bypassing the effects of several relevant gastrointestinal hormones active with oral glucose load. Glucose (25 g as 50% solution) is infused over 3 min and samples are obtained every 10 min for 1 h. Through a formula, the K coefficient can be calculated, whose normal value is between 1.2 and 2.2; values =1 indicate diabetes, values between 1 and 1.2 are regarded as borderline. Determination of insulin during OGTT is not recommended for routine diagnostic purpose (because of extreme variability in fasting state and after glucose load), although it can be of prognostic value. Values are elevated in subjects with insulin resistance. HbA1c measurement is not currently used for diagnosis of diabetes whereas it is useful in monitoring the metabolic control. Normal values of HbA1c range from 4.0–4.5 to 6.0–6.4% of total hemoglobin, although differences exist among values depending on laboratories and/or methods. According to the IDF guidelines [1999] to type 2 diabetes, HbA1c can be useful for the diagnosis provided that confirmatory venous plasma glucose estimations are obtained, the assay is DCCT standardized, an HPLC chromatogram is reviewed for presence of abnormal hemoglobins, and erythrocyte turnover is not abnormal. Approximately: HbA1c ?7.5% B fasting plasma glucose q7.0 mmol/l (?125 mg/dl), and HbA1c ?6.5% B fasting plasma glucose ?6.0 mmol/l (q110 mg/dl). Glycosuria is not useful for the diagnosis, being present only when glycemia is higher than the renal threshold for glucose. It may be useful for a coarse monitoring of diabetic control. The aged people may have a higher than normal renal threshold for glucose (having glycosuria only at elevated glucose levels), whereas pregnant women often have a lowered glucose threshold (showing glycosuria even with normal glycemia).

Testing for Diabetes mellitus Type 1 Diabetes. In type 1 diabetes, routine testing for immune markers (outside of clinical trials or research studies) is not recommend for many reasons, including: (a) cut-off values have not been completely established for clinical settings; (b) there is no consensus on proven measures that can prevent

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or delay the clinical onset of disease (when a positive autoantibody test is obtained); (c) the cost-effectiveness of the screening is questionable. The autoantibody tests, however, may be useful to detect which newly diagnosed patients have immune-mediated type 1 diabetes. Type 2 Diabetes. Type 2 diabetes is commonly undiagnosed in about 50% of affected subjects. On the other hand, retinopathy may develop early, even 7 years before the diagnosis of overt diabetes. Thus, the unapparent hyperglycemia can cause microvascular complications and favor macrovascular disease. Therefore, the undiagnosed diabetes is a serious problem. Early detection and treatment are indispensable to reduce the late complications of type 2 diabetes. Thus, testing for diabetes (especially with FPG) should be recommended in the clinical setting and in high-risk subjects. In asymptomatic and undiagnosed individuals, testing for type 2 diabetes by FPG should be performed in: (a) all individuals at age 45 and above, repeated at 3-year intervals if results are normal; (b) individuals at younger age if at risk (obese subjects, first-degree relatives of diabetic patients, components of high-risk ethnic populations, women with GDM, mothers of obese baby ?9 lb or 4 kg, etc.); (c) hypertensive subjects with low HDL cholesterol (p35 mg/dl) or high triglycerides (q250 mg/dl); (d) individuals with IGT or IFG on previous testing.

Suggested Reading Expert Committee on the Diagnosis and Classification of Diabetes mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes mellitus. Diabetes Care 1997;20:1183–1197. Fajans SS: Classification and diagnosis of diabetes; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and Practice, ed 4. New York, Elsevier, 1990, pp 346–356. International Diabetes Federation (IDF), 1998–1999 European Diabetes Police Group: A Desktop Guide to Type 2 (Non-Insulin-Dependent) Diabetes mellitus. Brussels, IDF, 1999. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28:1039–1057. O’Sullivan JB: Diabetes mellitus after GDM. Diabetes 1993;40(suppl):131–135. Velho G, Blanche H, Vaxillaire M, et al: Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia 1997;40:217–224. World Health Organization: Diabetes mellitus: Report of a WHO Study Group. Tech Rep Ser No 727. Geneva, WHO, 1985. Yamagata K, Furuta H, Oda N, et al: Mutations in the hepatocyte nuclear factor-4a gene in maturity-onset diabetes of the young (MODY-1). Nature 1996;384:458–460. Yamagata K, Oda N, Kaisaki PJ, et al: Mutations in the hepatocyte nuclear factor-1a gene in maturity-onset diabetes of the young (MODY-3). Nature 1996;384:455–458.

F. Belfiore, Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, I–95123 Catania (Italy) Tel. +39 095 330981, Fax +39 095 310899, E-Mail [email protected]


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Chapter II

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Insulin Secretion and Its Pharmacological Stimulation F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Insulin Secretion Introduction Pancreatic b-cells synthesize a large polypeptide chain, the proinsulin, which is then cleaved into the so-called connecting peptide (C-peptide) and the insulin molecule, composed of two peptide chains containing 51 amino acid residues. Both insulin and C-peptide are packaged in the secretory granules. During the secretory process, the granule content is discharged outside the b-cell through a process of exocytosis, leading to the release of insulin and C-peptide in equimolar amounts, together with small quantities of uncleaved proinsulin. In contrast to insulin, C-peptide is not taken up by the liver (and the other insulin-sensitive tissues), and therefore its plasma level is a good index of insulin secretion.

Regulation of Insulin Secretion by Substrates Glucose Glucose is the main physiological regulator of insulin secretion. In vitro, prolonged stimulation with glucose (or sulfonylureas) induces a biphasic insulin secretory response by pancreatic islets characterized by an initial rapid first phase lasting about 5 min, during which about 2–3% of the insulin content of pancreas is released, followed by a slower second phase in insulin secretion, which results in the liberation of up to 20% of total pancreatic content during

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a period of 60 min of glucose perfusion. A similar biphasic pattern of secretory response to glucose has also been reported in vivo in man with the hyperglycemic clamp technique. The two secretory phases, however, are not apparent after a carbohydrate-rich meal because the elevation in blood glucose is not rapid enough. Nevertheless, an efficient initial insulin secretory response (dependent upon the b-cell sensitivity to glucose elevation) is required for an optimal glucose control and for avoiding an excessive secretion during the second phase, which entails the risk of late hypoglycemia (reactive hypoglycemia). Glucose, besides its direct stimulation of insulin release, also potentiates the secretory response to nonglucose stimuli, which may play a role during the absorption of mixed meals. In addition, glucose exerts a priming effect of bcells, as a previous exposure of b-cells to glucose causes an enhanced secretory response to a subsequent stimulation with glucose (or even with nonglucose stimuli), as if the b-cell has memory of the previous glucose exposure. Chronic exposure to glucose, however, induces desensitization of b-cells, which does not seem to be due to a reduced content or synthesis of insulin. This is relevant to the condition of persistent hyperglycemia occurring in the diabetic state. With regard to insulin secretion, three concepts should be distinguished: the set point for blood glucose, the b-cell threshold for glucose, and the bcell glucose sensor. The set point entails the concept that there is a control system that ‘sets’ the level of glucose at a given value, which in man is fixed to about 5 mmol/l glucose. The set point is the result of the activity of b-cells as well as of a-cells and d-cells. The glucose threshold for both b-cells and a-cells is between 5 and 6 mmol/l: when glucose rises above this level, the insulin-secreting b-cells are turned on whereas the glucagon-secreting a-cells are turned off, and vice versa. Glucose threshold increases during starvation, when b-cells are blind to even relatively high glucose levels, and returns to normal upon refeeding. In order to be able to respond to increase in glucose concentration above the threshold value, b-cells must be equipped with a glucose sensor, which has been identified in the glucose-phosphorylating enzyme glucokinase (GK). This enzyme, long known to be present in the liver, has been shown to occur also in the b-cells (the liver and the b-cell enzymes differ at genetic level). GK differs from the ubiquitous enzyme hexokinase (which catalyzes the same reaction as GK, i.e. glucose phosphorylation), in that hexokinase has a high affinity (or a low Km) for glucose and therefore works at the maximum activity at very low, underphysiological glucose concentration, whereas GK has a low affinity (or a high Km) for glucose, which entails that its activity increases with increasing glucose concentration. Its presence in the liver allows this organ to take up glucose when glycemia in the portal vein increases (such as during the absorption

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period), whereas its presence in the b-cells allows these cells to perceive the increase in blood glucose and to respond with adequate insulin release. In order to stimulate insulin release, glucose must first be transported into the b-cell by the glucose transporter (GLUT-2 isoform), and then phosphorylated by GK to produce glucose-6-P. However, glucose transport in bcells possesses a very high capacity and therefore plays a little regulatory role. Glucose-6-P produced by GK is further metabolized along several pathways, through which ATP is generated. Shortly, glucose metabolism results in elevation of the ATP/MgADP ratio which inhibits ATP-sensitive K+-channels, thus lowering membrane potential and triggering Ca influx through the voltagedependent Ca2+-channels, which stimulates insulin secretion (fig. 1). Genetic alterations of key components of the insulin secretory machinery have been described. Mutations of KATP-channels or the associated sulfonylurea receptors may cause hyperinsulinemia and hypoglycemia due to persistent depolarization of the b-cell membrane. Mutations in the GK gene (most of which affect the glucose-binding site) may result in hyporesponsiveness to glucose, as it occurs in MODY-2 patients, or in hyperresponsiveness, as noted in the familial GKlinked hyperinsulinemia and hypoglycemia (FHI-GK). Oscillations in the glycolytic pathway and b-cell metabolism contribute to the oscillatory nature of b-cell ionic events and insulin secretion. Insulin release is a complex oscillatory process with rapid pulses (10 min) superimposed on slower circhoral oscillations (50–100 min). Moreover, ultradian oscillations of insulin secretion appear to be an integral part of the feedback loop between glucose and insulin secretion, and are abnormal in states of glucose intolerance. Other Substrates Fats also influence insulin release. In man, FFA were shown to enhance the secretory response to glucose, which is in agreement with the demonstration that pancreatic islets are equipped with the enzymes necessary for the utilization of FFA and ketone bodies. Amino acids such as isoleucine, arginine and lysine, potentiate the secretory effect of glucose, whereas leucine may be regarded as a primary stimulus, active even in the absence of glucose. Amino acids do not seem to act by serving as fuels for b-cells. They might act by contributing to activate Ca channels. An important signal for insulin secretion may reside in the inextricable interplay between glucose and lipid metabolism. Specifically, glucose metabolism leads to the generation of malonyl-CoA, which inhibits carnitine palmitoyltransferase-1, with the attendant accumulation of long-chain acyl-CoA esters in the cytosol (see also chapter III and figure 3). Malonyl-CoA and long chain acyl-CoA esters may act as metabolic coupling factors in b-cell signalling.

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Fig. 1. Regulation of insulin secretion by the b-cell. (Continuous lines ending with black arrows indicate transformation or translocation of substrates or ions; dotted lines ending with white arrows indicate stimulation; dotted lines ending with filled circles indicate inhibition). Glucose metabolism (regulated by GK which acts as ‘glucose sensor’) results in production of ATP which inhibits ATP-sensitive K+-channels, thus lowering membrane potential and triggering Ca influx through the voltage-dependent Ca2+-channels. High cytosolic Ca stimulates (through complex processes, not shown) insulin secretion. Sulfonylureas stimulate insulin secretion by acting through their receptor, closely associated with the ATP-sensitive K+channels. Parasympathetic stimulation (acetylcholine) promotes insulin secretion through activation of PLC, which produces IP3 and DAG (from PIP2); IP3 causes release of Ca from the intracellular stores (endoplasmic reticulum) into cytosol; DAG activates PKC which in turn stimulates secretion. Glucagon enhances secretion by activating AC (with the participation of Gs), thus producing cAMP and activation of PKA. Epinephrine (through the a2receptor) inhibits secretion by inhibiting AC (with the participation of Gi), thus exerting effects opposed to those of glucagon. Abbreviations (alphabetic order): a2>a2-Adrenergic receptor; AC>adenylate cyclase; cAMP>cyclic AMP; DAG>1,2-diacylglycerol; GK>glucokinase; Glg>glucagon receptor; GLP1>glucagon-like peptide 1; Gq>a further type of G protein; Gs and Gi>stimulatory and inhibitory G proteins; IP3>inositol-1,4,5-trisphosphate; M3>a type of muscarinic receptor; PIP2>phosphatidylinositol-4,5-P; PKA>protein kinase A; PKC>protein kinase C; PLC>phospholipase C.


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Regulation of Insulin Secretion by Hormones and Neurotransmitters Acetylcholine, produced by parasympathetic activity, stimulates insulin secretion through muscarinic receptors (which can be blocked by atropine), probably by enhancing DAG (diacylglycerol) and IP3 (inositol-3-P) formation (fig. 1). Parasympathetic stimulation may occur during the early (cephalic and intestinal) phase of insulin secretion following a meal as well as during hypoglycemic episodes. In the latter instance, however, hypoglycemia limits the parasympathetic effect on insulin secretion, because this effect is glucosedependent. The parasympathetic innervation of the pancreas may also trigger the release of vasoactive intestinal polypeptide (VIP), which stimulates the secretion of insulin (and glucagon) while increasing the blood flow to the pancreas and the external pancreatic secretion. Norepinephrine (released upon sympathetic stimulation) and epinephrine (produced by adrenal medulla) exert both an inhibitory effect, through the aadrenergic receptors (fig. 1), and a stimulatory effect, through the b-adrenergic receptors, the overall effect being an inhibition of glucose-stimulated insulin release and a little effect in the basal state. Sympathetic nerve activity may also release other neurotransmitters, such as galanin, which would inhibit both basal and stimulated insulin secretion. Gastrointestinal hormones (or gut hormones) contribute to the overall insulin secretion, as shown by the higher insulin secretion after glucose given per os compared to intravenous glucose. For this action, they are also called incretins. They include: the gastric inhibitory polypeptide (GIP), secreted by the endocrine cells of duodenum and jejunum; cholecystokinin (CCK), both the long (CCK-33) and the short (CCK-8) peptide chain, released by duodenum and proximal part of jejunum after ingestion of fats and proteins; the glucagon-like peptide-1 (7–36) amide, or GLP-1 (7–36), formed from GLP-1 (the precursor proglucagon, produced by the L-cells in the distal part of small intestine, is processed by tissue-specific proteolysis to produce glucagon in pancreatic a-cells and GLP-1 in the intestine), is released after carbohydraterich meals (fig. 1); the neuropeptide Y (NPY), a neurotransmitter present in both the central nervous system and the enteric nervous system which produces stimulation of food intake (and of resting metabolic rate), while probably acting as an incretin to enhance insulin release. The counterregulatory hormones (or stress hormones) also affect insulin secretion. Glucagon is a potent stimulus for the islet b-cell (fig. 1), and intravenous bolus injection of 1 mg glucagon has been widely used to assess endogenous insulin secretion for clinical or research purposes. Glucagon stimulates insulin release mainly through glucagon receptors but not GLP-1 receptors on islet b-cells. On the other hand, insulin may affect glucagon secretion

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because capillaries go from the central part of the islets, where insulin is mainly produced, to the periphery of the islets where glucagon-producing a-cells are mainly located. The other stress hormones affect insulin secretion through a generally inhibitory action. The effect of epinephrine has been mentioned above. Cortisol and growth hormone (GH) are thought to play a role during prolonged stress periods. Leptin may potentiate glucose-induced insulin secretion by a mechanism involving cAMP or phospholipase C/protein kinase C activation. It also inhibits NPY release. In contrast to early studies, recent data indicate that amylin is a third active pancreatic islet hormone that works with insulin and glucagon to maintain glucose homeostasis. It would regulate glucose inflow to the circulation by influencing the rate of gastric emptying and would also inhibit hepatic glucose production in the postprandial period.

Assessment of Insulin Secretion Fasting Insulin Level. The fasting insulin level (normally between 5 and 15 lU/ml) may reflect the insulin secretory capacity. It may be very low (=5 lU/ml) in subjects with high insulin sensitivity (lean and/or trained subjects) and elevated (?15 lU/ml) in insulin-resistant subjects. It should be pointed out that an apparent normal insulin level in insulin-resistant diabetic subjects indicates decreased secretory capacity, since an equal level of glucose in a ‘normal’ subject would be associated with a higher insulin level which would promptly normalize glucose. It should be pointed out that the insulin values usually referred to are those obtained with the commonly used radioimmunoassay method, which yields the total insulin levels, whereas more sophisticated methods are available that allow to distinguish the true insulin from the proinsulin. True insulin may be lower than total insulin by 15–20%. Acute Insulin Response to Glucose (AIRG). AIRG following glucose given as intravenous bolus consists of a rapid increase in insulin level which returns towards normal within 10 min. The magnitude of AIRG is not affected by the preexisting glucose level, which makes this test feasible even in diabetic patients. AIRG is often absent in patients with type 2 diabetes whereas it is enhanced in insulin-resistant obese subjects. Acute Insulin Response to Non-Glucose Stimuli (AIRNG). AIRNG includes response to amino acids, neurotransmitters and hormones. AIRNG obtained with arginine increases with the increase in the preexisting glucose level. By plotting the AIRNG values against those of glycemia, a ‘curve’ is obtained which reflects the correlation between these two variables. From the analysis


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of this curve, it is possible to deduce the insulin secretory capacity of the pancreas, the maximal acute insulin response to nonglucose stimuli or AIRMAX , and the b-cell sensitivity to the potentiation effect of glucose. The AIRMAX (which indicates the maximal secretory response) is reduced in type 2 diabetes and may increase in insulin-resistant hyperinsulinemic subjects. The b-cell sensitivity to the potentiation effect of glucose is little changed in type 2 patients, suggesting preserved b-cell sensitivity in these patients.

Insulin Secretion in Type 2 Diabetes Both impaired insulin action (insulin resistance) and reduced insulin secretion (insulin deficiency) may contribute to the development of type 2 diabetes. It is now accepted that in type 2 diabetes the situation may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance. It is noteworthy that recent data would suggest that the hyperinsulinemia of insulin resistance may result from an increase in insulin secretion secondary to increased b-cell sensitivity to glucose, as well as a decrease in insulin clearance. In type 2 diabetes the b-cell mass is reduced by about 50%, which is known from experimental pancreatectomy to be not enough to cause fasting hyperglycemia. Therefore, in most type 2 patients a functional defect in b-cells may occur, leading to insulin secretory defect. This is confirmed by the almost absent acute insulin response to glucose (AIRG), diminished maximal acute insulin response to nonglucose stimuli (AIRMAX), decreased insulin secretory capacity, with normal b-cell sensitivity to the potentiation effect of glucose. Type 2 diabetes subjects have their own ‘set’ of fasting plasma glucose which is more or less increased compared to normal. This is due to reduced insulin secretion into portal vein which is unable to completely suppress hepatic glucose production, resulting in hyperglycemia. The latter, on the other hand, is somewhat ‘useful’ in that it forces the hypofunctioning b-cell to secrete more insulin. The apparently ‘normal’ fasting insulin in type 2 diabetes in the presence of fasting hyperglycemia should indeed be considered as reduced. In fact, restoring normal glucose levels in mild diabetes by an insulin infusion reduces the endogenous insulin concentration to subnormal values. The same reasoning apply for the insulin response to oral glucose, i.e. to the insulin curve during OGTT. The insulin response (area under the curve or AUC) may be normal or most often elevated in absolute terms, but should be regarded as reduced considering the elevated glycemic values. Moreover, the insulin response during OGTT may show a sluggish initial response and elevated values in the later stages, the latter perhaps resulting

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from the elevated glucose values. In type 2 diabetes there is also an increased release of proinsulin, which may account for 30% of total insulin compared to 15% in normal subjects. Concerning the insulin response to intravenous glucose, as occurs during IVGTT, in type 2 diabetes there is a marked reduction in the first phase of insulin release. The second phase may also be reduced in diabetic patients with fasting glycemia ?250 mg/dl, but may be normal or increased in ‘compensated’ patients with fasting glycemia =200 mg/dl (even if also in these instances the insulin response should be regarded as diminished, considering the existing hyperglycemia). Reduced insulin response is also recorded during prolonged glucose infusion. The insulin response to nonglucose stimuli, such as intravenous arginine, secretin, isoproterenol, isoprenaline, tolbutamide, or even a mixed meal, may be normal in type 2 diabetic patients with fasting glycemia =200 mg/dl. This is due to the potentiation of the insulin response to nonglucose stimuli exerted by the hyperglycemia present in the diabetic patients. Finally, in type 2 diabetic patients the oscillations in insulin secretion, which are significant for glycemic control, cannot be detected, even in the patients with mild form of the disease.

Causes of the Insulin Secretory Defect A major role is certainly played by genetic predisposition, but several biochemical mechanisms and neurohormonal factors may contribute. Little is known about susceptibility genes to the common polygenic forms of type 2 diabetes. Studies of genes involved in insulin secretion or insulin action have been successful to a certain extent by showing the implication of the insulinreceptor substrate-1 (IRS-1) gene, the ras associated with diabetes (rad) gene, the glucagon receptor gene, or the sulfonylurea receptor (SUR) gene (among others) in a low percentage of cases of type 2 diabetes in particular populations. However, the majority of susceptibility genes are still to be described. Recently, an inherited or acquired defect of FAD-linked mitochondrial glycerophosphate dehydrogenase in b-cells has been proposed to contribute to the impairment of insulin release in type 2 diabetes. Intravenous administration of b-endorphins or naloxone to type 2 diabetic patients enhances both basal and OGTT stimulated insulinemia, which suggests a possible pathogenetic role of these compounds in the dysfunction of b-cells. Prostaglandins may also be implicated, as suggested by the improvement of insulin response to intravenous glucose and the increase of the slope of


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glucose potentiation after infusion of sodium salicylate (inhibitor of prostaglandin synthesis). A similar effect has been observed with the a-adrenergic blocking agent phentolamine, which suggests a role of the a-adrenergic system. It has also been suggested that galanin and pancreostatin, peptides which inhibit insulin secretion, may be increased in the pancreatic islets of type 2 diabetic patients. Finally, hyperglycemia, once established, may contribute to aggravate the b-cell dysfunction, through several mechanisms most of which are included in the concept of ‘glucotoxicity’. The glucotoxicity concept may help to explain the beneficial effect on insulin secretion obtained in type 2 diabetic patients after adequate treatment achieving glycemic control as well as the transient improvement in the b-cell function which may occur in type 1 diabetic patients after therapeutical control of hyperglycemia (‘honeymoon’ phenomenon). It has been proposed that at least one factor contributing to the pathogenesis of type 2 diabetes is desensitization of the GLP-1 receptor on b-cells. At pharmacological doses, infusion of GLP-1, but not of GLP, can improve and enhance postprandial insulin response in type 2 patients. Agonists of GLP-1 receptor have been proposed as new potential therapeutic agents in type 2 diabetic patients. It should also be emphasized that complex alterations of glucidic and lipidic metabolism in the b-cells may play a role. In particular, in obese/diabetic hyperinsulinemic subjects, LC-CoA derived from the enhanced availability of FFA may affect the b-cells’ secretory response according to the following mechanism: as the glycemic level increases, the b-cells utilize more glucose; this leads to enhanced production of malonyl-CoA, which blocks the intramitochondrial transport of LC-CoA, which therefore accumulates in the cytosol and (through its complex biological effects) stimulates insulin secretion (see also chapter III and figure 3 for details). Altered expression of genes encoding enzymes in the pathway of malonylCoA formation and FFA oxidation contributes to the b-cell insensitivity to glucose in some patients with type 2 diabetes. Clearly, the detrimental impact of diabetic hyperlipidemia on b-cell function has been a relatively neglected area, but future pharmacological approaches directed at preventing ‘lipotoxicity’ may prove beneficial in the treatment of diabetes.

Insulin Secretion in Other Types of Diabetes Various, less common types of diabetes are known to occur, in which the secretory defect is based upon different mechanisms, as outlined in chapter I on Etiological Classification.

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Pharmacological Stimulation of Insulin Secretion Insulin Secretion as Modified by Sulfonylureas The main drugs able to stimulate insulin secretion are the sulfonylureas. These compounds have been used in the management of type 2 diabetes since 1955 and, when properly utilized, are easy to use and appear to be effective and safe. It is estimated that 30–40% of diabetic patients are taking oral sulfonylureas. Indications and contraindications for sulfonylureas are shown in tables 1 and 2, respectively.

Table 1. Patients candidate for sulfonylurea treatment Most patients with type 2 diabetes, not well controlled with dietary restriction and exercise Children and adults with the MODY (maturity-onset diabetes of youth) type of diabetes Obese-diabetic patients with marked insulin resistance Lean type 2 diabetic patients with preserved insulin secretory capacity

Table 2. Contraindications to sulfonylurea treatment Patients with type 1 diabetes Patients with pancreatic diabetes Patients with an acute illness or stress or undergoing surgery Patients with hepatic or liver diseases Patients predisposed to hypoglycemia: Underweight or malnourished Elderly Diabetic pregnancy: Potential teratogenicity Perinatal mortality Severe neonatal hypoglycemia Diabetic female patients during lactation Patients with a history of severe adverse reactions to sulfonylureas

Different Sulfonylureas The first oral hypoglycemic drug was synthesized in 1926 by altering the guanidine molecule. The sulfonylureas used today are derived from this native molecule. The ‘first-generation’ sulfonylureas, which were developed initially, are effective in large doses, while the ‘second-generation’ drugs, developed more recently, are effective in smaller doses. Some sulfonylureas, such as tolbutamide,


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Table 3. Main characteristics of sulfonylureas Compound

Dose, mg/day Doses q.d. Duration of hypoglycemic effect, h

Metabolism/ excretion

First generation Acetohexamide Tolbutamide Chlorpropamide Tolazamide

250–1,500 500–3,000 100–150 100–1,000

1–2 2–3 1 1–2

12–18 6–12 60 12–14

Liver/kidney Liver Kidney Liver

Second generation Glibenclamide (or glyburide) Glyburide, micronized Glipizide Gliclazide Gliquidone Glimepiride Repaglinide1

1.25–20 0.75–12 2.5–40 80–320 30–120 1–8 0.5–16

1–2 1–2 1–2 1–3 1–3 1 1–4

16–24 12–24 12–24 10–20 6–12 D24 4–6

Liver/kidney Liver/kidney Liver/kidney Liver/kidney Liver Kidney Liver

1

Repaglinide is a nonsulfonylurea hypoglycemic agent of the meglitinide family.

have a short duration of action (6 h), others, such as chlorpropamide, have a long duration of action (up to 60 h), several others show an action of intermediate duration. Some characteristics of the sulfonylureas which are or have been in clinical use are summarized in table 3. ‘First-Generation’ Sulfonylureas. Tolbutamide has a ‘short’ duration of action (see table 3) and is carboxylated by the liver to a totally inactive derivative. Being metabolized only in the liver, this compound may be useful in nephropathic diabetic patients. Tolazamide has a more potent hypoglycemic activity than tolbutamide and an ‘intermediate’ duration of action (see table 3). It is metabolized only by the liver with the production of some very little active metabolites excreted in the urine (85%). It is safer in the elderly and in nephropathic diabetic patients. Tolazamide also has a diuretic action. Chlorpropamide has a more potent hypoglycemic activity than tolbutamide and a ‘very long’ duration of action (see table 3), and therefore it can induce more hypoglycemic episodes than tolbutamide. It is hydroxylated by the liver with production of some active metabolites excreted in the urine (by 80–90%) and, thus, is contraindicated in the elderly and in nephropathic diabetic patients. Several side or toxic effects may occur with chlorpropamide,

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such as alcohol-induced flushing, occasional hypersensitivity reactions as well as water retention and hyponatremia (due to sensitization of renal tubules to antidiuretic hormone). Acetohexamide has a more potent hypoglycemic activity than tolbutamide and an intermediate duration of action. It is reduced by the liver to 1-hydroxyhexamide which is a potent hypoglycemic drug, excreted by 60% in the urine. Thus, it is contraindicated in the elderly and in nephropathic diabetic patients. Acetohexamide also has diuretic and uricosuric actions. ‘Second-Generation’ Sulfonylureas. Glyburide or glibenclamide has been used since 1969. It has a 50–100 times more potent hypoglycemic activity than the ‘first-generation’ drugs and has a relatively long duration of action. It is metabolized by the liver to several both inactive and mildly active metabolites, excreted partially in the urine (50%) and partially in the bile (50%). It may induce severe hypoglycemic episodes and is contraindicated in the elderly and in nephropathic diabetic patients. Glyburide absorption is not affected by food but it takes 30–60 min to achieve adequate plasma levels, so that this drug should be taken before the morning meal. Glipizide has been used since 1973, has a 50–100 times more potent hypoglycemic activity than the ‘first-generation’ drugs (comparable to that of glyburide) and has an ‘intermediate’ duration of action (see table 3). It is metabolized by the liver to several inactive metabolites, excreted in the urine (by 68%) and in the feces (by 10%). It may induce severe hypoglycemic episodes (similarly to glyburide) and is contraindicated in the elderly and in nephropathic diabetic patients. The absorption of glipizide is delayed by about 30 min when it is ingested with a meal, so that it is recommended to take the drug 30 min before meals. Glipizide has a greater effect than glyburide in raising postprandial plasma insulin level and lowering postprandial plasma glucose level while glyburide has a better effect than glipizide in raising fasting insulinemia and reducing fasting glycemia (probably, reducing fasting hepatic glucose production). For this metabolic difference, a ‘combined’ administration of the two sulfonylureas was suggested. Gliclazide has a potent hypoglycemic activity (comparable to that of glyburide and glipizide) and has an ‘intermediate’ duration of action. It is metabolized by the liver to several probably inactive metabolites, excreted in the urine (by 60–70%). It has been suggested that gliclazide exerts antiplatelet aggregating activity, with a potential preventing effect on diabetic microangiopathy, although this effect has not been confirmed. Gliquidone has a short duration of action (the mean half-life was approximately 1.2 h and the mean terminal half-life was 8 h), is metabolized in the liver to totally inactive or minimally active derivatives, and is excreted in the intestine (by about 100%). For these reasons, gliquidone is safer in the elderly


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and in nephropathic diabetic patients. A newly developed sulfonylurea, glimepiride, has been reported to have a more potent hypoglycemic action than glibenclamide while its ability to stimulate insulin secretion is much weaker, possibly due to less stimulation of insulin secretion and more pronounced extrapancreatic effects. It is effective at lower dosage, has a more rapid onset of action than glibenclamide and a long duration of action. There is increased plasma elimination of glimepiride with decreasing kidney function, which is explainable on the basis of altered protein binding with an increase in unbound drug. Efficacy and Interactions. Good response with sulfonylureas will occur in 70–75% of patients during the first years of treatment, provided that the patient selection is appropriate. Primary failure occurs in 15–25% of cases and may depend on a poor selection of the patients (unrecognized type 1 diabetic patients treated with sulfonylureas). Chronic therapy may be associated with progressively less beneficial effects (secondary failure), sometimes as result of intercurrent factors which impair insulin action and secretion (such as stress, infections, dietary disregard, etc.) (see also chapter III on Insulin Resistance and Its Relevance to Treatment). The response to the hypoglycemic drugs may be restored with the disappearance of the intercurrent event. All sulfonylureas are bound to serum albumin and, since a large number of drugs may compete for ionic binding sites on albumin, sulfonylureas can influence the effect of many drugs (and these drugs, conversely, can influence the effect of sulfonylureas). The physician must understand potential interactions with a number of commonly used drugs, that may significantly alter the activity of the sulfonylureas both diminishing (diuretics, b-blockers, corticosteroids, estrogens, indomethacin, alcohol, rifampicin, etc.) or increasing (sulfonamides, salicylates, clofibrate, chloramphenicol, MAO inhibitors, probenecid, allopurinol, b-blockers, alcohol, etc.) their hypoglycemic effect. It is noteworthy that some drugs (such as b-blockers and alcohol) can alter sulfonylureas activity in opposite directions. Sulfonylureas of ‘second generation’ may have less interactions than those of the ‘first generation’. Some data of literature demonstrate that serum levels of sulfonylureas (tolbutamide, chlorpropamide, glyburide and gliquidone) in treated diabetic patients show extremely interindividual variations, with no correlation between the dose and the plasma level. Mechanism of Sulfonylurea Action Acute Effects on Insulin Secretion. Sulfonylureas act primarily by acutely stimulating release of insulin from pancreatic b-cells (obviously, in presence of functioning pancreatic islets), and this stimulation of insulin secretion is a

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direct effect, as unquestionably proven by studies with perfused pancreases, isolated perifused islets and cultures of b-cells. Available data suggest that sulfonylureas bind to a specific receptor (closely associated with the ATP-sensitive K+-channels) on the outside of plasma membrane of the b-cells. Recent studies with human pancreatic islets showed that 3H-glibenclamide binds to saturable sites in islet membrane preparations in a linear fashion. This binding was both temperature- and time-dependent. Scatchard analysis of the equilibrium binding data indicated the presence of a single class of saturable, high-affinity binding sites. The displacement experiments showed the following rank order of potency of the oral hypoglycemic agents tested: glibenclamide > glimepiride ? tolbutamide ? chlorpropamide A metformin. This binding potency order was parallel with the insulinotropic potency of the evaluated compounds. Glimepiride has been reported to bind to a 65-kDa subunit of the sulfonylurea receptor. This characteristic may entail a minor effect of the K-channel in other tissues, such as myocardium (where the closure of K-channels may interfere with the repolarization process). Upon binding to their receptors, sulfonylureas inhibit the K+-channels, diminish K+ efflux and cause depolarization of the plasma membrane. This depolarization induces voltage-dependent Ca2+-channels to open and extracellular Ca2+ to enter the cell. Increased cytoplasmic Ca2+ stimulates the fusion of the secretory granule membrane with cell membrane, followed by extrusion of insulin outside the cell (exocytosis) (see also fig. 1). Metabolic studies demonstrate that sulfonylureas stimulate the first phase of insulin release and have little effect on the second phase. They can act in the absence of glucose but also may potentiate glucose-mediated insulin release. As consequence of the stimulation of secretion, sulfonylureas can induce morphological alterations of the b-cells such as degranulation, loss of zinc and aspects of emiocytosis. Chronic Effects on Insulin Secretion. Whether chronic sulfonylurea treatment results in increased insulin secretion is a controversial problem. The finding that after chronic treatment of type 2 diabetic patients insulinemia returns to pretreatment level, without deterioration of glucose control, suggests long-term extrapancreatic effects of sulfonylureas. The lower plasma glucose achieved with sulfonylurea drugs in type 2 diabetic patients might be expected to stimulate less insulin secretion (blood glucose is the major stimulus to insulin release), and this can explain the inability of some studies to demonstrate the chronic effect of sulfonylurea in stimulating insulin secretion. Available literature data, however, do not support the concept that the improvement of glycemia during chronic sulfonylurea treatment can be attributed solely to an increased insulin secretion.


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Table 4. Extrapancreatic effects of sulfonylureas Hormonal effects Potentiation of insulin action on skeletal muscle and adipose tissue glucose transport Potentiation of insulin action on hepatic glucose production (activation of glycogen synthase and glycogen synthesis) Decrease of hepatic insulin extraction Decrease of insulin degradation (inhibition of insulinase activity) Stimulating effect on gastrointestinal hormone release Direct metabolic effects Insulin receptors (partial restoration of their number in plasma membrane in type 2 obesediabetic patients) Liver (increase in fructose 2,6-bisphosphate; increase in glycolysis; decrease in gluconeogenesis; decrease in long-chain fatty acid oxidation) Skeletal muscle (increase of glucose and amino acid transport; increase of fructose 2,6bisphosphate) Myocardial tissue (increase of contractility; increase of oxygen consumption; increase of glycogenolysis; decrease of Ca2+-ATPase; increase of glucose transport and glycolysis; increase of phosphofructokinase activity and pyruvate oxidation) Adipose tissue (increase in glycogen synthase; inhibition of lipolysis, increase in glucose transport) Platelet arachidonic acid metabolism (inhibition of cycloxygenase and 12-lipoxygenase pathways)

Other Effects. Sulfonylurea treatment does not appear to stimulate proinsulin biosynthesis. On the other hand, studies performed with in vivo and in vitro animal perfused pancreases, or with isolated perifused islets and isletcell cultures, reported an acute and chronic sulfonylurea-induced inhibition of the biosynthesis of proinsulin (through unknown mechanisms). Sulfonylureas, acutely or chronically, do not alter glucagon secretion both in normal subjects and diabetic patients. Sulfonylureas appear to stimulate pancreatic d-cell somatostatin release (with unclear physiological effect). Extrapancreatic Effects of Sulfonylureas. Diverse in vitro and in vivo extrapancreatic effects of sulfonylureas have been reported over the last 30 years (most of which, however, were obtained with drug concentrations larger than those achieved in therapeutic use) (table 4). These effects of sulfonylureas are due to direct actions on liver and/or muscle and, occurring in the absence of changes in insulin binding, are probably mediated by postreceptor events. As a whole, the extrapancreatic effects of sulfonylureas are of minor clinical significance. A possible exception is glimepiride, which may exert more significant extrapancreatic actions, including activation (through dephosphorylation) of GLUT-4.

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Table 5. Sulfonylurea side or toxic effects Hematologic reactions (agranulocytosis, bone marrow or red cell aplasia, hemolytic anemia) Skin reactions (rash, pruritus, erythema, purpura, photosensitivity) Hypersensitivity reaction (rush, fever, arthralgia, angiitis, jaundice, etc.) Alcohol-induced flushing (most frequently associated with chlorpropamide treatment) Gastrointestinal complaints (nausea, vomiting, jaundice or hepatitis or cholestasis) Antithyroid activity Diuretic effect or antidiuresis with hyponatremia Cataract formation (reported in some dogs treated with high doses of glimepiride) Teratogenicity

Side or Adverse Effects of Sulfonylureas. The most important adverse effect of sulfonylureas is hypoglycemia which, although occurring less often than with insulin, when it occurs it tends to be more severe, prolonged and sometimes fatal. The incidence of sulfonylurea-induced hypoglycemia is 0.19–4.2/1,000 treatment years (compared to 100/1,000 patients/year for insulin-induced hypoglycemia) and is most frequent in patients taking long-acting drugs (such as glyburide and chlorpropramide) which, for this reason, should be avoided in patients with predisposing conditions (the best treatment of hypoglycemia is prevention). The case fatality rate of hypoglycemia induced by sulfonylureas is 4.3% (see also chapter VIII on Clinical Emergencies in Diabetes. 2: Hypoglycemia). It is noteworthy that sulfonylureas predispose to hypoglycemia during and after exercise. In this regard, it has been claimed that glimepiride maintains a more physiological regulation of insulin secretion during physical exercise, with less risk of hypoglycemia. Other sulfonylurea side effects or toxic reactions occur at low rate (1.5% for glyburide) (table 5) and appear within the first 2 months of treatment. The chlorpropamide alcohol flushing (CPAF), occurring in 30–40% of type 2 and 10% of type 1 diabetic patients, is linked to a genetic predisposition to diabetes development (autosomic trait) and can be considered a good genetic marker of type 2 diabetes mellitus.

Other Drugs Modifying Insulin Secretion Repaglinide is a nonsulfonylurea hypoglycemic agent of the meglitinide family, a new class of drugs with insulin secretory capacity which exert a rapid- and also short-acting effect, thus entailing reduced risk of long-lasting, and hence dangerous, hypoglycemia. Repaglinide appears to bind to receptor


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sites different from those of sulfonylureas (two binding sites have been identified). Repaglinide lowered fasting and postprandial blood glucose levels in animals, healthy volunteers and patients with type 2 diabetes mellitus. Repaglinide is rapidly absorbed and eliminated, which may allow a relatively fast onset and offset of action. Excretion occurs almost entirely by nonrenal mechanisms. In comparative clinical trials in patients with type 2 diabetes mellitus, repaglinide 0.5–4 mg twice or 3 times daily before meals provided similar glycemic control to glibenclamide (glyburide) 2.5–15 mg/day. Addition of repaglinide to existing metformin therapy resulted in improved glycemic control. In contrast with glibenclamide, use of repaglinide allowed patients to miss a meal without apparently increasing the risk of hypoglycemia. GLP-1 has insulinotropic action, which may explain the increased insulin response after oral compared to intravenous glucose administration, and exerts several other functions such as reduction of glucagon concentration, reduction of gastric emptying, stimulation of proinsulin biosynthesis and reduction of food intake (upon intracerebroventricular administration in animals). On these grounds, GLP-1 seems to offer an interesting perspective in treatment of diabetic patients. The observations that GLP-1 induces both secretion and production of insulin, and that its activities are mainly glucose-dependent, led to the suggestion that GLP-1 may present a unique advantage over sulfonylurea drugs in the treatment of type 2 diabetes. This peptide is able to lower and perhaps normalize fasting hyperglycemia and to reduce postprandial glycemic increments (especially in type 2 diabetic patients) but its usefulness is not completely established. Due to rapid proteolytic cleavage, the half-life of GLP-1 is too short for therapeutical use with subcutaneous injections. GLP-1 analogues with different pharmacokinetic properties (or some preparations that could be orally administered) are in development. Given the large amount of GLP-1 present in L-cells, it appears worthwhile to look for some agents that could ‘mobilize’ this endogenous pool of the ‘antidiabetogenic’ gut hormone GLP-1. Interference with sucrose digestion using a-glucosidase inhibition moves nutrients into distal parts of the gastrointestinal tract and, thereby, prolongs and augments GLP-1 release. Antiarrhythmic agents with Vaughan Williams class Ia action have been found to induce a sporadic hypoglycemia. Recent investigation has revealed that these drugs induce insulin secretion from pancreatic b-cells by inhibiting ATP-sensitive K+ (K-ATP) channels in a manner similar to sulfonylurea drugs. It is possible that in the future, pharmacological compounds will be found that may act on GK and improve b-cell insulin secretion.

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Suggested Reading Belfiore F, Rabuazzo AM, Iannello S, Campione R, Castorina S, Urzı´ F: Extrapancreatic action of glibenclamide: Reduction in vitro of the inhibitory effect of glucagon and epinephrine on the hepatic key glycolytic enzymes phosphofructokinase and pyruvate kinase. Eur J Clin Invest 1989;19:367–371. Draeger E: Clinical profile of glimepiride. Diabetes Res Clin Pract 1995;28(suppl):139–146. Drucker DJ: Glucagon-like peptides. Diabetes 1998;47:159–169. Goldberg RB, Einhorn D, Lucas CP, Rendell MS, Damsbo P, Huang WC, Strange P, Brodows RG: A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes. Diabetes Care 1998;21:1897–1903. Lebovitz HE: Oral hypoglycemic agents; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and Practice, ed 4. New York, Elsevier, 1990, pp 554–574. Matschinsky FM: Banting Lecture 1995: A lesson in metabolic regulation inspired by glucokinase glucose sensor paradigm. Diabetes 1996;45:223–241. Philipson LH, Steiner DF: Pas de deux or more: The sulfonylurea receptor and K+ channels. Science 1995;268:372–373, 423–429.



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Chapter III

............................

Insulin Resistance and Its Relevance to Treatment F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Insulin Action Introduction Insulin exerts its metabolic effects on the insulin-sensitive tissues, i.e. on liver, muscle and adipose tissue. In these tissues, insulin action is the result of complex mechanisms. We can distinguish (1) insulin binding to specific receptors and the following sequence of events along the insulin signalling pathway, which ultimately lead to (2) the insulin metabolic effects at postreceptor level.

The Insulin Receptor The insulin receptor is a heterodimer composed of two chains or subunits, the a- and the b-chain, linked by disulfide bridges. The a-subunit is extracellular in location and is the site of insulin binding. The b-subunit is transmembrane in location and originates from the signal transduction. Normally there is a large surplus in the number of receptors (i.e. there is a large amount of spare receptors). Nevertheless, considering that insulin binding to its receptors is a random phenomenon, it follows that the higher the number of insulin molecules or receptor units, the higher the number of insulin molecules which will bind to the receptor units. An increase in the insulin level causes a decrease in the receptor number on the plasma membrane (downregulation of insulin receptors), a phenomenon that may occur in conditions of persistent hyperinsulinemia (insulin-resistant states, including obesity).

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Fig. 1. Schematic representation of dose-response curves of insulin action in the normal state and in conditions of impaired insulin action. For explanation, see the text.

When the receptor number is decreased, the number of insulin molecules that bind to the receptors at a given insulin level will be reduced, and therefore the insulin effects will be diminished, i.e. there is insulin resistance. However, by increasing the insulin level, the number of insulin molecules that bind to the receptors can be increased toward the normal and therefore the insulin effects can be restored; moreover, by increasing further the insulin level, the maximum effect can be reached. This condition is called decreased insulin sensitivity. By plotting the insulin concentrations (on the abscissa) against the insulin effect (on the ordinate), the insulin dose-response curve is obtained. This curve, in the case of insulin resistance due to reduced receptor number, will be shifted to the right, as the maximum effect is reached at very high insulin levels. On the other hand, when the insulin resistance is due to defects in postreceptor steps of insulin action (see below), the dose-response curve is flattened and the maximum insulin effect is not reached even at very high insulin concentrations. When the two conditions coexist, the insulin doseresponse curve will be shifted to the right and flattened (fig. 1). Concerning the fate of the insulin-receptor complexes, several data suggest that they are internalized and delivered to endosomes, the acidic pH of which induces the dissociation of insulin molecules from insulin receptors and their sorting in different directions: insulin molecules are targeted to late endosomes

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and lysosomes where they are degraded whereas receptors are recycled back to the cell surface in order to be reused. To understand the function of insulin receptors, it should be recalled that protein kinases that directly phosphorylate proteins are divided into two major classes: those that phosphorylate tyrosine (tyrosine-specific protein kinases) and those that phosphorylate serine and threonine (the serine/threonine-specific protein kinases). The receptor b-subunit can be phosphorylated on serine, threonine and tyrosine residues and possesses intrinsic protein-tyrosine kinase activity. Insulin stimulates this activity (i.e. the insulin receptor is itself an insulin-sensitive enzyme) which is responsible for both autophosphorylation of the receptor itself and phosphorylation of tyrosine residues of various cellular substrates, including the insulin receptor substrates (IRS-1 and IRS-2). The latter, through a mechanism not yet fully understood, trigger a sequence of events which include phosphorylation/dephosphorylation of several cytoplasmatic proteins which, in turn, will induce the spectrum of insulin effects (fig. 2). Two insulin receptor isoforms have been identified, the A and the B form, which, however, revealed no difference in their tyrosine kinase activity in vivo. Protein-tyrosine phosphatases (PTPases) play an essential role in the regulation of reversible tyrosine phosphorylation of cellular proteins that mediate insulin action. In particular, some data suggest a possible role of the transmembrane PTPase in insulin receptor signal transduction. Recent studies suggest that the insulin receptor tyrosine kinase inhibitor, the membrane glycoprotein PC-1, may modulate insulin activity (and may play a role in insulin resistance – see the second part of this chapter).

Metabolic Effects of Insulin (Postreceptor Effects) The mechanisms of postreceptor insulin effects can be distinguished into: (a) translocation (and activation) of glucose transporters (the GLUT-4 isoform) from the intracellular pool to the cell membrane; (b) activation/inhibition of several enzymes of intermediary metabolism through either changes in concentrations of ions or regulatory compounds which bind to the enzyme at sites distinct from the substrate-binding site (allosteric effectors), or covalent modifications of the enzyme molecules often consisting of phosphorylation/ dephosphorylation processes; (c) induction/repression mechanisms leading to changes in enzyme concentration through regulation of the synthesis of the enzyme proteins. Translocation and activation/inhibition processes are shortterm mechanisms (occurring within seconds or minutes), the induction/repression processes are long-term mechanisms (hours).

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Stimulation of glucose transport across the cell membrane is one of the main effects of insulin in muscle and adipose tissue, and is the result of the translocation of glucose transporter (the GLUT-4 isoform)-containing vesicles from an intracellular storage pool to the surface membrane. This event is mediated through IRSs, which in turn activate PI-3-kinase isoforms (fig. 2). Translocation and activation of GLUT-4 is favored by its dephosphorylation. In addition to glucose transport, insulin also stimulates the transport across the cell membrane of amino acids and ions, mainly potassium and phosphate. Insulin regulates several key metabolic steps (fig. 1). In doing so, insulin is opposed by the four counterregulatory hormones (the rapid-acting glucagon and catecholamines, and the slow-acting growth hormone and cortisol). Insulin affects the pathways of glucose utilization as well as the synthesis and degradation of macromolecules (glycogen, triglycerides and proteins) by regulating the activity of ‘key enzymes’. Indeed, along each metabolic pathway, there is one or more key step(s) catalyzed by key enzymes. These are enzymes which, because of their low activity and sensitivity to regulatory factors (including hormones), regulate the overall rate of the pathway to which they belong. In particular, insulin (or, better, its prevalence over the counterregulatory hormones) exerts the following effects (fig. 1): (a) favors glucose utilization by activating the three key glycolytic kinases, namely hexokinase (and GK in the liver), phosphofructokinase and pyruvate kinase; in the liver, this is associated with repression of the opposing key gluconeogenic enzymes: glucose-6-phosphatase, fructose bisphosphatase and phosphoenolpyruvate carboxykinase plus pyruvate carboxylase; (b) stimulates glucose oxidation, by activating the key enzyme pyruvate dehydrogenase in the mitochondria; (c) lowers FFA level by inhibiting lipolysis in the adipose tissue and reduces ketogenesis from FFA in the liver (see chapter VII on ketoacidosis for further explanation); (d) favors glycogen synthesis and depresses glycogenolysis by activating the enzyme glycogen synthase while inhibiting glycogen phosphorylase; (e) enhances triglyceride synthesis and refrains triglyceride hydrolysis (lipolysis) by inhibiting the hormone sensitive lipase; (f ) finally, insulin stimulates protein synthesis and opposes protein degradation (or proteolysis). The main insulin actions are summarized in table 1. Thus, the overall action of insulin is (1) to increase glucose utilization in muscle, liver and adipose tissue while depressing glucose production in the liver, which results in blood glucose lowering; (2) to lower FFA level by refraining lipolysis, and (3) to prevent ketone formation in the liver by opposing ketogenesis.


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Fig. 2. Simplified representation of the mechanisms of action of insulin, glucagon, catecholamines (sympathetic activation) and acetylcholine (parasympathetic activation). (Continuous lines ending with black arrows indicate transformation or translocation of substrates or ions; dotted lines ending with white arrows indicate stimulation; dotted lines ending with filled circles indicate inhibition.) Insulin: Insulin receptors, with their tyrosine kinase activity, phosphorylate several protein substrates (IRS1, IRS2, Shc, etc.) which in turn phosphorylate (activate) several protein kinases (PI3-K, MAP-K, PKB, PKCz, PKCl, etc.) and these, through a complex cascade of phosphorylation/dephosphorylation, produce the various insulin effects (glucose transport, enzyme activation/inhibition, induction/repression of enzymes and other proteins). Other hormones: Glucagon and catecholamines (b-receptors) activate adenylate cyclase (with the participation of Gs proteins), thus producing cAMP and stimulating PKA. Catecholamines (a2-receptors) inhibit adenylate cyclase (with the participation of Gi proteins) and therefore exert opposite effects. Acetylcholine (parasympathetic stimulation) activate PLC (with the participation of Gp proteins) which split PIP3 thus producing IP3 and DAG. IP3 favors the increase in cytosolic Ca (release of Ca from the endoplasmic reticulum stores or Ca influx from outside the cell) thus activating the CaCalm PK. DAG activates PKC. The activation of these protein kinases will eventually result in enzyme activation-inhibition. Note that protein kinases may activate (through phosphorylation) some protein phosphatases, resulting in dephosphorylation of some key enzymes. Most key enzymes of anabolic pathways are active in the dephosphorylated form (example: glycogen synthase), and are activated by insulin and inhibited by glucagon and catecholamines. Most key enzymes of catabolic pathways are active in the phosphorylated form (example: glycogen phosphorylase, hormonesensitive lipase) and are activated by glucagon or catecholamines and inhibited by insulin. Abbreviations (alphabetic order): a2>a2-adrenergic receptor; AC>adenylate cyclase; b>b-adrenergic receptor; cAMP>cyclic AMP; DAG>1,2-diacylglycerol; G-4>isoform 4

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Table 1. Metabolic effects of insulin Stimulation

Inhibition

Synthesis of macromolecules (and allied processes): Glycogen Glucose transport Glucose phosphorylation Triglycerides Lipoprotein lipase Proteins Amino acid transport Nucleic acids Other: Ion transport Substrate utilization: Glycolysis Glucose oxidation

Degradation of macromolecules (and allied processes): Glycogen Proteins Amino acid oxidation Gluconeogenesis Lipolysis FFA oxidation Ketogenesis

Insulin Resistance Introduction Insulin resistance can occur because of defects in insulin action at prereceptor, receptor or postreceptor level. Besides rare cases of abnormal insulins or presence of receptor antibodies (prereceptor defects), reduction in the insulin receptor number is a relatively common factor contributing to insulin resistance. In addition, insulin binding (and therefore insulin action) may also be affected in rare conditions in which qualitative alterations occur in the receptor (e.g. decrease in the receptor affinity). Postreceptor mechanisms include the signals triggered by insulin binding to the receptor as well as the resulting changes in several key steps of intracellular metabolism. of the glucose transporter; Glg>glucagon receptor; Gq>a further type of G protein; Gs and Gi> stimulatory and inhibitory G proteins; Ins>insulin receptor; IP3>inositol-1,4,5trisphosphate; IRS1>insulin receptor substrate-1; IRS2>insulin receptor substrate-2; M>muscarinic receptor; MAP-K>mitogen-activated protein kinase; PC-1>an ecto-protein kinase probably interfering with insulin receptor tyrosine kinase; PI3-K>phosphatidylinositol-3 kinase; PIP2>phosphatidylinositol-4,5-P; PKA>protein kinase A; PKB>protein kinase B; PKC(f, k)>protein kinase C, forms f and k; PKC>protein kinase C; PLC> phospholipase C; Shc>protein containing a single SH2 domain, substrate of insulin receptor tyrosine kinase; TNFa>tumor necrosis factor-a; Tyr-K>tyrosine kinase activity of the insulin receptor.


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Insulin Resistance in Type 2 Diabetes and Obesity In type 2 diabetic patients, insulin resistance is due to impaired insulin action either at receptor and postreceptor level, and may result from two etiological components, the genetic background and some acquired factors, of which overweight and obesity are certainly the most important ones. Insulin Receptor Defects A common cause contributing to decreased insulin action consists of reduction in the insulin receptor number which, however, most often is secondary to insulin resistance and the associated hyperinsulinemia, through the ‘downregulation’ mechanism. In type 2 diabetes, an incomplete activation of the insulin receptor tyrosine kinase appears to contribute to the pathogenesis of the signalling defect. Available data suggest that the impaired tyrosine kinase function of the insulin receptor is not due to an inherited defect but rather is caused by a modulation of insulin receptor function. The B isoform is increased in the skeletal muscle in type 2 diabetes, which may not have significant functional significance. In this context, it is worthwhile noting that in obese subjects, increased PTPase activity has been found in the adipose tissue that can dephosphorylate and inactivate the insulin receptor kinase. The membrane glycoprotein PC-1 (PC-1) has been proposed to be an ecto-protein kinase capable of phosphorylating itself as well as exogenous proteins, and would act as an inhibitor of the tyrosine kinase activity of the insulin receptor. PC-1 was found to be increased in tissues (muscle and fibroblasts) of insulin-resistant subjects. Moreover, in transfected cell lines that overexpress PC-1 there is a reduction in the insulin-stimulated insulin receptor tyrosine phosphorylation. These and other data raise the possibility that PC-1 has a role in the insulin resistance of noninsulin-dependent diabetes mellitus as well as of obesity. In obese patients, skeletal muscle shows reduction in the phosphorylation of insulin receptor and IRS-1 and in PI-3-kinase activation. The scarce expression of these proteins would contribute to determine muscular insulin resistance. Hyperglycemia might directly inhibit insulin-receptor tyrosine kinase activity and the receptor function. This appears to be mediated by activation of certain protein kinase C isoforms which form stable complexes with the insulin receptor and modulate the tyrosine kinase activity of the insulin receptor through serine phosphorylation of the receptor b-subunit.

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Postreceptor, Metabolic Mechanisms Key Metabolic Steps Resistant to Insulin. Concerning glucose metabolism, by means of complex procedures including the glucose clamp technique, labelled compound infusion and indirect calorimetry, it has been shown that in patients with type 2 diabetes there is an impairment of insulin-mediated glucose utilization by peripheral tissue (muscle) as well as a reduced insulin suppression of hepatic glucose production. Thus, reduction in insulin sensitivity occurs for both the peripheral glucose utilization and the hepatic glucose production. Reduction in the receptor number may play a role, although it is more probable that this is a secondary phenomenon due to the downregulation of receptors by the hyperinsulinemia which accompanies insulin resistance. A defect in intracellular dissociation of the insulin-receptor complex might contribute by altering the receptor recycling and insulin processing. However, especially in the most severe cases, reduction in insulin responsiveness of peripheral glucose utilization does occur, suggesting postbinding defects in insulin action. Impairment of insulin-mediated glucose utilization by peripheral tissue (muscle) is due mainly to reduction in nonoxidative glucose utilization (glycogen synthesis) and to a minor extent to reduced glucose oxidation. Concerning nonoxidative glucose utilization (glycogen synthesis), the defect has been tentatively located at the level of the key enzyme glycogen synthase, or the glycogen-synthase-activating enzyme, protein phosphatase-1. Other data suggest the implication of earlier steps of glucose utilization, such as glucose transport and/or glucose phosphorylation to glucose-6-P (effected by the enzyme hexokinase), which may secondarily impair glycogen synthase activation. On the other hand, the defect in glucose oxidation has been located at the level of the pyruvate dehydrogenase reaction. Concerning lipid metabolism, resistance of lipolysis to the antilipolytic action of insulin often occurs in type 2 diabetic patients, especially when overweight or obesity is present, which results in elevated FFA plasma levels. However, it should be noted that, when obesity is present, elevation of plasma FFA may also be due to the increased fat mass, even in the presence of normal lipolysis. Insulin suppresses VLDL production in insulin-sensitive humans partly by suppressing plasma FFA levels and partly by a non-FFA-mediated, direct hepatic mechanism (inhibition of ApoB synthesis). Insulin-resistant hyperinsulinemic obese individuals are resistant to this suppressive effect of insulin on VLDL-ApoB production. Resistance to the normal suppressive effect of insulin, in addition to other metabolic abnormalities associated with insulin resistance, may contribute to postprandial and postabsorptive hypertriglyceridemia. When obesity is present, insulin resistance of fat storage may also be present, which may be an adaptation limiting further fat deposition, but is maladaptive in terms of risk factors for atherosclerosis.


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Genetic Factors (Changes in Predisposed Individuals). The genetic component of the insulin resistance is suggested by the observation that in firstdegree relatives of type 2 patients, the insulin-stimulated glucose metabolism was reduced, which was accounted for by a defect in nonoxidative glucose utilization (glucose storage as glycogen), whereas glucose oxidation rate appeared normal. Consistently, impaired activation of glycogen synthase by insulin has been reported in these individuals. The glycogen-synthase-activating enzyme, protein phosphatase-1, also has an abnormally low level of activity in these subjects. Moreover, in insulin-resistant offspring of parents with noninsulin-dependent diabetes mellitus, after muscle glycogen-depleting exercise, there is a severely diminished rate of muscle glycogen synthesis during the recovery period (2–5 h), which is known to be insulin-dependent. These data, however, do not necessarily mean that the defect is located at the glycogen synthase level, since defects in the earlier step of glucose metabolism, such as transport and/or phosphorylation, may also impair glycogen synthase activation. Acquired Factors: The Reciprocal Negative Influences of FFA and Glucose Metabolism. Among the acquired factors favoring insulin resistance, obesity, which results from absolute or relative hyperphagia and/or hypoactivity, is certainly the most important one. Obesity is associated with elevated FFA levels, as well as with enhanced availability of glucose (hyperphagia) and insulin. In these conditions, there is a competition between FFA and glucose as energetic fuels. Indeed, reciprocal negative influences between FFA and glucose metabolism occurs through the mechanisms outlined below (fig. 3). In fact, the utilization of FFA (tendencially enhanced in obesity, because of the trend to high plasma FFA levels) leads to the formation of long-chain CoA or acyl-CoA (LC-CoA) in the cytosol, followed by the entry of LC-CoA into the mitochondria through the action of the enzyme carnitine palmitoyl transferase-1 (CPT-1) and by the b-oxidation of LC-CoA to acetyl-CoA. Both these compounds inhibit glucose utilization, thus inducing insulin resistance. In fact: (a) acetyl-CoA inhibits the key enzyme of glucose utilization, pyruvate dehydrogenase; the resulting inhibition of oxidative glucose utilization will maintain saturated the glycogen stores, thus refraining further glucose conversion to glycogen, i.e. the nonoxidative glucose utilization; (b) LC-CoA (directly or through the generation of regulatory metabolites) exerts complex metabolic effects, including inhibition of nonoxidative glucose metabolism (fig. 3). On the other hand, the metabolism of glucose (favored in obesity by dietary carbohydrates and hyperinsulinism) leads to the formation of malonyl-CoA (fig. 3), a regulatory compound which inhibits CPT-1, thus reducing the intramitochondrial transport of LC-CoA and therefore its b-oxidation. This favors the accumulation of LC-CoA in the cytosol.

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Fig. 3. Reciprocal inhibitory effects between the metabolism of glucose and that of FFA. Metabolism of FFA (gray background, steps 1–6): The metabolism of FFA leads to inhibition of glucose oxidation (through the effect of acetyl-CoA on pyruvate dehydrogenase – step 4) and of nonoxidative glucose utilization (through the complex effects of LC-CoA – steps 5 and 6). Moreover, glycolysis is also inhibited through the effect of citrate on the key glycolytic enzyme phosphofructokinase (step 9). The inhibition of pyruvate dehydrogenase (step 4) by acetyl-CoA is the basis of the Randle’s glucose-FFA cycle. Metabolism of glucose (white background, steps 4, 7–13): Glucose utilization leads to formation of malonyl-CoA which, by inhibiting carnitine palmitoyl transferase-1 (step 3), reduces FFA b-oxidation and increases LC-CoA concentration. Dotted arrows indicate the regulatory effects. From: Belfiore F, Iannello S, Mol Genet Metab 1998;65:121–128.

In summary, when the metabolism of FFA is stimulated (as it occurs in obesity), the enhanced production of LC-CoA (cytosol) and of acetyl-CoA (mitochondria) leads to inhibition of glucose utilization, thus inducing insulin resistance which is often followed by hyperinsulinemia. The latter stimulates glucose utilization and therefore the production of malonyl-CoA, which inhibits CPT-1, thus decreasing intramitochondrial transport and b-oxidation of FFA (and therefore acetyl-CoA formation). This, however, may further increase the LC-CoA concentration in the cytosol, which may maintain insulin resistance (fig. 3). It is noteworthy that obesity, through the increased formation of acetylCoA and LC-CoA (derived from the enhanced availability and oxidation of FFA), exerts an inhibitory effect on the two metabolic steps (glycogen synthesis


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Fig. 4. Scheme showing the metabolic effects of enhanced availability and oxidation of FFA, as occurs in obesity. In muscle: reduction of glucose utilization. In liver: reduced glucose utilization (and insulin uptake) and enhanced gluconeogenesis. In the pancreas: stimulation of insulin secretion. From: Belfiore F, Iannello S, Mol Genet Metab 1998;65: 121–128.

and glucose oxidation) which are already defective in the type 2 diabetic patients and in the genetically predisposed subjects. The metabolic picture resulting from increased FFA availability and oxidation in obesity is outlined in figure 4. Hormonal Factors Counterregulatory Hormones. Prevalence of counterregulatory hormones (stress hormones) over insulin may contribute to the insulin resistance phenomenon. Glucagon tends to be elevated because of a decreased b-cell/a-cell ratio in the pancreas. This hormone counteracts the insulin actions, especially in the liver, by favoring glycogenolysis and gluconeogenesis over the opposing processes of glycogeno-synthesis and glycolysis (promoted by insulin). In occasional patients or under particular circumstances (intercurrent infections or other illnesses, stress, trauma, etc.), other counterregulatory hormones, primarily cortisol, might participate in opposing the insulin actions. Tumor Necrosis Factor-a (TNFa). TNFa is one of the proteins formed by adipocytes, whose production increases with increasing adipocyte mass (obesity). Indeed, TNFa (as well as chronic hyperinsulinemia that induces insulin resistance) triggers increased Ser/Thr phosphorylation of the insulin

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receptor (IR) and of its major insulin receptor substrates, IRS-1 and IRS-2, which may be a molecular mechanism for uncoupling insulin signaling, as enhanced Ser/Thr phosphorylation of IRS-1 and IRS-2 impairs their interaction with the juxtamembrane region of IR. Thus, the TNFa produced by adipocytes may function as a local ‘adipostat’ to limit fat accumulation. Increased production of TNFa by fat cells stimulates downregulation of the insulin-sensitive glucose transporter, GLUT-4, in adipocytes. TNFa is overexpressed in the adipose tissue of obese rodents and humans, and is associated with insulin resistance. The exact role of TNFa, however, remains to be established. Leptin. Leptin is the product of OB gene. This 16-kDa protein is produced by mature adipocytes and is secreted in the plasma. Its plasma levels are strongly correlated with adipose mass in rodents as well as in humans. Leptin inhibits food intake, reduces body weight and stimulates energy expenditure. Leptin binds to a long-form of leptin receptor in the hypothalamus, thus stimulating the release of GLP-1 and decreasing the production of neuropeptide Y, a neuromediator (stimulator) of food intake. Recent studies have shown that leptin inhibits insulin secretion and has anti-insulin effects on liver and adipose tissue. If these effects are confirmed, leptin could play a role similar to that of TNFa and could participate in the insulin resistance of obesity and type 2 diabetes. Serum leptin is increased in insulin-resistant offspring of type 2 diabetic patients. Other Factors Contributing to Insulin Resistance Decreased blood flow and capillary density has been proposed as mechanisms contributing to insulin resistance both in type 2 diabetes and in obese insulin-resistant Pima Indians. It has been suggested that insulin action may be modulated by blood flow. Insulin resistance in moderately obese women was associated with an abnormal vascular reactivity to stress, entailing exaggerated blood pressure response; an enhanced vasoconstriction to stress may mediate this response. Insulin-induced attenuation of noradrenaline-mediated vasoconstriction is impaired in the obese rats. This defect in insulin action could reside in the endothelial generation of nitric oxide, as endothelial function is also abnormal. A distinct capillary endothelial dysfunction may be involved in the insulin resistance syndrome. However, the capillary wall crossing is rate-limiting for muscle glucose uptake (and lactate release) in control subjects but not in postabsorptive hyperglycemic insulin-resistant subjects. On the other hand, in a prospective (15 years) study it was found that capillary density was increased rather than decreased in subjects with impaired


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glucose tolerance who later developed diabetes, a fact that might be regarded as a compensatory mechanism for intracellular defects in glucose metabolism. In healthy young men, there is a negative relationship between directly measured whole-blood viscosity and insulin sensitivity (clamp technique) as a part of the insulin resistance syndrome, which supports the hypothesis that insulin resistance has a hemodynamic component. Insulin-resistant first-degree relatives of type 2 diabetic patients were shown to have an increased number of the glycolytic, fast-twitch (white), type IIb muscle fibers compared to the oxidative, slow-twitch (red), type I and IIa fibers (which are those normally responsive to insulin). Whether this finding reflects a reduced physical activity level and fitness in the relatives or is of primary genetic origin remains to be determined.

Insulin Resistance in Type 1 Diabetes Although type 1 diabetes is due to severe insulin deficiency, it should be considered that chronic lack of insulin action may produce insulin resistance, through several mechanisms. As already pointed out, insulin exerts both short-term and long-term effects, the latter consisting of induction or repression of the synthesis of key enzymes. Therefore, in the tissues of the insulin-deficient subject there will be a decreased content of the enzymes ‘induced’ by insulin (example: hepatic GK) and accumulation of the enzymes repressed by insulin (example: gluconeogenic enzymes). Upon insulin administration, some degree of ‘resistance’ (reduced effect) may occur until the enzyme balance is normalized, i.e. until the amount of those enzymes ‘induced’ by insulin is restored and the accumulation of those enzymes ‘repressed’ by insulin decreases to the normal level, which may takes several hours or even 1–2 days. In addition, severe insulin deficiency is always associated with active lipolysis and enhanced release of FFA, which counteract insulin action through the mechanism of the glucose-FFA cycle, already discussed. When the type 1 diabetic patient becomes severely decompensated and ketoacidosis supervenes, the insulin action may be further disturbed by the interference of the acidosis with insulin binding to its receptor as well as by the reduced response of the intracellular enzymes caused by the hyperosmolality.

Rare Genetic Forms of Insulin Resistance These are described in chapter I on Etiological Classification, Pathophysiology and Diagnosis.

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Drugs Ameliorating Insulin Resistance Introduction The recognized major role played by insulin resistance in the pathogenesis of type 2 diabetes is the rational basis for the use of drugs capable of improving insulin sensitivity and consequently enhancing insulin action. The most used of these drugs today is the biguanide compound metformin (dimethylbiguanide), but other potentially useful agents, today under clinical investigation, will also be considered, such as the thiazolidinediones (pioglitazone, troglitazone and rosiglitazone) and still others.

Metformin The main biguanides (phenformin and metformin) were first synthesized in 1929 and were shown to be potent antihyperglycemic agents. They were rediscovered in 1957 and were widely used in Europe to treat obese type 2 diabetic patients. Phenformin was withdrawn in many countries because of an association with lactic acidosis, but metformin, which does not bear the same risk when appropriately prescribed, resurfaced in the 1980s and was shown to increase insulin sensitivity. This led to its approbation for use in the USA in 1994. Actions. Unlike sulfonylureas (and the biguanide phenformin), metformin does not bind to plasma proteins and is not metabolized by the liver. Metformin has an absolute oral bioavailability of 40–60%, and gastrointestinal absorption is apparently complete within 6 h of ingestion. An inverse relationship was observed between the dose ingested and the relative absorption with therapeutic doses ranging from 0.5 to 1.5 g, suggesting the involvement of an active, saturable absorption process. Metformin is eliminated rapidly by the kidney and has a mean plasma elimination half-life after oral administration of between 4.0 and 8.7 h (approx. 6 h). The elimination is prolonged in patients with impairment of renal function and correlates with creatinine clearance. Therapeutic blood levels may be 0.5–1.0 mg/l in the fasting state and 1–2 mg/l after a meal. However, monitoring of blood levels may be useful only to confirm the diagnosis of lactic acidosis. Metformin has no effect in the absence of insulin, because the drug seems to act primarily by enhancing insulin action at postreceptor level. Metformin ameliorates hyperglycemia by improving peripheral sensitivity to insulin and reducing hepatic glucose production (via gluconeogenesis) as well as by limiting gastrointestinal glu-


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cose absorption. Metformin also increases glucose utilization by intestine, primarily via nonoxidative metabolism. This results in extra lactate prodution, which is taken up by the liver and used as a gluconeogenic substrate. Unlike sulfonylureas, it does not stimulate insulin secretion, nor does it aggravate hyperinsulinemia or cause hypoglycemia or weight gain (weight stabilizes or decreases mainly because of loss of adipose tissue). Its more prominent effect in type 2 diabetic patients is on postprandial hyperglycemia. In the UKPDS, it was noted that among patients allocated intensive blood-glucose control (aimed to reduce fasting plasma glucose to =6 mmol/l), metformin showed a greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint, all-cause mortality and stroke. Addition of metformin in sufonylurea-treated patients was associated with an increased risk of diabetes-related death compared with continued sulfonylurea alone, but this point was not supported by sufficient evidence. Moreover, epidemiological assessment in 4,416 patients did not show an increased risk in diabetes-related death in patients treated with a combination of sulfonylurea and metformin. Other Effects. Metformin, alone or added to a sulfonylurea (glyburide), besides its lowering effect on fasting plasma glucose and glycated hemoglobin, also reduces plasma total and LDL cholesterol and triglycerides. Metformin may exert other potential beneficial effects, such as weight loss (or minimal weight gain), improved blood flow in patients with peripheral vascular disease, reduction in tissue plasminogen activator inhibitor (tPAI-1) and fibrinogen. Metformin action on fibrinolysis and von Willebrand factor (vWF) was evaluated in the ‘Biguanides and the Prevention of the Risk of Obesity (BIGPRO)1’ trial; weight loss was the main factor associated with the decrease in PAI-1, in accordance with the recent demonstration of production of PAI-1 by adipocytes. Metformin had a significant lowering effect on two factors, tPA antigen and vWF, mainly secreted by the endothelial cells, which suggests an effect of the drug on the production or the metabolism of these two hemostatic proteins. Use in Type 1 Diabetic Patients. For its potentiation of insulin actions, metformin has been evaluated as an adjunct to insulin in type 1 diabetic patients. Although when metformin is added to insulin therapy the insulin requirement is likely to decrease, further studies on large populations and of long duration are required before the insulin+metformin therapy can be routinely recommended for type 1 diabetic patients. Side Effects. The most common side effects of metformin are mild, transient, gastrointestinal symptoms (diarrhea, nausea, anorexia, abdominal pain, metallic taste, in decreasing order) which are usually self-limiting, as well as malabsorption of vitamin B12 and folic acid (although reported

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cases of megaloblastic anemia are rare). Gastrointestinal side effects can be minimized by initiating metformin therapy at a low dose and gradually titrating upward, and by taking metformin with meals. Unlike phenformin, metformin can be used with a very low risk of lactic acidosis. The observed association between metformin and lactic acidosis may be coincidental rather than causal. Intravascular administration of iodinated contrast media to patients who are receiving metformin can result in lactic acidosis. However, this rare complication occurs only if the contrast medium causes renal failure. Therefore, metformin must be withheld after the administration of the contrast agent for 48 h, during which the contrast-induced renal failure becomes clinically apparent. If renal function is normal at 48 h, the metformin can be restarted. Concerning drug interactions, it should be noted that plasma levels of metformin may be reduced by fibers (guar gum) and a-glucosidase inhibitors, and increased by cimetidine (which decreases the elimination of metformin). Dose. In the UKPDS, metformin treatment was started with one 850-mg tablet per day. If normoglycemia was not obtained, the dose was increased to 850 mg twice daily and, if hyperglycemia still persisted, to 1,700 mg in the morning and 850 mg with the evening meal (maximum dose 2,550 mg). Conclusions. Metformin is actually an antihyperglycemic (rather than hypoglycemic) drug, which has shown some lipid-lowering effect and vasoprotective properties. It should be considered a first-line agent, particularly in obese and/or hyperlipidemic type 2 diabetic patients. Metformin will be most useful in managing patients with poorly controlled postprandial hyperglycemia, as its postprandial effect is much greater than that of the sulfonylureas. In contrast, sulfonylureas or insulin are more effective for managing patients with poorly controlled fasting hyperglycemia. In secondary sulfonylurea failure, combined metformin+sulfonylurea treatment significantly improves glycemic control beyond that achieved with either agent alone. Metformin-sulfonylurea also appears to be as effective as insulin or insulin plus sulfonylureas, suggesting that such combination therapy may obviate or substantially delay insulin therapy in type 2 diabetic patients (‘combined’ therapy is discussed in chapter VI on Overview of Diabetes Management: Combined Treatment and Therapeutic Additions).

Thiazolidinediones Thiazolidinediones (pioglitazone, troglitazone, rosiglitazone) reduce fasting hyperglycemia and insulinemia by improving insulin sensitivity in skeletal


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muscles, adipose tissue and hepatocytes, while normalizing a wide range of metabolic abnormalities associated with insulin resistance. Reported effects include: (a) decrease in plasma triglyceride, FFA and LDL cholesterol levels and increase in plasma HDL cholesterol; (b) increased expression of glucose transporters GLUT-1 and GLUT-4; (c) activation of glycolysis in hepatocytes; (d) antagonism towards some of the effects of TNFa; (e) decrease in blood pressure; (f ) inhibition of vascular smooth muscle cell proliferation and hypertrophy; (g) enhanced endothelium-dependent vasodilation, and (h) antioxidant action. Finally, although thiazolidinediones do not stimulate insulin secretion, they improve the secretory response of b-cells to insulin secretagogues. Rosiglitazone (a PPARc Agonist). Rosiglitazone, like other thiazolidinedione compounds, is a PPARc agonist, inasmuch as it potently and specifically stimulates peroxisome proliferator-activated receptors-c (PPARc) and sensitizes cells to insulin. Indeed, rosiglitazone is an antidiabetic agent which enhances sensitivity to insulin in the liver, adipose tissue and muscle, resulting in increased insulin-mediated glucose disposal. This compound, therefore, improves insulin resistance, which is a key underlying metabolic abnormality in most patients with type 2 diabetes. In contrast with troglitazone, rosiglitazone does not appear to be hepatotoxic, on the basis of clinical and in vitro studies, and does not induce cytochrome P450 3A4 metabolism. However, the drug is contraindicated in patients with history or signs/symptoms of liver diseases and its use requires monitoring of liver function tests. Moreover, rosiglitazone does not interact significantly with nifedipine, oral contraceptives, metformin, digoxin, ranitidine, or acarbose. In clinical trials, rosiglitazone 2–12 mg/day (as single daily dose or two divided daily doses) improved glycemic control in type 2 diabetic patients, as shown by decrease in fasting plasma glucose and glycated hemoglobin (HbA1c). Addition of rosiglitazone 2–8 mg/day to existing sulfonylurea, metformin or insulin therapy achieved reductions in fasting plasma glucose and HbA1c. Consistent with its mechanism of action, rosiglitazone appears to be associated with a low risk of hypoglycemia (=2% of patients receiving monotherapy) and did not increase the risk of alcohol-induced hypoglycemia.

Other Compounds The long-acting, nonsulfhydryl-containing ACE inhibitor, trandolapril, alone and in combination with the Ca2+-channel blocker, verapamil, can significantly improve whole-body glucose metabolism by acting on the insulin-

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sensitive skeletal muscle glucose transport system in obese Zucker rats. Data on the role of TNFa raise the possibility that pharmacological inhibition of this factor may provide a novel therapeutic target to treat patients with type 2 diabetes.

Suggested Reading American Diabetes Association: Consensus Development Conference on Insulin Resistance, Nov 5–6, 1997. Diabetes Care 1998;21:310–314. Bell PM, Hadden DR: Metformin. Endocrinol Metab Clin North Am 1997;26:523–537. Scheen AJ: Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996;30:359–371. Daniel JR, Hagmeyer KO: Metformin and insulin: Is there a role for combination therapy? Ann Pharmacother 1997;31:474–480. Davidson MB, Peters AL: An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 1997;102:99–110. DeFronzo RA, Bonadonna RC, Ferrannini E: Pathogenesis of NIDDM: A balanced overview. Diabetes Care 1992;15:318–368. Melchior WR, Jaber LA: Metformin: An antihyperglycemic agent for treatment of type II diabetes. Ann Pharmacother 1996;30:158–164. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865.



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Chapter IV

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Diet and Modification of Nutrient Absorption S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Diet Introduction In the treatment of diabetes mellitus, changes in lifestyle play a major role, in addition to treatment with insulin or oral glucose-lowering drugs. For most patients with type 2 diabetes, the changes in lifestyle (concerning diet and exercise) are the cornerstone of treatment whereas the pharmacologic intervention represents a supplementary treatment for those patients who do not respond adequately to lifestyle changes. Dietary caloric restriction ameliorates hyperinsulinemia and hyperglycemia in obese type 2 diabetics (and improves other metabolic parameters; see table 1) and reduces the incidence of type 2 diabetes in subjects at risk or with impaired glucose tolerance (IGT). Glucose tolerance and insulin sensitivity improve when normal body weight is achieved or approached. Indeed, even a 7–10% of weight loss is enough to improve insulin resistance in all obese type 2 diabetics. Nutritional needs are different in type 1 (lean) or type 2 (overweight or obese) diabetic patients. Diet education is crucial and requires the participation of the patient and its family in the planning-diet process and in the implementation of the adequate strategies to promote adherence to dietary intervention. Goals of dietary therapy in diabetes are to reach and maintain ideal body weight (IBW), to maintain fasting and postprandial glycemic levels as close as possible to normal and to achieve optimal blood lipid values, while providing adequate caloric intake as required for the various metabolic needs.

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Table 1. Effects of weight loss on altered parameters in obese type 2 diabetics

Insulin resistance B Hyperglycemia B Hypertriglyceridemia B Total hypercholesterolemia B LDL cholesterol B HDL cholesterol C Hypertension B

Modern recommended diet for diabetes is relatively high in complex carbohydrates (55–60% of total calories) and fibers, low in fats (25–30%) especially saturated (=10%, to reduce dyslipidemia and atherosclerosis associated to diabetes) and limited, but adequate, in proteins (15%).

Body Weight and Fat Distribution Increase in body weight (related to height) or frank obesity are highly relevant to the pathogenesis of type 2 diabetes. The ‘ideal’ body weight (actually the weight associated with the lowest mortality) for each inch of height can be derived from the 1983 Metropolitan Life Insurance Weights for Heights tables, referring to 4.2 million subjects aged 20–59. For people over 55, the tables of median weights derived from the data of the National Health and Nutrition Examination Surveys (NHANES) may also be used. A commonly used parameter relating weight to height is the body mass index (BMI), which is calculated as follows: BMI>weight (kg)/height (m)2. In the clinical setting, a BMI from 20 to 25 can be regarded as ‘normal’ while a BMI ?27 can be regarded as indicative of overweight. In some studies, the following values have been suggested for the BMI: =23.9>normal value for women; =25> normal value for men; 23.9–28.6 (female) and 25–30 (male)>overweight; ?28.6 (female) or ?30 (male)>obesity. In 1995, the WHO established the following BMI values: normal>18.5–24.9; overweight, 1st degree>25.0–29.9; overweight, 2nd degree (or obesity)>30.0–39.9; overweight, 3rd degree (or severe obesity) q40. It should be noted that the BMI associated with the lowest mortality increases with age, ranging from =20 at age 20 to about 28 at age 70. It should be noted that from the above values of BMI it is possible to calculate the corresponding weight values through the formula: weight (kg)>BMI¶height (m)2. Assessment of adipose tissue distribution is of paramount importance to distinguish between visceral (or central or abdominal

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or android) obesity and subcutaneous (or gynoid) obesity. A largely used parameter is the the waist-to-hip ratio (WHR), i.e. the ratio between the circumference at the waist and that at hip level. The cut-off value distinguishing normal from abnormal WHR has not yet been definitely established. In some studies, values of WHR ?0.81 for female and ?0.92 for male subjects were considered indicative of visceral/android obesity whereas lower WHR values were regarded as indicative of subcutaneous/gynoid obesity. The American Heart Association has reported that a WHR ?0.80 should be used to indicate increased risk of cardiovascular disease in women. Other recent data suggest an upward shift in the critical threshold for WHR to q0.90, at which point there is an elevation in cardiovascular disease risk factors. It has also been shown that the simple waist circumference is a good index of central (visceral) obesity, as is also the sagittal diameter. The values of waist circumference indicating increased visceral fat and cardiovascular risk were found to be ?94 cm in men and ?80 cm in women. Recently, it has been reported that, while a waist circumference q96.5 cm is associated with high cardiovascular risk, even a waist circumference q76.2 cm entails significant risk. Interestingly, threshold values of waist girth corresponding to critical amounts of visceral adipose tissue do not appear to be influenced by sex or by the degree of obesity. It has also been estimated that a waist girth of approximately 95 cm in both sexes, WHR values of 0.94 in men and of 0.88 in women, and sagittal diameters of 22.8 cm in men and 25.2 cm in women correspond to a critical amount of visceral adipose tissue, equal to a fat area of 130 cm2. The amount of intra-abdominal (visceral) fat may be precisely measured with computed tomography (CT), which however is an expensive procedure. Echography is also being used to quantify the fat tissue and its distribution.

Total Caloric Requirement The caloric requirement of diabetic patients is similar to that of normal subjects and changes with age, sex and occupational daily work or physical activity (i.e. patients engaged in a heavy activity require a larger caloric intake). Other factors may influence dietary regimen, as the type of diabetes and the associated diseases. In lean adult diabetic patients, caloric intake should maintain a normal weight, while in obese diabetic patients (especially with upper body fat distribution) a caloric restriction is required to achieve a desirable weight. Noticeably, dietary restriction may improve metabolic control even before weight loss is attained.

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Sedentary normal patients need approximately 30 cal/kg IBW/day while active normal patients need approximately 35–40 cal/kg/day. Overweight sedentary patients need 20–25 cal/kg/day and active obese patients need 30–35 cal/kg/day, while underweight patients need 35 cal/kg/day if sedentary and 40–50 cal/kg/day if active. In elderly sedentary diabetic patients, 20 cal/kg/day are usually required (after 50 years of age approximately 10% less calories for each decade is required). A more accurate assessment of the caloric needs may be achieved by using appropriate formulas to calculate the rest metabolic rate (RMR), such as those of Harris & Benedict which are based on weight, height, age and sex. Since subjects of the same weight but of different height have similar RMR, formulas may be simplified by considering only weight, age and sex. RMR should be increased by 30, 50 or 70% for low, medium or high levels of physical activity. Table 2 shows the caloric requirement according sex and age for selected weights and activity levels, based on similar formulas. In diabetic children the caloric needs depend on the rate of growth and activity pattern. Children 4–6 years old require 90 cal/kg/day and children 7–10 years old require 80 cal/kg/day. It is important to allow an adequate caloric intake in juvenile diabetes. Caloric requirement in children may also be calculated by adding to the baseline value of 1,000 cal/day the amount of 100–125 cal for every year of age up to 12 years. Youngsters should consume 3 meals daily with 2 or 3 snacks (eaten at the same time each day) to minimize glycemic fluctuations and the risk of hypoglycemic episodes. After the caloric content and the composition of the diet are established, the prescription of a diet was in the past made by utilizing the data in the Exchange Lists for Meal Planning published by the American Diabetes Association. A more useful approach might be to use the precalculated diets (of various caloric content) prepared by several diabetes associations or other authoritative sources. However, it is now recognized that the diet should be individualized and prepared by taking into account the eating habits and other lifestyle factors. It is clinically relevant that 7–35% of adolescent females with type 1 diabetes may have an eating disorder, such as anorexia or bulima nervosa.

Dietary Components Dietary Carbohydrate Carbohydrates are the most important source of energy and provide about 4 cal/g. The carbohydrate intake of diabetic patients should be equal to that of nondiabetic subjects. A dietary carbohydrate content of about 50–60% of total energy intake seems adequate in diabetic patients.


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Table 2. Caloric needs according to age, sex, weight1 and physical activity Sex and age group

Weight kg

Men 18–30 years old

Average 31–60 years old

Average Women 18–30 years old

Average 31–60 years old

Average

Physical activity rest rest low low medium kcal/kg kcal/day kcal/kg kcal/day kcal/kg

medium high high kcal/day kcal/kg kcal/day

68 72 76 80 74

25 25 24 24 24.5

1,723 1,784 1,844 1,905 1,814

33 32 32 31 31.9

2,240 2,319 2,397 2,476 2,358

38 37 36 36 36.8

2,585 2,675 2,766 2,857 2,721

43 42 41 40 41.7

2,929 3,032 3,135 3,238 3,084

68 72 76 80 74

25 24 23 23 23.5

1,667 1,713 1,760 1,806 1,736

32 31 30 29 30.6

2,167 2,227 2,288 2,348 2,257

37 36 35 34 35.3

2,500 2,570 2,639 2,709 2,605

42 40 39 38 40.0

2,833 2,912 2,991 3,070 2,952

56 60 64 68 62

24 23 23 22 22.8

1,323 1,383 1,442 1,502 1,413

31 30 29 29 29.7

1,720 1,798 1,875 1,953 1,836

35 35 34 33 34.2

1,985 2,074 2,164 2,253 2,119

40 39 38 38 38.8

2,249 2,351 2,452 2,553 2,401

56 60 64 68 62

23 22 21 21 22.0

1,309 1,342 1,374 1,407 1,358

30 29 28 27 28.6

1,701 1,744 1,787 1,829 1,765

35 34 32 31 33.0

1,963 2,012 2,062 2,111 2,037

40 38 37 35 37.4

2,225 2,281 2,336 2,392 2,309

1

Caloric needs at rest (RMR) per day were calculated according to the following formulas (as reported by G. Bray): for 18- to 30-year-old men: (0.0630¶kg weight+2.8957)¶240; for 31- to 60-year-old men: (0.0484¶kg weight+3.6534)¶240; for 18- to 30-year-old women: (0.0621¶kg weight+2.0357)¶240; for 31- to 60-year-old women: (0.0342¶kg weight+3.5377)¶240. RMR was then multiplied by 1.3, 1.5 or 1.7 for low, medium or high physical activity, respectively.

Carbohydrates are available as complex or simple sugars. In diabetic patients, complex carbohydrates or polysaccharides should be preferred. Complex carbohydrates include: starches (present in large amounts in rice, cereals, potatoes, pulses and vegetable roots), dextrins (derived from hydrolyzed starch), glycogen (contained in liver and muscle), cellulose or pectins (indigest-

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Table 3. Glycemic index of some foods Bread Rice Potatoes Bananas Spaghetti Oranges

100% 83% 81% 79% 66% 66%

Beans Grapes Apples Milk Pears Lentils

65% 62% 53% 49% 47% 43%

ible complex carbohydrates contained in plant foods). In diabetics, simple carbohydrates should be restricted. They include monosaccharides (glucose present in oranges and carrots, fructose present in honey and ripe fruits, and galactose derived from hydrolyzed lactose) and disaccharides (sucrose present in beetroot and sugar cane, lactose present in milk, and maltose derived from hydrolyzed starch). The formerly claimed diabetogenic effect of sucrose overconsumption has not been confirmed by epidemiological or experimental studies. However, in diabetic patients, sucrose-rich foods cause a rapid rise in glycemic values, which can be prevented by consuming these foods as part of a mixed meal. The recommended disaccharide (sucrose plus other glucosecontaining disaccharides) consumption by diabetic people should not exceed 5–10% of the total caloric intake. Sucrose addition as sweetener should not exceed 20 g/day. Fructose is a natural monosaccharide, used as a sweetener. It is converted to glucose (and stored as glycogen) or triglyceride in liver. In diabetics with insulin deficiency and impaired hepatic glycogen synthesis, fructose-derived glucose contributes to the hyperglycemia. Thus, the safety of fructose use in diabetes is a debated topic. Starches are hydrolyzed to dextrins, then to maltose and finally to glucose (through the effect of gastric acid and intestinal enzymes). They are useful in the diabetic diet because they are slowly digested and absorbed, inducing lower increments of the glycemic and insulinemic values than equivalent amounts of glucose or simple sugars. It is well established that equimolar amounts of carbohydrate in different foods induce different glycemic postprandial excursions. Jenkins et al. [1981] have elaborated a ‘glycemic index’, representing the incremental area under 2 h glycemic curve of food divided by the corresponding area under 2 h glycemic curve after ingestion of a portion of white bread containing equivalent amounts of carbohydrates, multiplied by 100 (table 3). Reference can also be made to the glycemic response after glucose ingestion, in which instance the glycemic index for glucose is 100. Foods containing simple sugars have a high glycemic index, raising glycemia and insulinemia faster and to a greater extent, and therefore are contraindicated in diabetic patients. However, several factors can influence the food glycemic response, including: (a) type of diabetes, age,


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sex, body weight, physical activity and race; (b) physical form of starches, size of food particles, food processing and preparation, fiber or fat or protein content of food, different digestion or absorption or transit of different starchor sugar-containing foods, etc. Dietary Fat Fats are an important source of energy, providing about 9 cal/g, and difference in the amount and type of dietary fat can have relevant metabolic effects. In patients with IGT or type 2 diabetes or decompensated type 1 diabetes, elevated plasma levels of triglycerides and cholesterol frequently occur. Both hypertriglyceridemia and hypercholesterolemia respond in part to diet alterations. The recommended fat intake is p30% of total calories (=10% of saturated fats, 6–8% of polyunsaturated fats and 14–12% of monounsaturated fats given as olive oil). Low-fat diets are often high in carbohydrate (being the proportion of proteins relatively constant), which may favor hypertriglyceridemia. This effect may be attenuated by supplementation with fibers. Saturated fats (which are solid at room temperature) are most often from animal source (milk, butter, cheese, bacon fat, fatty meat, etc.), but they are also contained in high concentrations in coconut and palm oils. Diets high in saturated fat are atherogenic (increasing total and LDL cholesterol levels) and favor insulin resistance; thus, a diet restricted in saturated fats is recommended. Unsaturated fats (which are liquid at room temperature) derive from vegetable source and include monounsaturated and polyunsaturated fats. A diet high in monounsaturated fatty acids or MUFA (most often assumed as olive oil, as it occurs with the Mediterranean diet) does not increase LDL levels, may improve insulin sensitivity, glycemic control and HDL cholesterol levels, and decreases plasma triglycerides. For this reason, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) set free the intake of monounsaturated fat in diabetic patients. On the contrary, a diet high in polyunsaturated fatty acids or PUFA (such as corn, sunflower and safflower oils) reduces total and LDL cholesterol but decreases HDL cholesterol as well; moreover, some data from the literature would suggest that they may promote carcinogenesis in experimental animals. The intake of cholesterol should be restricted to =300 mg daily, avoiding cholesterol-rich foods (table 4), which can produce a 15–20% reduction of plasma cholesterol level. Excessive cholesterol intake causes increase in total plasma cholesterol and LDL cholesterol, which can be reduced by increasing the polyunsaturated/saturated fat ratio (which should be kept at ?0.8). The polyunsaturated fatty acids of the omega-3 class (eicosapentaenoic and docosahexaenoic acids), which can be formed from a-linolenic acid

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Table 4. Cholesterol content of some foods (mg/100 g) Brain Egg yolk Lamb kidney Chicken liver Caviar Butter

2,000 1,480 804 746 350 250

Oysters Lobster Cream Cheese, cheddar Whole milk Egg white

200 150 133 100 34 0

(through elongation and desaturation), are contained in fish oils and are useful to reduce the coronary risk of diabetic patients (decreasing VLDL production, lowering arterial blood pressure, reducing platelet aggregation and prolonging bleeding time). This explains the low prevalence of coronary heart disease in the Greenland Eskimos (consuming 5–10 g of fish oil fatty acids daily for a lifetime) and in the Japanese fish eaters of coastal villages. A dietary supplementation with fish or fish oil should, therefore, be recommended. It would be advisable to replace in 2–3 meals a week the red meat with fish. However, three considerations speak against an excessive intake of fish or fish oil: (a) fishes of coastal waters and lakes accumulate a large quantity of mercury and chlorinated hydrocarbons; (b) in some type 2 diabetic patients, 3-omega fatty acids may deteriorate glycemia (both increasing hepatic glucose production and impairing insulin secretion), and (c) in patients with hypercholesterolemia but without hypertriglyceridemia the metabolic effects of fish oil are uncertain. Recently, new fat substitutes were proposed for use in the diet of diabetic patients. One of these products is named Olestra and is made from sucrose and long-chain fatty acids, is heat-stable, tastes like vegetable oil, promotes cholesterol excretion and is calorie-free being not metabolized or absorbed. Another fat substitute is named Simpless and is made from egg white or whey protein of milk (using a process of microparticulation which confers a taste of fat), has a low-calorie content, and is useful to make ice-cream, yogurt, margarine, cheeses, etc. Dietary Protein Proteins are formed by amino acids and provide about 4 cal/g of energy. Some amino acids cannot be synthesized by humans and must be introduced with diet (essential amino acids). The animal proteins (contained in meat, chicken, fish, egg, milk, etc.) are of high biological value, containing adequate amount of essential amino acids, while vegetable proteins (peas, beans, dry fruits, cereals, etc.) are of low biological value, laking some essential amino acids. Leucine and arginine have important biologic effects, stimulating insulin


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secretion, while other amino acids are gluconeogenic and ketogenic. The amount of proteins that should be recommended to diabetic patients depends upon several factors, such as the patient age, the nutritional status (undernutrition or malnutrition) and particular situations (growing, pregnancy, lactation, debilitating diseases, nephropathy, uremia, hepatic diseases, etc.). The role of dietary protein in the development and progression of diabetic nephropathy is debated while it is clearly defined that a moderately low protein diet is the best approach for treating renal disease of diabetic patients (see chapter on Diabetic Nephropathy). The recommended amount of proteins in diabetic diet is of 12–20% of total calories. In diabetic subjects a high-protein diet can increase renal blood flow, glomerular filtration rate and intraglomerular pressure, accelerating glomerulosclerosis to end-stage renal failure (Brenner’s hypothesis). It is useful to substitute, at least in part, vegetable proteins for animal proteins, even if proteins from animal source do not seem to significantly increase kidney workload. In subclinical or incipient stages of diabetic nephropathy, glycemic control and low protein intake (0.8 g/kg IBW/ day) may reduce renal blood flow, restore normal glomerular hemodynamics, decrease proteinuria and delay the progression of nephropathy. In overt diabetic nephropathy with albumin excretion, the recommended protein restriction should be from 0.6 to 0.8 g/kg/day. In cases of protein restriction, essential amino acids should be supplemented. To maintain energy balance, a low protein diet must be high in carbohydrates and fats and may exacerbate hyperglycemia, hypertriglyceridemia or hyperinsulinemia, increasing total and LDL cholesterol and decreasing HDL cholesterol. Moreover, in diabetic patients a low protein dietary content may favor a negative nitrogen balance and muscle wasting. Dietary Fibers In normal subjects and type 2 diabetic patients, several studies demonstrated an improvement of glucose tolerance and a reduction of insulin secretion when a diet high in fiber was consumed. In type 1 diabetics, high-fiber diet was found to decrease glycosuria, as well as basal and postprandial glycemic levels. Moreover, high-fıber intake may improve other metabolic parameters, and may also exert a preventive effect on cancer of bowel and diverticular disease (diseases favored by the modern tendency to consume lowfiber, refined foods). Dietary fibers are heterogeneous and consist of several complex polysaccharides resistant to gastrointestinal digestive enzymes (even if certain fibers are metabolized in the colon). Fibers can be water soluble or insoluble and their effects are variable according to the different biochemicalphysiological characteristics. Celluloses, hemicelluloses and lignins bind water and cations and are insoluble (wheat products and bran) whereas pectins,

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Table 5. Foods naturally rich in fibers Legumes

Beans, peas, chickpeas, lentils

Vegetables

Broccoli, artichokes, zucchini, carrots, eggplants, string beans, squash, potatoes, tomatoes, celery, cabbage, onions, beets, fennels, turnips, radishes, asparagus, cucumbers, cauliflower, mushrooms

Fruits

Apples, blackberries, pears, strawberries, oranges, plums, bananas, grapefruit, pineapples, peaches, cherries, apricots, kiwis, mandarins

Cereals

Bran (100%), bread (rye), bread (whole-grain wheat), rice, wheat flour (whole grain)

gums and mucilages form gels and are soluble (oats, fruits and legumes). The foods naturally rich in fibers are legumes, roots, tubers, whole-grain cereals, fruits and green leafy vegetables (table 5). Usually, the soluble fibers (especially those with high viscosity) exert useful metabolic effects, whereas insoluble fibers contribute to increase fecal bulk, promote movements of intestinal content, being useful in constipation (which may also result from autonomic diabetic neuropathy). The physiological effects of fibers are influenced by osmolality or pH, mixture of fibers and foods, water retention, fermentation by bacteria, etc. Soluble fibers would exert their beneficial effects on carbohydrate and lipid metabolism through several mechanisms, which include: (a) satiating effect; (b) delayed gastric emptying time; (c) decreased release of gut hormones, including intestinal insulin secretagogues (as GIP); (d) delayed small intestine transit time and altered colonic emptying time; (e) binding of bile acids, with impaired intestinal absorption of cholesterol; (f ) formation of gels that sequester or hide nutrients (carbohydrates, fats, cholesterol, etc.), providing a physical barrier that separates complex carbohydrates from digestive enzymes, with reduced digestion and absorption in small intestine; (g) increase of fecal bulk with accelerated intestinal transit, which may reduce absorption of nutrients; (h) fermentation by the bacteria in the colon to gases and short-chain fatty acids, which would suppress neoglucogenesis, and (i) improved peripheral insulin sensitivity and increased insulin receptor binding. It is interesting that fibers have the best effects when naturally contained in aliments while they have poorer effects when added as pharmaceutical products to dietary foods. Diets useful to improve both fasting and postprandial hyperglycemia in diabetic patients have been suggested, which are rich in fibers naturally contained in foods. These diets are very rich in carbohydrates (up to 70%) and fibers (up to 35 g/day/1,000 kcal, both in soluble


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and insoluble forms). In these fiber-rich diets, fibers would mitigate the deleterious effect of the high carbohydrate content on glucose metabolism, and would reduce total or LDL cholesterol and triglycerides (only in diabetics), while lowering blood pressure and favoring weight loss in obese patients. In hypocaloric diets, the usually recommended fiber supplementation is in the amount of 25 g/1,000 kcal (associated with high water assumption to induce fiber swelling). High-fiber diets can cause (especially in the first 7–10 days) cramping, abdominal discomfort, flatulence and diarrhea. These diets may also impair absorption of minerals and vitamins if used for a long time (in which instance, supplementation of calcium, trace elements and vitamins may be required). They may also increase the risk of bezoar formation, especially when a diet high in fibers is contraindicated (patients with gastrointestinal dysfunction, gastroparesis or altered absorption from pancreatic enzyme deficiency). Large amounts of dietary fibers may not be well tolerated by children, pregnant diabetic women and elderly subjects. Alcohol and Other Nutrients Alcohol provides about 7 cal/g, is not a food but is another source of energy that should be considered in a dietary plan. Interestingly, in women a decreased risk (50%) of developing diabetes with increasing alcohol intake was found and this effect was probably related to lower BMI linked with alcohol consumption. Allowed intake should not exceed 10 g/day. Excessive alcohol intake should be avoided in diabetic patients, because it inhibits gluconeogenesis and can favor hypoglycemic episodes in subjects treated with insulin or drugs. In hypertriglyceridemic patients, alcohol may exacerbate dyslipidemia and liver steatosis. Diabetic patients may also suffer from associated diseases which require special modified diets. In the presence of congestive heart failure, hypertension and kidney disease, dietary sodium should be restricted. The sodium restriction may range from 500 to 1,000 mg/day (maximum intake =3 g/day), although the use of diuretics may reduce the need for a severe sodium restriction, which makes foods less palatable and may provocate hypotension and fluid or electrolyte disorders. Sweeteners Sweeteners can be distinguished into caloric (or natural) sweeteners and noncaloric (or artificial) sweeteners (table 6). In both type 1 and 2 diabetic patients, the classical sweetener, sucrose, can be allowed in the maximum amount of 20 g/day, especially if associated to a mixed meal, because it does not deteriorate metabolic control. An excessive sucrose intake should be avoided,

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Table 6. Sweeteners for diabetic patients Caloric or natural sweeteners Sucrose Fructose Sugar alcohols (sorbitol, mannitol, xylitol) Noncaloric or artificial sweeteners Saccharin Cyclamates Aspartame

especially in hypertriglyceridemic or obese or severely decompensated diabetic subjects. Sucrose is the most cariogenic of the nutritive sweeteners, and caries is a problem in people with diabetes. Alternative sweeteners have been proposed (sometimes as combinations of caloric and noncaloric sweeteners). An ideal sucrose substitute for diabetic patients should taste good and not induce hyperglycemia or elevation of plasma lipids; it should also contain few calories, have an adequate stability and consistency and be of low cost. Fructose is naturally found in honey and fruits and is 1–1.8 times as sweet as sucrose. Its caloric content is about 4 cal/g (equal to that of sucrose) but fewer calories are required to provide the same sweetness. The ingested fructose is phosphorylated to fructose-1-P in the liver, independently by insulin, and after splitting by aldolase it enters the glycolytic pathway and may be converted into glucose or triglyceride. The fructose intake does not cause side effects unless it exceeds 75 g (0.5 g/kg/day in children). Large oral amounts (?50 g) may cause diarrhea. In doses up to 30–35 g it does not impair glycemic control in well-compensated diabetics while in decompensated patients it may aggravate hyperglycemia and hypertriglyceridemia. Xylitol is a sugar alcohol derived from xylose, which is naturally present in fruits and vegetables. It has a sweetness equivalent to that of fructose, produces about 4 cal/g, is slowly absorbed and does not exacerbate glycemia or triglyceridemia (although it may induce a transient increase of uric acid synthesis). In excessive doses it may cause osmotic diarrhea. Sorbitol (as well as mannitol) is a sugar alcohol, obtained by reduction of glucose or fructose, which contains about 4 cal/g. It is slowly absorbed, yet it may increase glycemia in poorly compensated diabetic patients. Large amounts (30–50 g/day) may induce osmotic diarrhea. Saccharin is the most used artificial sweetener with no caloric content. It is not metabolized and is excreted unchanged in urine. In high doses, saccharin was reported to induce malignancy of the urinary bladder in experimental animals, but studies in diabetic subjects indicate no relationship between sac-


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charin and bladder cancer. The FAO/WHO suggests a dose of 0–2.5 lg/kg in adults. Cyclamates are 30 times as sweet as sucrose and have no caloric value; in very high doses (2,500 mg/kg/day) they are reported to induce tumors of the urinary bladder in rats. Although no evidence of malignancy exists in humans, cyclamates were banned from the US market; however, they are still available outside the USA. Aspartame is a nutritive sweetener consisting of a synthetic dipeptide. Compared to sucrose, it has the same caloric content (about 4 cal/g) but is 180–200 times more sweet, so that negligible calories are required to provide the same sweetness. It has a good taste, but it is instable in liquid solution and during heating, and is 4–5 times as expensive as saccharin. Some side effects were reported such as phenylketonuria in predisposed subjects, neuroendocrine disorders and brain tumors. These data were not confirmed by FDA, that has set 50 lg/kg/day as a safe daily aspartame intake. The alternative sweeteners with no or low caloric value are certainly useful in the management of diabetic and obese patients that find pleasantness in sweet foods.

Hypocaloric Diet in Overweight Type 2 Diabetes In type 2 diabetes, caloric restriction should be correlated with the degree of overweight or obesity, and the calculation of appropriate calories depends upon the body weight and the physical activity of the patient. In slightly overweight patients, a 1,600–1,800 kcal/day diet may be appropriate. In the cases with more marked overweight, a hypocaloric diet of about 1,000–1,500 kcal/day should be prescribed. In these diets, the protein content should not be =0.8 g/kg IBW. With weight loss, in most obese diabetic patients the carbohydrate metabolism will improve, so that insulin or hypoglycemic drugs may be reduced or withdrawn. Even a modest weight loss may be associated with significant metabolic improvement, although marked individual variations occur. This improvement primarily involves fasting glycemia and is correlated with decreased hepatic glucose output. These favorable effects may have a positive impact on the overweight diabetic patient with regard to the compliance to the hypocaloric diet. The very low calorie diet (VLCD: 800–500 kcal/day, mostly derived from high-quality proteins, with vitamin and mineral supplementation) should be avoided in diabetic patients for the risk of severe arrhythmias or coronary symptoms. Moreover, a long-term evaluation of VLCD (compared to conventional diets) has demonstrated no significant difference on weight loss. A VLCD should be limited to type 2 diabetic patients who are 50% or more

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over IBW and who do not respond to conventional balanced diets, excluding those with recent myocardial infarction, hepatic disease, renal failure or cerebrovascular disease. Monitoring of electrocardiographic changes, urea or creatinine level and electrolyte disorder is required.

Diet and Exercise Exercise is a relevant component in a program of weight loss in diabetic patients. It improves glucose tolerance, lowers glycemia, increases peripheral insulin sensitivity and reduces risk factors for coronary heart disease (ameliorating hypertension and blood lipid profile). The combination of diet plus exercise is more effective than diet alone or exercise alone in producing longterm weight loss, in maintaining the weight loss over time and in reducing the dose of hypoglycemic drugs. The recommended exercise (walking or stationary bicycle riding) should be of low or moderate intensity but of long duration, and is especially useful in adult or older obese type 2 diabetic subjects. The exercise should be performed at least every 2–3 days for optimum effect (examples: stationary bicycle riding or brisk walking for 30 min/day, or active swimming for 1 h 3 times/week). Because exercise may increase the risk of acute or delayed hypoglycemia, a prospective reduction in insulin dose for regular exercise should be used as well as a supplementary snack of about 40 g of carbohydrates. In decompensated diabetic patients with insulin deficiency, exercise is contraindicated (especially if prolonged, severe or unusual) raising glycemia and ketone levels. Alcohol may exacerbate the risk of hypoglycemia after exercise. Diabetic patients should be encouraged to increase their physical activity gradually, with increments of the activities within their daily lives (walking to work, using stairs rather than elevators, etc.). However, the effects of exercise on the caloric balance (and therefore on weight loss) may be less than expected for several reasons. In fact, from the energy lost during exercise, those calories should be subtracted that the patient would have lost with his usual activity. Moreover, often the exercise stimulates the appetite, leading to enhanced caloric assumption. Finally, in some tense individuals, exercise may induce muscular relaxation, which means decreased isometric muscular work.

Conclusion In conclusion, the reduction of the caloric intake in obese people may have a relevant effect on the frequency of type 2 diabetes. On the other hand, a proper nutritional management of obese diabetic patients is the most


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important factor of treatment (even if often patients are unable to lose weight or to maintain the reduced weight). A professional consultation with the physician or the dietician is recommended (especially for new patients) at the beginning of diet and then at regular intervals to promote the adherence to dieting and to verify metabolic control of diabetes and weight loss. Dietary adherence is a serious problem in both type 1 and, especially, type 2 diabetic patients. To improve compliance to diet, some strategies were recommended: (a) a meal plan (adequate to the patient’s lifestyle and to the stage of the disease) that involves long-term changes of eating and nutritional habits; periodical reviews of meal plan are needed; (b) the education, which can improve motivation and dietary adherence providing the patient with useful information in an acceptable form to manage effectively nutrition and exercise; (c) a strong feeling between physician and patient (and his relatives for young people), and (d) an interaction afforded by group sessions, in which diabetic patients can exchange experiences and information, providing solutions and behavioral changes through peer example.

Modification of Nutrient Absorption Agents capable of modifying the absorption of complex carbohydrates or lipids, such as a-glucosidase inhibitors and Orlistat, will be discussed in Chapter VI (Overview of Diabetes Management).

Suggested Reading American Diabetes Association: Nutritional principles for the improvement of diabetes and related complications. Diabetes Care 1994;17:490–518. American Diabetes Association: Clinical practice recommendations 1997. Diabetes Care 1997;20(suppl 1): 1–70. Diabetes and Nutrition Study Group of the EASD: Nutritional recommendations for individuals with diabetes mellitus. Diabetes Nutr Metab 1995;8:1–5. Han TS, van Leer EM, Seidell JC, Lean ME: Waist circumference as a screening tool for cardiovascular risk factors: Evaluation of receiver operating characteristics (ROC). Obes Res 1996;4:533–547. International Diabetes Federation (IDF), 1998–1999 European Diabetes Police Group: A Desktop Guide to Type 2 (Non-Insulin-Dependent) Diabetes mellitus. Brussels, IDF, 1999. Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, et al: Glycemic index of foods: A physiological basis for carbohydrate exchange. Am J Clin Nutr 1981;34:362–366. Lemieux S, Prud’homme D, Bouchard C, Tremblay A, Despres JP: A single threshold value of waist girth identifies normal-weight and overweight subjects with excess visceral adipose tissue. Am J Clin Nutr 1996;64:685–693. Perry AC, Miller PC, Allison MD, Jackson ML, Applegate EB: Clinical predictability of the waist-tohip ratio in assessment of cardiovascular disease risk factors in overweight, premenopausal women. Am J Clin Nutr 1998;68:1022–1027.

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Rexrode KM, Carey VJ, Hennekens CH, Walters EE, Colditz GA, Stampfer MJ, Willett WC, Manson JE: Abdominal adiposity and coronary heart disease in women. JAMA 1998;280:1843–1848. Vinik A, Wing RR: Nutritional management of the person with diabetes; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and Practice, ed 4. Amsterdam, Elsevier, 1990, pp 464–496. WHO Expert Committee: Physical Status: The use and interpretation of anthropometry. WHO Tech Rep Ser No 854. Geneva, WHO, 1995.

S. Iannello, Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, I–95123 Catania (Italy) Tel. +39 095 330981, Fax +39 095 310899, E-Mail [email protected]


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Chapter V

............................

Insulin Treatment in Type 1 and Type 2 Diabetes: Practical Goals and Algorithms F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Introduction In type 1 diabetes, insulin therapy is focused on the replacement of insulin secretion, even if lifestyle changes are required to optimize insulin treatment. In type 2 diabetes, insulin treatment may be required when diet and oral therapy do not suffice. A variety of highly purified preparations of human insulin (the only form of insulin today sold in industrialized countries) are commercially available, differing in time of onset and duration of action. These pure human insulins result in very few problems linked to insulin antigenicity, because human insulins are less antigenic than porcine and much less antigenic than bovine insulins. The production of human insulins by recombinant DNA technology has made possible a limitless use of different insulin preparations, thus solving the previous problem of a limited supply of animal pancreases for the large demand of insulins. The most important indications for insulin treatment are listed in table 1.

Types of Insulins Insulin is formed by two peptide chains, the A and B chains (consisting of 21 and 30 amino acids, respectively), joined by disulfide bridges. Different kinds of insulin are available for clinical use, which differ according to the species of origin, the degree of purity and the duration of action.

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Table 1. Indications for insulin treatment Type 1 diabetes Ketoacidosis or ketoacidotic coma Hyperosmolar coma Diabetic pregnancy Acute diabetes decompensation for: Severe illness or fever Infections or sepsis Stress or steroid treatment Injury or surgery

Diabetic vascular complications Liver diseases in diabetic patients Renal failure in diabetic patients Secondary failure with oral hypoglycemic drugs in type 2 diabetes

Species: Bovine insulin differs from human insulin because it contains alanine, valine and alanine at the sites A-8, A-10 and B-30, respectively, whereas human insulin contains threonine, isoleucine and threonine at the same sites. Porcine insulin is more similar to human insulin inasmuch as it has the same amino acids as bovine insulin at positions A-8 and B-30 but the same amino acid as human insulin at position A-10. Human insulin can be obtained by modification of animal (pork) insulin (human semisynthetic insulin) or can be synthesized by the recombinant DNA technique. Human insulin is today the type of insulin most used in many countries. Human insulin (especially the long-acting preparations – see below) is more rapidly absorbed and has a quicker and shorter action than the porcine insulins, perhaps because it is more soluble in subcutaneous tissues. Some patients may have less awareness of hypoglycemia with human insulins than with animal insulins. Purity: In the past years, conventional insulin preparations contained a significant amount (10,000 parts per million (ppm)) of impurities (proinsulin and proinsulin-like compounds, insulin dimers, glucagon, somatostatin, VIP, PP, etc). Impurity content was much less in ‘single peak’ (monocomponent) insulins (=50 ppm) and even lower in purified insulins (1–10 ppm). Today, in most countries, only very pure human insulin prepared by the recombinant DNA technique is used. Duration of Action: Three types of insulin are available which differ in the duration of action: (a) the rapid-acting, (b) the intermediate-acting and (c) the long-acting insulin. (a) The rapid-acting insulin preparations include the regular insulin as well as the semilente insulin which is a suspension of insulin and zinc in acetate buffer (with formation of zinc-insulin crystals). (b) The intermediate-acting insulins comprise the lente insulin, which is a 30:70% mixture of semilente and ultralente (see later) insulin as well as the

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Neutral Protamine Hagedorn (NPH) insulin, obtained by adding the protein protamine to insulin and adjusting the pH. (c) The long-acting insulin preparations include the ultralente insulin, obtained by modifying, during the preparation, the pH of a mixture of zinc and insulin to produce larger zinc-insulin crystals (the larger the crystals, the slower the release of the injected insulin) as well as the protamine-zinc insulin obtained by adding also protamine and adjusting the pH. After subcutaneous injection, regular insulin presents a rapid onset of action (0.5–1 h), an early peak of activity (2–4 h) and a duration of action of 4–6 h. Thus, rapid-acting insulin, beginning to act in about 30 min, should be given 20–30 min (perhaps 45 min) before a meal to optimize synchronization of postprandial glycemia and circulating insulin levels. It is effective in blunting elevations in glucose following meals and for rapid adjustments in insulin dosage, but the pharmacokinetics of rapid-acting insulins entails that a definite time interval is observed between insulin injection and eating. A better synchrony between insulin peaks and meal absorption after injection of rapid-acting insulin is observed with human insulin, which acts more rapidly after injection and exerts shorter effects compared to previously used animal insulins. Intermediate-acting NPH insulin presents a delayed onset of action (3–4 h), a delayed peak of activity (8–12 h) and a duration of action of 20–24 h; similar activity is possessed by the lente insulin. The NPH and lente intermediate-acting insulins have the same, long time-course of action, which is useful to provide the basal level of insulin through the 24 h when given twice per day. Intermediate-acting human insulin produces earlier peaks, that may cause hypoglycemic events during sleep and fails to maintain an adequate effect for a full 24-hour period. Ultralente (long-acting) insulins present a slow onset of action (6–8 h), a much more delayed peak of activity (14–24 h) and a duration of action of about 32 h. The ultralente human insulin has a shorter duration of action, compared to the animal preparations, and requires also twice-daily injections. Table 2 summarizes the most common insulin preparations and their onset, peak and duration of action. Insulin Analogues Recently, to improve the outcome of insulin therapy and to use human insulin products with more physiological effect, a short-acting monomeric insulin analogue, insulin lispro (Lys[B28], Pro[B29]), was developed which was approved for clinical use and is already commercially available. It has been used extensively in clinical practice. Reversal of the amino acids proline and lysine at position B28 and B29 of human insulin produces an analogue

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Table 2. Types of insulin Type

Preparation

Onset of action h

Peak action h

Duration of action h

Rapid-acting Intermediate-acting Long-acting

Regular NPH or lente Ultralente Bovine Human

0.5–1 3–4

2–4 8–12

4–6 16–24

4–6 4–6

14–24 10–20

28–36 24–28

There is great variability in the onset, peak and duration of insulin action from patient to patient, as indicated by the time intervals given. Human insulin tends to show somewhat earlier onset and peak and shorter duration of action, compared to nonhuman insulins. This is especially true for long-acting preparations. For this reason, different figures for the time intervals are reported in the table for this insulin preparation.

with less tendency to self-association. Conventional insulin preparations are prevailingly in hexameric form, which delays the absorption from subcutaneous injection sites, requiring the dissociation of hexamers into monomers. The monomeric insulin lispro is rapidly absorbed from subcutaneous tissues (so reducing the postprandial hyperglycemia) and shows a shorter duration of action that should decrease the risk of hypoglycemia between meals and at nighttime. Indeed, it shows early peak (1 h) (which allows a much shorter interval between injection and eating) and a shorter duration of action (3–4 h). The insulin lispro in appropriate dosage may result in a profile of insulin close to the physiological one and is suitable for treating both type 1 and type 2 diabetic patients under intensive insulin therapy. Another rapidacting insulin analogue is currently under evaluation (B28 Asp). Longeracting ‘basal’ analogues are also under development such as HOE 901 that is an insulin analogue with a lower peak of activity than NPH and a duration of action very long (about 24 h), especially appropriate for type 1 diabetics. Insulin Concentration The insulin preparation available on the market today is a concentration of 100 U/ml (U-100). In the past (and still today in some countries) a concentration of 40 U/ml (U-40) was in use. However, preparations with more concentrated insulin also exist (500 U/ml or U-500).


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Factors Influencing Insulin Concentration or Bioavailability Pharmacokinetics of Injected Insulin An optimal therapeutic use of insulin requires the knowledge of the factors affecting its absorption, disposal and action. Within 5–7 min, insulin given intravenously is concentrated in the heart, liver and kidneys and after 15 min mainly in the latter two organs. It has been shown that, in the range of physiological concentrations, liver extracts as much as 70% of insulin on a single passage, and that the kidney also removes a significant percentage of the insulin from the blood. The importance of liver and kidney in the insulin disposal is apparent as well as the need to adjust the insulin dosage in patients with hepatic or renal diseases. Insulin Concentration and Dose Insulin bioavailability is unaffected by insulin concentrations between 40 and 100 U/ml, while more diluted insulin is more rapidly absorbed. A more concentrated regular insulin (which has a more prolonged action) can be used for insulin-resistant patients. Increasing the dose of regular insulin delays the time of peak serum level and prolongs the duration of action, while increasing the dose of NPH insulin can reduce insulin absorption. It is noteworthy that, when the dose of insulin lispro is increased, the duration of action is not prolonged. Insulin Mixtures Manufactured insulin mixtures exist on the market. Biphasic premixed insulins have been developed in various ratios of rapid-acting to NPH (30/70, 40/60, 50/50, etc.). The effect of 30/70 mixtures of regular and NPH insulins is the same as if the components were injected separately and simultaneously, because regular insulin retains its pharmacokinetic characteristics. When a mixture of lente and regular insulins is used, the excess of zinc tends to bind to regular insulin and may cause precipitation of regular insulin out of solution, delaying its absorption and blunting its quick-acting effect. Thus, there are some advantages in using NPH for insulin mixtures. When two types of insulin are mixed, it is important to consider (to assure accuracy of the dose) the variable amount of ‘dead space’ between the hypodermic syringe and the needle. For this reason, it can be useful to always use syringes from the same manufacturer. Type of Administration and Site of Insulin Injection Subcutaneous administration (with all its disadvantages) remains the only practical method for the delivery of insulin. The peak concentration of insulin

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can be influenced by the site of injection, being achieved more quickly with abdominal injection than with injection in the anterior thigh. Absorption is faster in an upper than in a lower limb. When insulin is injected into an extremity, absorption increases if the extremity is subsequently involved in exercise. Absorption also increases if the injection site is massaged or warmed. Patients should inject insulin in the different locations at the same time each day, i.e. in the abdomen in the morning to optimize insulin delivery and in the leg or buttock at night to slow absorption. Rotation of sites within these areas is very important. It is noteworthy that the absorption rate of insulin lispro is consistent from each of the injection sites. Interestingly, it has been shown that the patient can safely reuse the plastic insulin syringes and the needles. Pen injectors have been introduced for clinical use, loaded with insulin cartridges of 1.5 ml (containing 150 U) or 3 ml (300 U). They are more practical than syringes, especially for the traveler patients, and give more accurate dosage. Only short-acting insulin and NPH insulins can be used with pens (lente insulins are in crystal form and crystals would be broken by the glass marble present in the pen cartridges to help insulin stirring). Intravenous administration (continuous or pulse) is not practical but permits much more physiological insulin profiles. Other routes of insulin delivery have been proposed, including the intraperitoneal route (which allows insulin to enter, at least in part, the portal vein, similarly to the endogenously secreted insulin), as well as the subcutaneous insulin pellets, skin iontophoresis, oral administration (insulin is degraded by gastrointestinal enzymes and therefore the absorption is extremely variable), nasal or pulmonary spray of insulin (mixed with 1% deoxycholate capable to increase the mucosal insulin absorption) and rectal suppositories (unable to induce a physiological profile of insulinemia). It should be underlined that the physiologically secreted insulin enters the portal vein and is taken up in substantial amount by the liver, so that only the remaining amount reaches the general circulation and is distributed to the peripheral tissues. In contrast, insulin given for therapeutic purposes through the commonly used routes (subcutaneous or intravenous) enters the general circulation and is distributed to all tissues (liver and peripheral tissues) in approximately similar amount. Therefore, during insulin treatment, liver is relatively hypoinsulinized and the peripheral tissues relatively hyperinsulinized. Depth of Injection and Massage The depth of insulin injection is an important variable. In fact, the deeper insulin is injected, the quicker the onset of action and the higher the peak.


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Usually, it is recommended to place insulin consistently into deep subcutaneous tissue by means of a lifted flap with the injection device at a 45º angle. Absorption is much faster when insulin is injected intramuscularly rather than subcutaneously, and erratic intramuscular injections in thin individuals may occur. Massage of the injection site increases insulin absorption. Exercise and Stress Exercise of a leg may increase absorption of the insulin injected in that extremity; moreover, stress (by increasing epinephrine) may affect local blood flow and absorption of insulin. Insulin Antibodies Insulin antibodies bind insulin and can delay the onset of action and the duration of its effect. Among patients, the time course of a given insulin preparation is highly variable, probably for differences in circulating insulin antibodies. Human insulin generates lower titers of insulin antibodies and therefore is most useful in patients who are initiating insulin therapy (and who have not yet produced antibodies) and in patients requiring insulin intermittently (intermittent use of insulin increases its antigenic effects). Destruction of Insulin Insulin is destroyed variably at the site of injection by some insulindegrading enzymes. An unusual cause of altered insulin pharmacokinetics may be the local degradation of insulin by proteases, at the site of injection. This mechanism, however, has not been established in patients with poorly controlled diabetes either at the injection site or by in vitro studies with patient’s fat incubated with insulin. Storage of Insulin Insulin can be kept at room temperature (=25 ºC) for 1–2 months without losing activity, whereas for longer conservation it should be stored in the refrigerator (between 4 and 8 ºC). Insulin does not withstand temperatures =2 ºC and freezing must therefore be avoided.

Insulin Requirement Insulin dose depends on the patterns of food intake and physical activity, on diurnal variations in insulin requirement, on experience of hypoglycemia, on the state of injection sites and on the type of diabetes. Insulin requirement of young, adolescent diabetic patients is sometimes high and changing. As a

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basic concept, it may be useful to bear in mind that the average insulin production in a normal subject is about 25 U/day. In diabetics, however, insulin requirement may be higher due to the presence of insulin resistance. Average starting doses of 0.7 U/kg body weight per day have been suggested. However, it may be more advisable to start with lower doses. In nonobese diabetics the starting daily insulin dose might be 15–20 U, whereas in obese diabetics it might be somewhat higher, in the range of 20–25 U. It is advisable to start therapy with caution, to avoid hypoglycemia, and to increase the insulin dose with prudence, after the previous dose has been experienced for a few days, with increases of 4–8 U per step.

Insulin Regimens Insulin treatment can range from the simple regimens based on one or two daily insulin injections (conventional insulin therapy) to the more complicated multiple daily insulin injection regimens (intensive insulin therapy) or the continuous subcutaneous insulin infusion (CSII). Single Daily Insulin Injection It is the simpler and easier regimen to administer insulin. Some newly diagnosed type 1 diabetic patients (with some degree of residual b-cell function) can achieve glycemic control with less intensive effort by means of a single injection of lente or NPH insulin alone or combined with regular insulin. Type 2 diabetic patients, poorly controlled with diet and oral hypoglycemic drugs, can be treated with a single daily insulin injection (often a night injection of lente or NPH insulin will suffice), as well as older patients with impaired vision or physically disabled who may experience difficulties with injections. This regimen is also useful for individuals with limited motivation and poor compliance to the diabetic therapy. The initial insulin requirement can depend on several factors: (a) the current degree of hyperglycemia; (b) the dietary habit; (c) the amount of remaining endogenous insulin secretion; (d) the physical activity or exercise, and (e) the body weight or degree of obesity. A total dose of intermediate-acting insulin of 0.5–0.7 units/kg has been suggested (usually from 20–30 to 40–50 units/day), with subsequent adjustments according to the glycemic values obtained 2–4 times daily (as well as according to the hypoglycemic episodes, the presence of urinary ketones and the HbA1c values). With large doses of intermediate-acting insulin, availability of insulin may be inappropriate at certain times and there is the risk of nocturnal hypoglycemia. For some patients, an insulin preparation consisting


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of a 30/70 mixture of regular and intermediate insulin can be used. In patients with persistent hyperglycemia there is the indication for changing insulin regimen (twice-daily insulin injections – see below). When a hospitalized patient is discharged, the diet may be slightly increased or the insulin dose reduced because the physical activity of the patient will increase; for this reason, during the first days after discharge a contact between the patient and the physician is important to adjust the insulin dose. Twice-Daily Insulin Injection When a single dose is inadequate or produces hypoglycemia, twice-daily injections of NPH insulin are frequently used in insulin-dependent diabetics. Most patients should use two daily injections of a mixture of intermediateacting (2/3) and rapid-acting (1/3) human insulins before breakfast and dinner. It is a relatively simple regimen that provides a good insulin availability over a 24-hour period, even if it may induce late afternoon and nocturnal hypoglycemia with pre-breakfast hyperglycemia. Twice-daily insulin regimen is little flexible, inasmuch as insulin must be given at the same time every day and meal times must also be kept constant. Multiple Daily Insulin Injections (MDI ) The intensive treatment regimens (as opposed to the simpler conventional regimens, described above) are not suitable for everyone and should be adopted in the appropriate patients. Intensive insulin therapy should be encouraged in type 1 diabetes without residual insulin secretion and when twice-daily insulin injections are no longer adequate. Recently, this regimen was also proposed for type 2 diabetics (particularly the younger patients with a life expectancy of 10–15 years or more). The scope is to obtain a good glycemic control which may reduce the development of diabetic microangiopathy, as shown by the DCCT (Diabetes Control and Complications Trial) study. However, this insulin intensive regimen may favor weight gain. Moreover, it has been postulated in the past that enhanced insulinization may be associated with increased risk of mortality from cardiovascular disease and it was suggested that chronic hyperinsulinemia may cancel the beneficial effects of the better glycemic control. However, more recent data (from the DCCT for type 1 diabetes and from UKPDS for type 2 patients – see chapter VI) allow us to exclude that intensive insulin therapy entails risk for macrovascular disease. An absolute indication for intensive therapy is pregnancy (see chapter XVIII on Managing Diabetes and Pregnancy). An optimal glycemic control requires that insulin delivery simulates the normal pattern of insulin secretion, which consists of continuous ‘basal’ insulin

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secretion (throughout the day and night) and acute increases of insulin levels connected to ingestion of meals. This regimen improves diabetic control, reduces excursions in glycemic levels and provides a good flexibility. Four different regimens may be used: (a) The simplest intensive regimen entails the use of three injections, regular and intermediate-acting insulin before breakfast, regular insulin before supper and intermediate-acting insulin at bedtime. This 3 times daily insulin dose regimen is useful in diabetic patients with frequent nocturnal hypoglycemia and pre-breakfast hyperglycemia. The primary disadvantage of this approach is that meal schedules must be fixed rather rigidly. (b) Regular insulin before each meal and intermediate-acting insulin at bedtime (4 daily insulin doses). This regimen provides the greatest flexibility because regular insulin can be adjusted to cover each meal, avoiding postprandial hyperglycemia. (c) Regular and intermediate-acting insulin before breakfast, regular insulin before lunch and supper, and intermediate-acting insulin at bedtime (4 daily insulin doses). (d) Regular insulin before each meal and ultralente insulin in the morning (to replace basal insulin secretion) or subdivided before breakfast and before supper (4 daily insulin doses). It is less preferable to the (b) regimen because ultralente presents unexpected small peaks 15–24 h after injection. Human insulin lispro is very appropriate for multiple injection therapy, especially in patients with marked postprandial hyperglycemia and nocturnal hypoglycemia or with a variable lifestyle. Patients on insulin lispro had significantly lower glucose levels following meals (however with the potentially unwanted result of a rise in preprandial glucose) and showed a reduction in the incidence of severe hypoglycemia by 30% (compared to regular human insulin). In patients treated with insulin lispro (compared to those treated with human regular insulin) there should be less need for snacks. The majority of patients on insulin lispro reported an improved quality of life. However, there are some ‘failures’ with this type of insulin, as a number of patients may appear unable to control their diabetes with insulin lispro. At present, insulin lispro should be used with caution in children under the age of 12 as well as in gestational diabetes or pregnancy, because of lack of experience. Other, far too complex, multiple-injection regimens have also been suggested. Certainly, the adherence to therapy is less likely to occur when the program of treatment is far too complicated. Some patients object to such frequent needle injections and ask for changing from this insulin regimen to a simpler program. Pen devices or jet injectors filled with insulin (that are easy to carry) make the multiple daily insulin regimens better accepted.


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It is advisable to use no more than two types of insulin. It is noteworthy that in some patients a morning fasting hyperglycemia (the dawn phenomenon) occurs, that depends on the hepatic glucose overproduction activated in the morning due to inadequate overnight delivery of insulin and a sleepassociated GH release. This phenomenon is most pronounced in type 1 diabetic patients for their inability to compensate by raising endogenous insulin secretion. The magnitude of the dawn phenomenon can be attenuated by designing insulin regimens which ensure that the effects of exogenous insulin do not peak in the middle of the night and then become dissipated by morning. Some patients (about 1/3 of type 1 diabetic patients) may experience early in the course of disease a brief honeymoon period, during which there is a partial recovery of b-cell function and a transient or a prolonged fall in the exogenous insulin requirement (=0.5 U/kg/day). The honeymoon phenomenon may be due to the termination of a ‘stress’ episode (infections, etc.) that has anticipated the manifestation of diabetes in a subject with ongoing b-cell destruction process. Spontaneous remission is less frequent in children and adolescent or pubertal patients, and more frequent in adult postpubertal patients. A low residual insulin secretion (probably linked to a more aggressive destruction of b-cells) can be implicated in children while a low insulin sensitivity (probably linked to the increased secretion of GH hormone) may be important in pubertal patients. The honeymoon should not be regarded as a signal to reduce efforts aimed at glycemic control, because optimized insulin therapy may help to preserve b-cell function. It is recommended to continue insulin treatment even at low doses (even 1–4 U/day), since this can preserve b-cell function and may favor the remission. Continuous Subcutaneous Insulin Infusion (CSII ) In sufficiently motivated diabetic patients, an alternative that provides a greater flexibility of insulin treatment (minimizing variations in its absorption) is CSII, with which insulin delivery may somewhat mimic that occurring in nondiabetic individuals. Insulin delivery pumps may be implantable or portable (with ‘closed loop’ or ‘open loop’ insulin infusion systems). The CSII method administers rapid-acting insulin around the clock using a battery-powered (externally worn) infusion pump, that delivers basal rates continuously (usually 0.5–2.0 U/h) and can be programmed to vary the flow rate automatically, reducing the flow rate at 1.0–4.0 a.m. and increasing it to compensate for increased insulin requirements early in the morning. Before meals, insulin boluses are given by manually activating the pump, in amounts based on frequent blood glucose self-monitoring determinations. Usually, a 3- to 5-day hospital stay is required for learning to use the insulin pump,

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Table 3. Problems limiting the use of CSII Interruption of insulin delivery (commonly due to insulin precipitation within the catheter) that leads to rapid severe hyperglycemia and ketoacidosis (because there is no depot insulin and all insulin being used is short-acting) Pump malfunction (a pump malfunction with insulin overdose can produce severe and even fatal hypoglycemia) Loss of battery charge Leakage from the catheter Empty insulin reservoir Needle displacement Local infections (such as abscesses at the catheter site, only occasionally reported)

and successively a health-care professional should be available 24 h/day to assist the patient. Most pumps contain a syringe or a reservoir filled with insulin attached to an infusion set consisting of a catheter and a 27-gauge needle which is inserted into subcutaneous tissue (preferably in the abdomen). Unfortunately, the CSII presents several problems that limit its use (table 3), and the patients with brittle diabetes (see below) may not be the best candidates for a successful use of CSII. Most modern pumps present alarm systems for the different pump problems. Some diabetic patients are absolutely incapable to safely employ the insulin pump and to use the appropriate infusion rates. The high cost is another relevant disadvantage of CSII.

Self-Monitoring Self-monitoring is an important component of diabetes management, which helps to achieve a good glycemic control and therefore to prevent complications (especially microangiopathy). Several factors may influence the method and frequency of self-monitoring, such as the type of insulin regimen prescribed, glycemic goals of therapy, capabilities of diabetic patient, etc. Selfmonitoring includes the following tests: (a) Urine testing for glucose (2 or 4 times/day) is the less reliable option for self-monitoring, inasmuch as it allows only a coarse estimation of glycemia. It might be used for insulin or dietary adjustments in patients with stable diabetes. (b) Urine testing for ketones is a component of self-monitoring routines of type 1 diabetic patients, especially in presence of unexplained hyperglycemia or to manage acute events of metabolic decompensation.


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(c) Blood glucose self-monitoring is the most important advance in diabetes care. It requires the use of devices or meters that read blood glucose testing strips. All the modern meters can store and recall obtained blood glucose readings. These glucose determinations provide an estimation of glycemic control at any given moment, from day to day, and may be especially useful for specific problems (hypoglycemia, acute illness, ketonuria, periods of unstable diabetes, etc.). Several factors may limit the use of this method, such as a low level of motivation, a poor accuracy of determination, technical errors, intellectual inability to use the glycemic results, low visual or physical abilities, lack of education, high costs, etc. For some diabetic patients, blood glucose self-monitoring is perceived as too difficult or intrusive into individual’s routine, while other patients who desire to improve their glycemic control may accept to perform blood glucose tests several times a day on a regular basis. In these motivated patients, it is very important to monitor their technical competence, to define the desired glycemic range to be achieved, and to provide all the appropriate technical instructions, including the comparison of meterobtained results with laboratory values.

Glycated Hemoglobin (HbA1c) The patient with diabetes should have a periodic determination of HbA1c because this measurement is the most objective method of glucose control measurement over a long period. HbA is glycated in an irreversible and nonenzymatic fashion, and the levels of HBA1c reflect the mean glycemia over the 2–3 months prior to the test.

Serum Fructosamine Test This test has been suggested as a less difficult to perform and less costly alternative to HBA1c determination, with which shows a good correlation. This test measures the level of glycosylated proteins in the blood (mainly albumin), and reflects the mean glycemic control during a 2- to 3-week period. Its validity is uncertain when interfering substances (bilirubin, hemolysis, etc.) are present or serum albumin concentration is abnormal. The test accuracy can be improved by correcting the fructosamine result for variations in serum albumin. HBA1c, compared to fructosamine test, should be considered as the preferable test for monitoring diabetic control.

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Complications of Insulin Treatment The most important complication of insulin therapy is hypoglycemia, which is discussed in chapter VIII (Clinical Emergencies in Diabetes. 2: Hypoglycemia). The other complications are listed below. Insulin Edema In poorly controlled diabetic patients, insulin therapy can result in a marked accumulation of fluid, with localized (periorbital, pretibial or presacral) or generalized edema. The causes are probably multiple (table 4). A dietary restriction of salt and a temporary use of diuretics can be recommended. Edema will most often subside within 3–5 days. Table 4. Causes of insulin edema ADH increase (ascribed to hypovolemia resulting from osmotic diuresis) Cessation of natriuretic effect of hyperglucagonemia Increased plasma volume and transcapillary escape of albumin (with reduced colloid osmotic pressure) Excessive infusion of isotonic saline Na retention (induced by excess of insulin infused or injected)

Insulin Lipoatrophy It was a common complication prior to the introduction of monocomponent insulins, consisting of a loss of fat at the site of insulin injection or, occasionally, at distant sites. In 25% of lipoatrophic patients, local allergy coexists. Lipoatrophy is frequently observed in young children (50%) or in young women (20%), compared to male adults (5%). Lipoatrophy, moreover, may occur after repeated injections of other substances such as narcotics or GH preparations. Thus, atrophy might be the result of a repeated mechanical trauma, even if insulin impurities can stimulate immune factors or immune complex formation which lead to local release of lipolytic substances. These reactions occur without overt inflammation and were considered also secondary to insulin degradation or aggregation products. Indeed, in biopsy specimens of lipoatrophic areas, antigen-antibody reactions were not seen. Local reactions to protamine (a constituent of insulin preparations) and to silicone oil (the lubrificant in disposable syringes) may play a role in some patients. Switching to purified or human insulins and rotating the site of injections result in improvement of skin alterations in 97% of lipoatrophic patients. Very few cases were reported with recombinant human insulins, and the reason why it


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still occasionally occurs is unknown. Injecting the purified insulin at the edges and center of the affected atrophic area improves lipoatrophy (due to the lipogenic effect of insulin). Addition of dexamethasone to the insulin in the syringe (4 lg/U, total daily dose not exceeding 0.75 mg) has also been suggested. In a recent case of severe well-circumscribed lipoatrophy, good results were obtained by treating the area with a fatty acid mixture while the patient was instructed to avoid this area for insulin injection. Insulin Lipohypertrophy It consists of visible or palpable increase of localized subcutaneous fat (most prevailingly in the anterior or lateral part of thighs) at the site of insulin injection, sometimes coexisting with lipoatrophy. Repeated and prolonged use of the same site for insulin injection is a main determinant in the development of lipohypertrophy. Often the affected patients report that injection into lipohypertrophic areas is less painful, perhaps because the subcutaneous tissue tends to be fibrous. Lipohypertrophy is due to a possible growth factor effect of insulin on cellular elements of subcutaneous tissue, and may alter the absorption rate of insulin, thus possibly affecting metabolic control. Prevalence rates of lipohypertrophy vary between 20–45% in type 1 and 3–6% in type 2 diabetic patients. Independent risk factors which contribute to the presence of lipohypertrophy are female sex, type 1 diabetes, higher BMI and missing rotation of insulin injections. The most severe cases of insulin lipohypertrophy can be treated with liposuction, but prevention is important, primarily by systematized rotation of injection sites within the recommended areas. An important role is played by educational interventions to establish an organized rotation system for insulin injection sites, to self-recognize lipohypertrophy and to normalize the high BMI. Syndrome of Immunologic Insulin Resistance All patients who receive insulin develop circulating antibodies, whose production can be influenced by several factors (table 5). Patients never treated with exogenous insulin may have circulating insulin antibodies, probably involved in the autoimmune reactions of type 1 diabetes. The high level of insulin antibodies may function as a reservoir from which insulin may be released unpredictably (thus inducing delayed hypoglycemia), or may bind insulin (thus causing hyperglycemia), or may form immune complexes (thus sequestering insulin in the reticuloendothelial system or stimulating procoagulant activity and favoring diabetic complications). In diabetic patients, this syndrome may result in an excessive insulin requirement (100–200 U/day in adults and up to 2.5 U/kg in children). In the most severe cases, steroids even at high doses for 3–4 weeks should be used. It is noteworthy that the immunogenicity of insulin

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Table 5. Factors influencing the formation of insulin antibodies Insulin species (human insulin is less immunogenic than animal insulins) Insulin purity (monocomponent insulins are less immunogenic) Insulin pharmaceutical form (regular insulin is less immunogenic than modified insulins) Pattern of insulin treatment (episodic therapy and CSII may increase insulin immunogenicity) Genetic factors (HLA-A2-B44 and HLA-B44-DR7 predispose to immune complications of insulin therapy) Residual insulin secretion (when present, it reduces immune response to insulin)

lispro has been found to be similar to that of human insulin in both type 1 and type 2 diabetic patients. Insulin Allergy It includes different forms: (a) Local allergy comprises immediate or biphasic or delayed reactions and consists of erythematous and pruritic indurated lesions or more severe reactions in subcutaneous areas injected with insulin preparations. Protamine or zinc have been implicated. These reactions are IgE-dependent and may occur with conventional insulin treatment or CSII in subjects with intermittent insulin treatment or with allergy to other drugs (such as penicillin) or with obesity. The affected patients will improve within 30–60 days continuing the use of insulin (probably because of a spontaneous desensitization), whereas in the most severe cases local steroids in low doses or oral antihistaminics may be considered. (b) Generalized allergy ranges from a simple urticaria to more severe reactions such as anaphylaxis with angioedema, bronchospasm, pharyngeal edema and collapse. These generalized reactions are due to the interaction of insulin (acting as an antigen) with specific IgE bound to mast cells or blood basophils and are very uncommon (=0.05%). No deaths for insulin allergy are reported. Human insulins are efficacious in the majority of allergic patients for the treatment of this systemic allergy, while in the remainder desensitization is successful (about half of patients who cannot be desensitized are overweight). Immunologic insulin resistance may coexist with or following insulin allergy. Insulin allergy is different from stress-induced urticaria, in which the central nervous system is important in the generation of immune response.

Conditions of Altered Insulin Responses Conditions of altered insulin responses include: (a) insulin resistance linked to occult infections; (b) iatrogenic hypoglycemia or factitious inten-


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tional insulin overdosing (see chapter VIII on Clinical Emergencies in Diabetes. 2: Hypoglycemia); (c) labile or ‘brittle’ diabetes, which can be idiopathic or secondary and includes a group of insulin-dependent diabetic patients (about 2–10%) characterized by unexplainable and extreme glycemic shortterm and long-term fluctuations with frequent ketosis proneness or hypoglycemic crises, or both. Brittle diabetes can depend on altered insulin absorption, or poor residual insulin secretion, or excess of counter-hormone regulation, or emotional stress. Some of these patients are adolescent women who distort their insulin treatment to prolong the stay in the hospital for psychosocial problems. In these instances, the treatment of brittle diabetes requires a strong effort by the patient’s family and the medical and psychological team.

Role of Education A successful insulin management requires actively applied systems of patient education. The aim of education and training is to provide adequate information in a simple form suitable to the ability of the subject, in order to allow the diabetic patients to develop the required knowledge to self-manage their disease and to ensure an optimal and appropriate use of insulin therapy (and other therapeutical measures). Behavioral changes and insulin treatment adjustments may be made in a graduated manner (step-by-step), and a systematic reinforcement is critical after the goals are achieved. Nutritional management is also an integral part of initial and following programs of education. The provision of a diabetes professional team (doctors, educators or diabetes nurse specialists, nutritionists or dieticians, and podiatrists or chiropodists) is also necessary as well as a continuing education for the professional staff. Several factors should be considered for a good therapy, including patient’s lifestyle, physical activity, dietary habits, glucose self-monitoring, correct time to injection (some patients may take regular insulin 5–15 min before the meal, instead of 30 min before), insulin dosage adjustments, usual injection sites and, finally, possible interactions with other drugs. How to avoid hypoglycemia, what to do during an episode of hypoglycemia or the correct behavior during acute illness or stress must be included in the education program. Each visit should be an opportunity to assess the current level of self-management, the behavioral change and goal achievement. Overall glycemic control is optimized when education and motivation are emphasized. In this approach, every diabetic patient should be considered unique.

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Suggested Reading Anderson JH, Brunelle R, Koivisto VA: Reduction of post-prandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin analog treatment. Diabetes 1997;46:265–270. Campbell PJ, May ME: A practical guide to intensive insulin therapy. Am J Med Sci 1995;310:24–30. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986. Dimitriadis G, Gerich J: Importance of timing of preprandial subcutaneous insulin administration in the management of diabetes mellitus. Diabetes Care 1983;6:374–377. Galloway JA, deShazo RD: Insulin chemistry and pharmacology; insulin allergy, resistance, and lipodystrophy; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and Practice, ed 4. Amsterdam, Elsevier, 1990, pp 497–512. Sane T, Helve E, Yki-Jarvinen H: One year’s response to evening insulin therapy in non-insulin-dependent diabetes. J Intern Med 1992;231:253–260. Strowing S, Raskin P: Insulin treatment and patient management; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and Practice, ed 4. Amsterdam, Elsevier, 1990, pp 514–525.



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Chapter VI

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Overview of Diabetes Management: ‘Combined’ Treatment and Therapeutic Additions F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Lessons from Recent Large Trials on Diabetes Treatment The Diabetes Control and Complication Trial (DCCT), a large multicenter study conducted on more than 1,400 type 1 diabetics (aged 12–39 years) for a period of 7–10 years, has established that close blood glucose control (even if complete normalization of glycemic level was not obtained) reduces the frequency of late diabetic complications. Patients were assigned randomly to either intensive insulin therapy (3 or more daily injections or insulin pump, glucose self-monitoring 4 or more times per day, and frequent contact with a diabetes health-care team) or conventional therapy (1 or 2 injections of insulin mixtures per day, less frequent monitoring and medical contacts). The target goals of therapy were markedly different. Compared to the conventional care group, the intensive care group showed lower glycated hemoglobin (by 1.5–2.0%) and mean glucose level (by 60–80 mg/dl), yet most of the intensive care patients group failed to achieve normal glycemic levels. However, intensive care reduced the development of retinopathy by 76% (and its progression by 54%), the risk of microalbuminuria by 39%, frank proteinuria by 54%, and clinical neuropathy by 60%. Major cardiovascular events were also reduced, although statistical significance was not reached, in any case excluding that intensive insulin therapy may entail risk for macrovascular complications. The correlation of mean blood glucose with the frequency of retinopathy progression was linear, suggesting that there is no threshold glycemic level at which complications occur, so that any degree of improvement in glycemic control exerts beneficial effects on the progression of complications. These

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beneficial effects, however, were obtained at the expense of a more common weight gain and, especially, of an increased (3-fold) risk of severe hypoglycemic episodes, often not accompanied by the classical symptoms (intensive treatment reduces the adrenergic response to hypoglycemia), which makes intensive treatment less appropriate for some people (hypoglycemia unawareness, special occupations, children, old people, etc.). Finally, it should be noted that the DCCT results were obtained through a close cooperation between the patients themselves and an expert team, primarily nurse educators and dieticians. Therefore, it may not be easy to follow the DCCT criteria in everyday clinical practice. The data from DCCT conclusively demonstrate that in type 1 diabetes the control of blood glucose really matters to prevent late complications. A recently concluded multicenter investigation on a very large study population (?5,000 patients), the United Kingdom Prospective Diabetes Study (UKPDS), whose results were presented at the European Association for the Study of Diabetes in Barcelona, September 1998, has obtained similar results in type 2 diabetic patients. As summarized by Laakso [1999], this study has shown that, compared to ‘diet alone’, the intensive control of blood glucose (regardless of the treatment used – sulfonylureas, metformin or insulin) reduced retinopathy or nephropathy by 25%, myocardial infarction by 16% and any diabetesrelated endpoint by 12%. For every one percentage point reduction in HbA1c, there is a 35% reduction in retinopathy, nephropathy or neuropathy, and a 25% reduction in diabetes-related deaths (stroke frequency was not affected). As observed in the DCCT, there was no evidence of any glycemic threshold for micro- or macrovascular complications. With strict metabolic control, the risk of hypoglycemic episodes increased. Obese type 2 diabetic patients treated with metformin, compared with diet treatment, had even more pronounced benefits, showing reduction of 32 and 42% of diabetes-related endpoints and diabetes-related deaths, respectively, as well as a 36% reduction of all-cause mortality. In addition, they gained less weight and had fewer hypoglycemic episodes compared to the insulin- or sulfonylurea-treated patients. The UKPDS also pointed out that type 2 diabetic patients with tight control of blood pressure (mean 144/82 mm Hg), obtained either by ACE inhibitors or b-blockers, compared to the untreated group (154/87 mm Hg), showed reduction of any diabetes-related endpoint (by 24%), diabetes-related deaths (by 32%), stroke (by 44%) and microvascular complications (by 37%). Reduction of myocardial infarction of 21% occurred but did not reach statistical significance. It should be noted that in the UKPDS the treatment goal of maintaining fasting glycemia below 6 mmol/l (108 mg/dl) was not achieved. Strict metabolic control would consist of keeping glycemia below 10 mmol/l or 180 mg/dl at

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all times during the day. The UKPDS conclusively demonstrated that strict control of blood glucose and of blood pressure are greatly beneficial in type 2 diabetes for preventing micro- and macrovascular complications. UKPDS also has evidenced that about 50% of newly diagnosed type 2 diabetic patients already show early signs of complications. This study has also showed that treatment with insulin or sulfonylureas is not harmful. However, this study did not demonstrate that this is also the case for elderly diabetic patients. Moreover, metformin was compared with other intensive treatments combined, not separately, with insulin and sulfonylureas. Concerning the possible negative effects of the association sulfonylurea-metformin, UKPDS did not provide sufficient evidence to suggest that this combination should not be used. Not all possible therapeutical combinations were tested, as, for instance, the combination insulin-metformin, which might bear the advantage that weight gain is prevented. Finally, it should be noted that the glucose levels fixed as therapeutical goal in the UKPDS may not be achievable in all patients; individual patient targets should be defined in relation to age and other risk factors. On the basis of the UKPDS data, the British Diabetic Association recommends that the treatment should be aimed at the following goals: blood pressure levels of 140/80 mm Hg or below; HbA1c levels of 7.0% (or within 1% of the upper end of the laboratory’s normal range); fasting blood glucose levels of 4–7 mmol/l (72–126 mg/dl), and self-monitored blood glucose levels before meals of 4–7 mmol/l (72–126 mg/dl). According to the IDF guidelines [1999] for type 2 diabetes, the risk for vascular complications as related to metabolic compensation (blood glucose and HbA1c) is as follows: ‘Low risk’: HbA1c (DCCT standardized) p6.5%; fasting/preprandial venous plasma glucose (VPG) =100 mg/dl (6.0 mmol/l); fasting/preprandial selfmonitored blood glucose (SMBG) =100 mg/dl (p5.5 mmol/l); postprandial SMBG =135 mg/dl (=7.5 mmol/l). ‘Arterial risk’: HbA1c>6.6–7.5%; fasting/preprandial VPG>110–125 mg/dl (6.1–6.9 mmol/l); fasting/preprandial SMBG>100–109 mg/dl (5.6–6.0 mmol/l); postprandial SMBG>135–160 mg/dl (7.5–9.0 mmol/l). ‘Microvascular risk’: HbA1c ?7.5%; fasting/preprandial VPG?125 mg/dl (?7 mmol/l); fasting/preprandial SMBG q110 mg/dl (q6.0 mmol/l); postprandial SMBG ?160 mg/dl (?9.0 mmol/l).

Type 2 Diabetes In those patients with type 2 diabetes in whom good metabolic control cannot be achieved with diet and physical exercise, pharmacological treat-

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ment should be introduced, based on sulfonylureas (to stimulate insulin secretion) or metformin (to ameliorate insulin action), as discussed in chapter II on Insulin Secretion and Its Pharmacological Stimulation and chapter III on Insulin Resistance and Its Relevance to Treatment. Further aspects of treatment will be considered in this chapter. According to the IDF guidelines [1999] to type 2 diabetes, oral therapy should be started when, despite an adequate trial of lifestyle intervention/education, HbA1c is ?6.5% and fasting VPG is ?110 mg/dl (?6.0 mmol/l), or (in thin subjects without arterial risk factors) HbA1c is ?7.5% and fasting VPG is ?125 mg/dl (q7.0 mmol/l). Sulfonylurea Failure In type 2 patients treated with sulfonylureas, the phenomenon of sulfonylurea failure, either primary or secondary, may occur. Primary Sulfonylurea Failure. It is the failure to show any significant response to therapy and it occurs in about 5% of the patients treated with sulfonylureas. It has been suggested that probably some of these patients are unrecognized type 1 diabetics. The cause of this failure is uncertain. Primary failure occurs with greater frequency in underweight diabetic patients, in those with diabetes duration longer than 5 years, or in diabetic patients previously treated with insulin. Secondary Sulfonylurea Failure. It is defined as a persistent hyperglycemia in spite of maximal doses of drug after an initial successful response for at least 6 months, and may occur in about 5–10% of type 2 diabetic patients, although this percentage varies with the populations studied. The majority of secondary failures occurs during the first 3 years of oral therapy. Most likely, secondary failure is caused by increased insulin resistance consequent to increased dietary intake and body weight, or to intercurrent illness and, usually, the correction of these causes restores sulfonylurea responsiveness. In other instances, a further deterioration of b-cell function may be the responsible factor (as revealed by decreased C-peptide response to intravenous glucagon). It is noteworthy that about 33% of the diabetic patients with sulfonylurea failure show islet cell antibodies (ICA or GAD antibodies), or multiple autoantibodies (islet cell, thyroid antimicrosomal, gastric parietal cell, etc.), or possess the HLA phenotype DR3/DR4, characteristics which suggest that these diabetic patients may actually be affected by late-onset type 1 diabetes. Among the firstgeneration sulfonylureas, failure was less often observed with chlorpropamide. With the indroduction of second-generation drugs the incidence of failure has become very low (about 0.3%). In the event that a complicating illness is causing a secondary failure, the patient can usually be treated with sulfonylureas again after the intercurrent problem has cleared.


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For the patients who show secondary failure of sulfonylureas or respond only partially to maximum doses of oral sulfonylureas, various combined therapies can be employed. In the IDF guidelines [1999] to type 2 diabetes, the following combination therapy is suggested: (a) metformin with sulfonylureas; (b) sulfonylureas with a-glucosidase inhibitors, and (c) sulfonylureas with PPARc agonists. Combined Sulfonylurea-Metformin Therapy The oral hypoglycemic drugs, sulfonylureas and metformin, are largely used in combination in the treatment of type 2 diabetic patients, inasmuch as they exert different and complementary effects. Sulfonylureas stimulate insulin secretion whereas metformin ameliorates insulin action by enhancing peripheral glucose utilization and repressing hepatic glucose production. Recent in vitro studies reported that metformin may potentiate glucosestimulated insulin release from human pancreatic islets. Not enough evidence exists to support the suggestion that the association sulfonylureas-metformin entails a risk for diabetes-related deaths. In some countries, tablets containing a mixture of metformin and sulfonylureas (examples: 400 or 500 mg of metformin and 2.5 mg of glibenclamide) are available on the market. Combined Sulfonylurea-Insulin Therapy This combined therapy may be successful in type 2 insulin-resistant diabetic patients who are no longer responsive to oral drugs. Sulfonylureas decrease the exogenous insulin doses required to achieve a good glycemic control. Many studies have tested this therapeutic combination and have shown that about 30–40% of patients require significantly less insulin or sulfonylureas when treated this way. These patients, usually, show higher basal and stimulated serum C-peptide levels and increased insulin-mediated glucose disposal. The beneficial effects of the combination sulfonylurea-insulin can depend on an increase of endogenous insulin secretion or on a reduction of liver and peripheral insulin resistance, and may be transient or prolonged. The recommended regimen is a dose of intermediate-acting insulin at night (to control overnight glucose production) and oral sulfonylureas during the day at meals (to reduce postprandial hyperglycemia). Therapy with Other Drugs Repaglinide. This is a nonsulfonylurea insulinotropic hypoglycemic agent of the meglitinide family (meglitinide is a compound with a poorly efficient insulinotropic activity), and shows a common conformation with the hypoglycemic sulfonylureas glibenclamide and glimepiride (see chapter II on Insulin Secretion and Its Pharmacological Stimulation).

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Orlistat. In obese-diabetic patients who need to lose weight, a new nonsystemically acting antiobesity drug, orlistat, may be a useful add-on. It possesses an inhibitory activity against gastrointestinal lipase A, thus selectively reducing the absorption of dietary fat in the gastrointestinal tract. After drug withdrawal, the lipase activity is rapidly restored, due to the continuous enzyme secretion. Orlistat has little or no effect on gastrointestinal enzymes other than lipase A such as amylase, trypsin, chymotrypsin and phospholipases. About 30% of dietary triglycerides remain undigested and is not absorbed, producing an additional caloric deficit compared to diet alone. Orlistat treatment also decreases the solubility and subsequent absorption of cholesterol, so improving lipid levels (both total and LDL cholesterol levels are reduced). More than 4,800 patients have received orlistat in clinical trials (the recommended dosage is 120 mg t.i.d. taken during meals), and the results demonstrate the efficacy (weight loss was 70% greater than with placebo plus diet), safety and tolerability of the drug for long-term use. Orlistat-treated obese-diabetic patients present a best compliance with dietary restriction (because a severe dietary fat restriction is unnecessary) and a metabolic improvement (lowering of fasting blood glucose or HbA1c and reduction of sulfonylurea dosage requirement). This drug is free of systemic side effects, and gastrointestinal symptoms (related to the increased fecal fat excretion) are mild and self-limited. Orlistat treatment does not seem to increase the risk of gallstone formation (which can be favored by weight loss). Other Drugs. The possible use of some thiazolidinedione derivatives, such as pioglitazone, troglitazone, and rosiglitazone, has been discussed in chapter III (Insulin Resistance and Its Relevance to Treatment). Since fasting hyperglycemia in diabetes is correlated with high hepatic glucose production, which is determined by an elevated gluconeogenesis favored by FFA, inhibition of both FFA release (from adipose tissue) and oxidation (in the liver) may be an efficient modality to treat fasting hyperglycemia. Several drugs have been developed which inhibit FFA release from adipose tissue (acipimox, a nicotinic acid derivative) or hepatic FFA oxidation (etomoxir, a mitochondrial inhibitor of the carnitine palmitoyl transferase-1, the rate-limiting step in FFA oxidation). Severe fasting hypoglycemia and other side effects may occur with these drugs and limit their clinical use. Somatostatin or somatostatin analogues improve glucose metabolism in diabetic patients, especially under stress, selectively inhibiting the secretion of glucagon and GH without influencing insulin secretion. A role of somatostatin was also suggested in late diabetic vascular complications, but it remains to be elucidated. Amylin is a recently discovered 37-amino-acid peptide, that is cosecreted with insulin by pancreatic b-cells (it is regarded as the second b-cell hormone)


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Table 1. Physiological actions of amylin or pramlintide Inhibition of food intake (through a central mechanism) Slowing of gastric motility and inhibition of gastric emptying Inhibition of postprandial glucagon secretion Suppression of postprandial hepatic glucose production Suppression of arginine-stimulated glucagon secretion Preservation of the glucagon increase in response to hypoglycemia Inhibition of insulin secretion in response to a variety of secretagogues Renal effects (stimulation of the renin-angiotensin-aldosterone system in rats and humans with possible induction of hypertension) Inhibition of gastric acid secretion, and gastroprotection

in response to nutrient stimuli. It has been isolated and characterized as the major component of pancreatic amyloid deposits present in type 2 diabetic patients. In normal humans, plasma amylin concentrations vary in response to blood glucose levels, whereas in type 1 diabetic subjects and in late-stage type 2 diabetics it is reduced (being often almost undetectable) and do not increase in response to glucose load. Amylin secretion appears to be delayed and diminished in these populations. Human amylin tends to aggregate or forms insoluble particles and is not suitable for therapeutical use. A synthetic analog of human amylin, pramlintide, was developed, which is readily soluble in water and which possesses the same biological activities as amylin. The physiologic actions of human amylin or pramlintide are shown in table 1. Amylin appears to complement the glucose disposal actions of insulin and improves glucose regulation in type 1 or type 2 diabetic patients, who are absolutely or relatively deficient in amylin. This peptide, administered subcutaneously at 10–100 lg 4 times/day, was able in a multicenter trial to effectively reduce the 24-hour plasma glucose profile in type 1 diabetic patients, without important side effects (only transient, dose-related, upper gastrointestinal symptoms such as nausea were observed). In type 2 diabetics treated with exogenous insulin, pramlintide improved metabolic control and produced statistically significant reduction of serum fructosamine, HbA1c and total cholesterol as well as a trend towards decreased body weight.

Type 1 Diabetes The treatment of type 1 diabetes with diet and insulin has been discussed in chapter IV on Diet and Modification of Nutrient Absorption and chapter

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Table 2. Immunoregulation therapies in animal models

IL-2, IL-4, IL-10 and TNF-a Anticytokine and anti-IFN-c antibodies Anti T-cell antibodies, anti-CD3, -CD4, -CD8 Anti T-cell-receptor antibodies Anti-MHC class I and class II antibodies Immunosuppressive drugs (cyclosporine) Immunomodulating agents Adjuvants (BCG vaccine and CFA) Nicotinamide Treatment with autoantigen: Insulin GAD Heat-shock protein

Table 3. Immunoregulation treatments in diabetic humans Cyclosporine treatment (low benefit, several toxic side effects and recurrence of disease limit its clinical use) Preventive treatment with intravenous or subcutaneous insulin (with a moderate protective effect in 60% of high-risk individuals, compared to 0% in controls) Daily oral insulin (7.5 mg/day) Low doses (nonhypoglycemic) of subcutaneous insulin (capable to prevent or delay type 1 diabetes in prediabetic subjects) Daily oral nicotinamide (3 g/day) (useful to prevent type 1 diabetes)

V on Insulin Treatment in Type 1 and Type 2 Diabetes. Here, additional aspects will be considered. Immunologic Treatment Immunoregulatory Therapy. This intervention is suggested in the prediabetic state (before the autoimmune b-cell destruction) and is directed to the following goals: to prevent the induction of diabetogenic T lymphocytes (or to delete these cells), to induce regulatory cells which inhibit these diabetogenic lymphocytes, and to induce immunological tolerance to autoantigens. Two animal models of autoimmune juvenile diabetes provide a very useful system to evaluate efficacy of the various proposed therapies, i.e. NOD (nonobesediabetic) mice and BB mice. In these animals, several immunoregulation strategies appeared capable to prevent type 1 diabetes (table 2). Only few of these therapies can be applicable to human diabetes. In high-risk prediabetic subjects, clinical trials are in progress with different treatments (table 3).


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Immunosuppression Therapy. This form of therapy is directed to prevent the action of diabetogenic T cells (in the early stage of insulitis) in order to preserve insulin secretion, at least in the short term. In a study, BCG antituberculosis vaccination was reported to be effective, with a 66% remission in the newly diagnosed treated patients as compared to 7% in the controls. Two other clinical trials with BCG vaccine in newly diagnosed type 1 diabetics have found no beneficial effects. Autoantigen Therapy. It is a new promising approach to prevent type 1 diabetes, explored in animal models but whose applicability in humans has not yet been established. It includes: nasal immunization or oral feeding with insulin (which is a b-autoantigen in susceptible subjects), and nasal immunization or oral feeding with GAD, IA-2, ICAp69 and heat-shock protein. Gene Therapy It is the frontier of immunological therapy in diabetes mellitus and is directed to express regulatory cytokines (such as IL-4, IL-10 and TGF-b) or autoantigens in the thymus (selection of T cells in the thymus results in deletion of cells that cause autoimmunity), thus preventing or delaying type 1 diabetes. In overt clinical diabetes, both immunoregulatory and immunosuppressive therapy are unsuccessful. However, it is useful to identify the appearance of antibodies already in the preclinical period in order to preventively treat susceptible people (who will develop type 1 diabetes). Pancreas or Islet Transplantation Pancreas Transplantation. Pancreas transplantation (total or segmental) is most often performed together with kidney transplantation, when the latter is needed. This requires immunosuppression treatment. Transplant of the pancreas alone is perhaps not advisable, because the advantage of good metabolic control should be evaluated against the risks of the immunosuppression therapy. However, successful pancreas transplantation, until rejection occurs, is able to normalize blood glucose. Pancreas transplantation is the only treatment of type 1 diabetes that consistently establishes an insulin-independent, normoglycemic state. Currently, long-term (?1 year) insulin independence is achieved in ?80% of recipients of pancreas grafts placed simultaneously with the kidney and ?70% in recipients of a pancreas after a kidney, and ?60% of nonuremic recipients of a pancreas alone. The penalty is immunosuppression, already obligatory for a kidney recipient, but the benefits are improvement in quality of life and the effect that perfect control of glycemia can have on secondary complications. Pancreas grafts may function for a long time and b-cell ‘exhaustion’ does not occur in patients with high preoperative C-peptide (?1.37 ng/ml) levels. Pancreas transplantation can reverse the lesions of dia-

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betic nephropathy, but reversal requires more than 5 years of normoglycemia. Moreover, with the improvement of metabolic control, reduction of hypertension is often observed. However, pancreas-kidney transplantation provokes proportional hyperproinsulinemia, which is closely associated with reduced clearance in the kidneys. Long-term follow-up after transplantation indicates that GAD antibodies persist and ICA reappear despite immunosuppressive therapy in patients with functioning pancreas transplants, which may entail a risk for diabetes recurrence. Islet Transplantation. Transplantation of isolated islets has not yet yielded fully satisfactory results. The same is true for the implantation of nonislet cells engineered to produce human insulin. Yet, islet transplantation could become an attractive alternative to whole organ transplantation, since it is a simpler and safer procedure. However, the requirement for long-term immunosuppression has limited the indication of islet transplantation to patients receiving a simultaneous kidney transplant or already bearing one. Although the majority of recipients of islet allografts did not become insulin independent, the long-term results in patients with even partial graft function are comparable or better than those achievable with intensive insulin therapy. Indeed, successful islet transplantation is a difficult challenge, but current achievements with human islet allografts may greatly improve glycemic control. In some studies, serum C-peptide levels diminished after a few months, and after 6–10 months were undetectable. Islet function loss is probably to be explained by rejection or cytomegalovirus infection. Moreover, trials of donor bone marrow infusions combined with solid organ transplants are in progress to determine whether donor-specific tolerance can be achieved with the potential to expand the future indications of islet transplantation in diabetes.

Drugs Suggested for Both Type 1 and 2 Diabetes a-Glucosidase Inhibitors. These include acarbose (an insoluble a-glucosidase inhibitor) and miglitol (a soluble short-term a-glucosidase inhibitor). Both are alternative drugs, orally active, that act at the brush border of the small intestine by inhibiting a-glucosidase, thus interfering with the conversion of disaccharides to monosaccharides. Therefore, they delay the digestion of complex carbohydrates and disaccharides by reducing absorption of glucose and flattening the postprandial glucose level. Acarbose is an antihyperglycemic agent which has been proposed as add-on therapy in type 2 diabetic patients not well controlled with diet alone, sulfonylureas, metformin or insulin, and in type 1 diabetic patients with large meal-related plasma glucose excursions. Treatment with acarbose has several effects (table 4). The efficacy and side


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Table 4. Effects of acarbose treatment Delay in digestion of complex carbohydrates Reduction in glucose absorption Decrease in postprandial glycemia Decrease in postprandial insulinemia Decrease in postprandial C-peptide level Decrease in fasting glycemia (only in some diabetic patients)

Increase in breath hydrogen Decrease in nutrient-stimulated insulin secretion Decrease in nutrient-stimulated GIP secretion Decrease in fasting serum triglycerides Decrease in fasting serum cholesterol

effects of this drug seem to depend on national nutrition habits. Numerous controlled studies in type 2 diabetes have demonstrated the usefulness of acarbose, at a dose of 150–600 mg/day, in decreasing fasting and postprandial glucose levels as well as HbA1c concentrations (mean decrease of 0.7%), whether acarbose was given as first-line therapy in diet-treated diabetic patients or in combination in individuals already receiving a sulfonylurea, metformin or insulin. Only a few controlled studies have compared the effects of acarbose with those of either sulfonylurea or metformin, yielding controversial results. In type 1 diabetic patients, a small reduction of HbA1c levels was also reported after addition of acarbose to insulin therapy, which in some cases allowed a slight reduction of daily insulin needs. All these favorable biological effects occurred without exposing the patient to hypoglycemia or weight gain. A few studies have also reported favorable effects on postprandial lipid profile and some other vascular risk factors. In a recent study, acarbose was suggested as a first-line drug in the treatment of either type 2 diabetic patients with mild elevation of glycemia, alone or as an adjunct to sulfonylureas, or in type 1 patients associated with insulin therapy. Acarbose was reported to reduce HbA1c by 0.4–1.5% with a maximum effect at 3 months, which was further well maintained. In the UKPDS, glibenclamide as well as insulin therapy induced a weight gain of 4.8 kg, whereas the intake of acarbose (probably through reduction of hyperinsulinemia) was associated with a mild weight loss (0.7 kg after 1 year follow-up). Acarbose also has the advantage that it does not cause hypoglycemia, being an antidiabetic rather than a hypoglycemic agent. It is well tolerated in the dose range of 25–250 mg t.i.d., but small doses (from 25 to 50 mg t.i.d.) can also be effective and cause only fewer gastrointestinal side effects. The latter include meteorism, flatulence, nausea, borborygmus, diarrhea and abdominal cramps or distension. The frequency of gastrointestinal complaints is not related to the acarbose dose and decreases over time. Adaptation of intestinal enzyme activity may account for the diminution of intestinal side

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effects. The drug was shown to be safe and well tolerated. It may also improve hyperlipoproteinemia. However, it is not clear whether the extra cost of acarbose, when compared to that of older oral antidiabetic agents, is justified since no study has yet demonstrated its potential benefit on the complications and long-term prognosis of diabetic patients. Insulin-Like Growth Factor I (IGF-I ). IGF-I (or somatomedin C) is one of the major components of nonsuppressible insulin-like activity. IGF-I and insulin share common steps in signal transduction, and the action of IGF-I on carbohydrate metabolism is preserved in certain insulin-resistant states. GH hypersecretion and reduced circulating IGF-I levels are prevalent in poorcontrolled insulin-dependent diabetes. Recently, both bacteria and fungi have been engineered to produce sufficient quantities of recombinant human IGF-I (rhIGF-I), so that rhIGF-I has been proposed as a potential therapeutic agent in the treatment of both type 1 and type 2 diabetic patients. rhIGF-I not only improves glucose tolerance and increases insulin sensitivity, but also improves insulin secretion in response to intravenous glucose. It is uncertain whether this is a direct effect of rhIGF-I on the pancreatic b-cell or an effect secondary to improved glycemic control (reduced glucose toxicity). The most appropriate dose to achieve efficacy and safety remains to be defined. Nicotinamide. This soluble vitamin of the B group, alone or with sulfonylureas, increases serum C-peptide release in type 1 patients as well as in type 2 diabetic patients with sulfonylurea failure, improving glycemic control.

Suggested Reading Alejandro R, Ricordi C: Current indications and limits of pancreatic islet transplantation in diabetic nephropathy. J Nephrol 1997;10:245–252. Bailey CJ, Turner RC: Metformin. N Engl J Med 1996;334:574–579. Fischer S, Hanefeld M, Spengler M, Boehme K, Temelkova Kurktschiev T: European study on doseresponse relationships of acarbose as a first-line drug in non-insulin-dependent diabetes mellitus: Efficacy and safety of low and high doses. Acta Diabetol 1998;35:34–40. Genuth S: Management of adult onset diabetes with sulfonylurea drug failure: Diabetes mellitus, perspective on therapy. Endocrinol Metab Clin North Am 1992;21:351–369. International Diabetes Federation (IDF), 1998–1999 European Diabetes Police Group: A Desktop Guide to Type 2 (Non-Insulin-Dependent) Diabetes mellitus. Brussels, IDF, 1999. Laakso M: Benefits of strict glucose and blood pressure control in type 2 diabetes. Lessons from the UK Prospective Diabetes Study. Circulation 1999;99:461–462. Lebovitz HE: Oral hypoglycemic agents; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and Practice, ed 4. New York, Elsevier, 1990, pp 554–574. Linse L, Brasseur R, Malaisse WJ: Conformational analysis of non-sulfonylurea hypoglycemic agents of the meglitinide family. Biochem Pharmacol 1995;50:1879–1884. Masetti M, Inverardi L, Ranuncoli A, Iaria G, Lupo F, Vizzardelli C, Kenyon NS, Sutherland DE: Pancreas transplantation as a treatment for diabetes: Indications and outcome. Curr Ther Endocrinol Metab 1997;6:496–499.


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Moses AC, Morrow LA, O’Brien M, Moller DE, Flier JS: Insulin-like growth factor I as a therapeutic agent for hyperinsulinemic insulin-resistant diabetes mellitus. Diabetes Res Clin Pract 1995;28(suppl): 185–194. Singh B: Possible immunological treatment for type 1 diabetes in the 21st century. Pract Diabetes 1997; 14:197–200. Thomson RG, Pearson L, Schoenfeld SL, Kolterman OG, and the Pramlintide in Type 2 Diabetes Group: Pramlintide, a synthetic analog of human amylin, improves the metabolic profile of patients with type 2 diabetes using insulin. Diabetes Care 1998;21:987– 993.


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Chapter VII

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Clinical Emergencies in Diabetes. 1: Diabetic Ketoacidosis and Hyperosmolar Nonketotic Syndrome F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Diabetic Ketoacidosis Diabetic ketoacidosis (DKA) is the classical acute metabolic complication of type 1 diabetes, although it may also occur much less commonly in type 2 diabetes, being primarily due to severe insulin deficiency. The hormonal pattern favoring DKA is represented by severe insulin deficiency and/or excess of counterregulatory hormones (or stress hormones) which include glucagon, catecholamines, cortisol and GH. Among counterregulatory hormones, however, glucagon plays the major role, so that the key hormonal condition favoring DKA is depression of the insulin/glucagon ratio. Insulin deficiency may occur because of interruption or inadequacy of insulin administration or in the setting of the first manifestation of type 1 diabetes. Counterregulatory hormones may increase following physical (infections, surgery, trauma) or emotional stresses, and oppose insulin action. In addition, epinephrine may also stimulate glucagon release, which is also favored by lack of insulin. The deficiency of insulin reduces peripheral glucose utilization, while the low insulin/glucagon ratio stimulates hepatic gluconeogenesis (and therefore hepatic glucose production) by inducing a decrease of the key regulatory compound fructose-2,6-P (which stimulates glycolysis and depresses gluconeogenesis). Gluconeogenesis utilizes the gluconeogenic precursors which come from muscle (pyruvate and lactate derived from glucose, alanine derived from proteolysis as well as from amination of pyruvate, and other amino acids derived from proteolysis) and to a minor extent from adipose tissue (glycerol, released together with FFA during lipolysis). These changes result in marked

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hyperglycemia. The lack of insulin will also produce a high rate of lipolysis (insulin exerts an antilipolytic action by inhibiting the hormone-sensitive lipase), so that the adipose tissue releases large amounts of FFA with consequent hyperafflux of FFA to the liver. As outlined in figure 2 and its legend in chapter I, in the liver the FFA may be reesterified to triglycerides (in the cytosol) or b-oxidized to acetyl-CoA. Triglycerides so formed may be deposited in the hepatocytes (causing steatosis) or may be incorporated into VLDL which are secreted into the circulation. The b-oxidation of FFA to acetylCoA occurs after the transport of FFA into the mitochondria, effected by the enzyme CPT-1. Glucagon activates the latter mechanism (ketogenesis) both by enhancing the availability of carnitine (a metabolite required for the CPT-1 reaction) and, especially, by lowering the concentration of malonyl-CoA, a key regulatory compound which inhibits CPT–1. Glucagon lowers the malonylCoA level by two mechanisms: (a) by inhibiting glycolysis (through the diminution of the regulatory compound fructose-2,6-P – see above) and therefore the concentration of pyruvate, through the sequence pyruvate (cytoplasm) K acetyl-CoA (mitochondria) K citrate (mitochondria) K citrate (cytoplasm) K acetyl-CoA (cytoplasm) K malonyl-CoA (cytoplasm), and (b) by inhibiting the enzyme acetyl-CoA carboxylase that catalyzes the latter step (conversion of acetyl-CoA to malonyl-CoA). The resulting activation of b-oxidation of FFA leads to formation of excessive amounts of acetyl-CoA which is then condensed to form b-hydroxybutyrate (two molecules of acetyl-CoA are converted into acetoacetate, which can then be converted to b-hydroxybutyrate). Thus, in DKA the liver exerts two main functions: (a) as concerns carbohydrate metabolism, it takes up gluconeogenic precursors and releases glucose (producing hyperglycemia, osmotic diuresis and dehydratation, with osmolality in the 310–330 mosm/l range) and (b) concerning lipid metabolism, it takes up FFA and releases VLDL and ketone bodies (which results in hypertriglyceridemia and acidosis). Clinical Picture Preceded by polyuria (due to osmotic diuresis), the clinical picture begins with anorexia, nausea, vomiting (which precludes oral fluid intake) and, often, abdominal pain (periumbilical and constant) which can mimic a surgical emergency. If treatment is not started, alterations in consciousness ensue, which may evolve to frank coma. Physical signs are due to dehydration and acidosis and include: sweet, sickly smell of the patient’s breath, deep and rapid respiration (Kussmaul respiration), low jugular venous pressure and tachycardia. In most severe cases, vascular collapse and acute renal failure may develop. White blood cell count may be markedly elevated, even in the absence of infection. Body temperature is normal or tendencially low, unless infections develop.

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Laboratory Data Laboratory data show increase of the anion gap, and abnormalities in potassium, sodium, triglycerides, azotemia and amylase. The anion gap is the difference between the routinely measured cations and anions. Normally, to maintain a pH close to neutrality (7.35–7.45), the sum of cations, including sodium, potassium, calcium and magnesium, should be approximately equal to the sum of anions, such as chloride, bicarbonate, and other routinely not measured anions comprising some organic acids (lactic acid, pyruvic acid, FFA, etc.) and inorganic acids (phosphates, sulfates) as well as anionic proteins (albumin and others). When, in pathologic conditions, an acidic compound enters or increases in the blood (ketone bodies in the case of DKA), it is neutralized with the sodium (and potassium) subtracted from bicarbonates. The latter in this way become carbonic acid which rapidly dissociates into CO2 (which will be lost with the breath) and H2O (which will be eliminated by the kidneys). As result of this process, the concentration of blood bicarbonates falls to an extent proportional to the amount of the acidic compounds which originate from the perturbation. In the clinical setting, the cations and anions measured as routine are Na+, K+, ClÖ and HCOÖ 3 whereas other cations and anions remain unmeasured. Therefore, considering only the routinely measured cations and anions there is, already in the normal state, an anion gap which can be calculated as follows: Serum anion gap> ([Na+]+[K+])Ö([ClÖ]+[HCOÖ 3 ]), with normal values of about 14–16 mmol/ l or, in a simpler way: Serum anion gap>[Na+]Ö([ClÖ]+[HCOÖ 3 ]), with normal values of about 10–12 mmol/l. About half of the normal anion gap is accounted for by albumin and the other by anionic proteins. With the technical procedures in use in recent years, which yield higher values for ClÖ, the normal anion gap may be remarkably lower. It is therefore useful to refer to the normal values of the local laboratory. In DKA, the increased anion gap is due to the fall in bicarbonate (6–10 mmol/l) caused by the accumulation in the blood of the ketone bodies (acetoacetate and b-hydroxybutyrate), with minimal contribution of lactate and FFA. Potassium content of total body decreases markely, although serum K+ levels may be initially normal due to the cell buffering mechanism (exchange of intracellular K+ for extracellular H+), before diminishing as a consequence of the osmotic diuresis (together with other electrolytes such as magnesium and phosphates). Sodium concentration tends to be moderately lowered (in the 130–132 range) due to the osmotic shift of water into the plasma space, and may become severe if prolonged vomiting plus water drinking occur. Triglycerides are elevated, sometimes to very high values, due to both enhanced hepatic prodution of VLDL (stimulated by the hyperafflux of FFA to the liver) and diminished VLDL disposal due to reduced activity of lipoprotein

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lipase (which is normally stimulated by insulin). It should be pointed out that, when VLDL are very high, artifactually low values of electrolytes may be obtained when measurement is done with the autoanalyzer, because of the high concentration of fats which occupy a substantial percentage of the total serum volume. Azotemia may develop as result of dehydration and volume depletion (prerenal azotemia). Elevation of serum amylase (of nonpancreatic origin) often occurs which, when associated to severe abdominal pain, may simulate pancreatitis. Complications and Mortality While the frequency and mortality rate have markedly diminished with the improvement of diabetes knowledge and patient care, in some settings mortality may still be as high as 10%, and it is due mainly to superimposed complications. The latter include: gastric dilation (vomiting of bloody or dark material), infections (especially pneumonia), mucormycosis (epistaxis, unilateral headache, alteration in mental status, eye symptoms), respiratory distress syndrome, myocardial infarction and vascular thrombosis (signs and symptoms of ischemia in the cerebral or other vascular regions). In addition, cerebral edema is a serious complication, more often seen in children than in adults. It may be due to the low osmolality of plasma compared to brain after therapeutically induced glucose fall and rehydration. Once diagnosed (on the basis of CT findings), it should be treated with mannitol (1 g/kg as 20% solution) and dexamethasone (whose efficacy is not certain); if improvement is not observed, hyperventilation (to lower PaCO2 to about 28 mm Hg) may be helpful. Diagnosis Diagnosis should be made by excluding lactic acidosis, alcoholic ketoacidosis, pancreatitis, uremia, and poisonings. The exact diagnosis is suggested by elevated plasma glucose and ketone bodies. Concerning the latter, measurement in plasma should be performed, since positivity in the urine may also occur with starvation ketosis. A semiquantitative assay can be performed using ketone reagent strips (Ketostix) or tablets (Acetest) on diluted plasma: a positivity with dilution higher than 1:1 suggests DKA (it may also be seen in patients with alcoholic ketoacidosis in whom, however, blood glucose rarely exceeds 160 mg/dl or 8.4 mmol/l). It should be pointed out that ketogenesis produces acetoacetate, which (in addition to undergoing spontaneous decarboxylation to acetone) may be converted into b-hydroxybutyrate through an oxido-reductive reaction, with simultaneous conversion of NADH to NAD. Normally, the ratio b-hydroxybutyrate/acetoacetate is around 3:1, but in severely ill patients with dehydration and vascular collapse, there is some degree

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of hypoxia and acidosis, which favors the conversion of acetoacetate to b-hydroxybutyrate with increased concentration of the latter compounds. When the patient improves with therapy, the total amount of ketone bodies will diminish, yet the accumulated b-hydroxybutyrate is reconverted into acetoacetate, whose concentration may not decrease or may even increase. Since ketone reagent strips measure acetoacetate (and to some extent acetone), this may give the false impression that the treatment is ineffective. Therefore, the correction of the pH and the diminution of the anion gap may be more reliable parameters for evaluating the effectiveness of treatment. Treatment Therapy of DKA relies upon rehydration and insulin administration. It is useful to prepare a local care protocol and to distribute it to relevant professionals. Saline solution should be given intravenously at the rate of 2 liters in 2 h, followed by infusion of 0.4 liter/h of saline or half-normal saline (0.45%) for about 6 h, based on the clinical response. The total fluid deficit is of about 3–5 liters. Hypotonic saline should be given with caution (if plasma Na+?155 mmol/l: 1 liter over 8 h). Colloid solutions should be used in presence of hypotension (systolic blood pressure=100 mm Hg after 2 h). When glucose level decreases to =250–300 mg/dl, infusion of 5% glucose should be added, to prevent excessively rapid glucose fall that may contribute to the severe complication of cerebral edema as well as to allow continuing insulin infusion until ketosis disappears (often plasma glucose falls more rapidly than plasma ketone bodies). Insulin (rapid-acting or regular) should be administered in low doses, by infusing a bolus of about 10 U followed by 8–10 U/h (in contrast to the higher doses previously used), until disappearance of ketone bodies and normalization of glycemia is obtained. This regimen often ensures a progressive decrease in blood glucose, avoiding a precipitous fall which may favor cerebral edema. These doses, however, should not be regarded as ‘low’ when compared to the amount of insulin produced in 24 h in the normal man (25–28 U). However, it should be considered that in DKA, a variable degree of insulin resistance is present, as result of several factors (see chapter III, paragraph on Insulin Resistance in Type I Diabetes). For this reason, in some patients, higher doses of insulin may be required, i.e. a bolus of 20 U or higher followed by infusion of 15 U/h or more. These excessive amounts of insulin are justified in view of the possibility that, after saturation of insulin receptors, the surplus of available insulin may act through activation of the IGF-1 receptors. It is noteworthy that up to 20% of insulin binds to the flask and tubing (much higher percentage with lower doses) and that, when we use the same set for a second infusion, the binding sites are saturated and therefore the amount of free insulin actually infused will be higher.


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Potassium administration is often required. This cation may be normal in serum even if the total body content is decreased. When the plasma level is low, 30–40 mmol/h of potassium should be infused, and a lower dose (20 mmol/h) should also be given when serum potassium is normal, because with the beginning of therapy a further fall in serum potassium occurs as a result of the effect of insulin (which causes a shift of potassium into the cells) and fluid replacement (that dilutes serum potassium). ECG represents a useful tool to assess intracellular potassium concentration, showing flat or inverted T waves when intracellular potassium is low and peaked T waves when intracellular potassium is high. Bicarbonate administration is only required in patients with severe acidosis (pH=7). Bicarbonate should be given at a slow rate (about 44 mEq during 1 or 2 h) and discontinued when the pH rises to 7.1. In DKA, 2,3-diphosphoglycerate (2,3-DPG) is low in red cells, which decreases oxygen delivery. This is counterbalanced by acidosis, which favors oxygen delivery. A rapid correction of acidosis with bicarbonate may leave the effect of the 2,3-DPG unopposed, causing impaired oxygen release which, in presence of volume depletion and reduced tissue perfusion may favor the development of tissue hypoxia and lactic acidosis. In presence of infections, antibiotic therapy should be employed. When the patient is comatose, insert a nasogastric tube, use a urinary catheter (if no urine passes within 3 h) and heparinize in case of hyperosmolar coma development or in presence of thrombosis risk factors. After the recovery from a diabetic ketoacidotic episode, it is useful to accurately review the causes to reduce the risk of recurrence.

Hyperosmolar Nonketotic Syndrome Hyperosmolar nonketotic syndrome (HNKS) is an acute complication observed most often in type 2 diabetic patients and is characterized by symptoms and signs due to volume depletion (caused by excessive hyperglycemia and consequent hyperosmolality and osmotic diuresis), with varying degree of clouding of sensorium, ranging from absence of mental impairment (about 10%) to frank coma (about 10%). HNKS is a serious complication, which entails a mortality rate as high as ?40%. Pneumonia (favored by sensory clouding which facilitates aspiration of oropharyngeal secretions) may develop in HNKS patients, as well as other infections. The dehydration elevates plasma viscosity and may favor thrombosis. Disseminated intravascular coagulation (DIC) may also occur, with bleeding manifestations.

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Laboratory findings include a marked hyperglycemia (usually higher than that occurring in DKA, reaching a level of ?800 mg/dl or 44 mmol/l) which causes increase in serum osmolality (which may be as high as ?350 mosm/l), whereas sodium is normal or slightly changed. Urea nitrogen and creatinine are elevated, together with inorganic acids (phosphates and sulfates) because of prerenal azotemia consequent to volume depletion. In contrast to DKA, in HNKS the metabolic acidosis is absent or mild, and bicarbonates are slightly changed. When present, acidosis is due to retention of inorganic acids (see above), i.e. a small amount of ketone bodies as well as a certain amount of lactate (due to tissue hypoperfusion consequent to volume depletion). The extreme hyperglycemia with the ensuing hyperosmolality may be favored by the abundant hyperglycemic diuresis in patients who are unable to compensate the large fluid loss with urine by adequate water drinking, as it often occurs in old patients, who have an attenuated sensation of thirst and who often live alone or in nursing homes. However, it should be kept in mind that HNKS may be precipitated by several factors, including infections, cerebrovascular events, hypertonic peritoneal dialysis, parenteral nutrition or administration of the osmotic agent mannitol or diuretics as well as corticosteroids and phenytoin. The lack of acidosis in HNKS may be the result of several factors. (1) HNKS develops in type 2 diabetic patients, who possess a varying degree of residual endogenous insulin secretion. Since lipolysis is more sensitive to insulin than the glucose homeostatic mechanisms, it is possible that the residual insulin secretion, while unable to stimulate glucose utilizaton and to repress hepatic glucose production, is able to refrain lipolysis, thus limiting the FFA afflux to liver and therefore the ketogenic process. (2) The endogenously secreted insulin reaches, through the portal vein, the liver, which is insulinized to a sufficient degree to prevent activation of ketogenesis (i.e. to allow glucose to be utilized in sufficient amount to produce enough malonyl-CoA, which inhibits the ketogenic process at the level of CPT-1. (3) There may be glucagon resistance, which prevents glucagon to exert its ketogenic effects (see under DKA). (4) There may be an enhanced activity of the Cori cycle, with increased afflux of lactate to the liver, where it may be in part metabolized to malonylCoA, thus refraining ketogenesis. HNKS treatment is primarily directed to restore blood volume and correct hyperosmolality. This may require the supply of intravenous fluid in the total amount up to 8–10 liters. Therapy may be started by intravenous infusion of saline at the rate of 1.5 liters/h for the first 2 h, followed by infusion of 0.5 liter/h of half-normal saline (0.45%) adjusted according to the clinical and laboratory response. Insulin should also be given. This may be done according to the small dose regimen described under DKA, although some patients may


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require larger doses. Potassium should be supplied (see under DKA) with special attention because, in the absence of acidosis, the intracellular K+ transfer induced by insulin administration is more pronounced. Attention should also be paid to the possible development of infections or thrombosis or DIC to start timely the appropriate therapy.

Suggested Reading Foster DW, McGarry JD: The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med 1983;309:159–169. Genuth SM: Diabetic ketoacidosis and hyperglycemic hyperosmolar coma. Curr Ther Endocrinol Metab 1997;6:438–447. Gonzalez-Campoy JM, Robertson RP: Diabetic ketoacidosis and hyperosmolar nonketotic state: Gaining control over extreme hyperglycemic complications. Postgrad Med 1996;99:143–152. Silink M: Practical management of diabetic ketoacidosis in childhood and adolescence. Acta Paediatr 1998;425(suppl):63–66. Siperstein MD: Diabetic ketoacidosis and hyperosmolar coma. Endocrinol Metab Clin North Am 1992; 21:415–432. Umpierrez GE, Khajavi M, Kitabchi AE: Review: Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Am J Med Sci 1996;311:225–233. Whiteman VE, Homko CJ, Reece EA: Management of hypoglycemia and diabetic ketoacidosis in pregnancy. Obstet Gynecol Clin North Am 1996;23:87–107.


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Chapter VIII

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Clinical Emergencies in Diabetes. 2: Hypoglycemia F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Definition The term hypoglycemia refers to a biochemical condition resulting from an abnormally low plasma glucose level, less than the lower value of the normal range (50–45 mg% or 2.8–2.5 mmol/l). Thus, the term hypoglycemia seems inappropriate to define a variety of clinical manifestations associated with abnormally low blood glucose and consisting of signs and symptoms of adrenergic activation and neuroglycopenia, responsive to glucose administration. In infants, during the first 48 h of life, hypoglycemia may occur, with glycemic values =30 mg% or 1.7 mmol/l, with a frequency of about 10% of live births. A brief hypoglycemic episode can cause moderate alterations of the brain whereas prolonged hypoglycemia can cause profound dysfunctions, tissue damage and also death of the brain. This depends on the fact that the deposit of glycogen in brain is negligible (the reserve of energy lasts 2–3 min) and that glucose is not synthesized by the central nervous system (CNS). Thus, glucose (together with oxygen) is an obligate primary energy substrate for the brain tissue and is entirely derived from the circulation. The brain tissue utilizes 120 g/day of glucose and about 90% of total energy needed for cerebral functions derives from glucose oxidation. The brain cannot utilize alternative substrates (as circulating FFA) as energy fuel thus being very sensitive to hypoglycemia. In some particular situations, at least some parts of the brain might utilize ketoacids. Hypoglycemia is a very uncommon event, apart from persons with diabetes treated with insulin or hypoglycemic drugs. The diagnosis of hypoglycemia is based upon Whipple’s triad, i.e. hypoglycemia, symptoms of hypoglycemia, and correction of the symptoms with the normalization of blood glucose.

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Glucose Counterregulation Insulin regulates glycemia through modulation of hepatic glucose production in the postabsorptive state and glucose utilization in the postprandial state, and it is the only hormone able to physiologically reduce glycemic level. In catabolic states (fasting), insulin concentration falls and the levels of counterregulatory hormones rise; in fact, hypoglycemia is capable of inducing the release of counterregulatory hormones, including glucagon, catecholamines (epinephrine and norepinephrine – released both from adrenal medulla and the sympathetic neurons), cortisol and GH. The glucagon secretory response to hypoglycemia is largely CNS-independent whereas catecholamine, cortisol and GH responses are prevailingly CNS-dependent. Glucagon acts within minutes and is the primary hormone of glucose maintenance (by stimulating hepatic glucose production through increase in glycogenolysis and gluconeogenesis). Catecholamines also act swiftly, stimulating glucose production and limiting glucose utilization in humans through both b2- and a2-adrenergic mechanisms. Cortisol and GH, on the contrary, act within several hours with a delayed glucoregulatory action (antagonizing insulin action, mobilizing substrate and activating hepatic gluconeogenesis through the induction of the relative gluconeogenic enzymes). All these hormones have a synergic action on the induction of hyperglycemia and on the prevention and correction of hypoglycemia. Glucagon plays the most important counterregulatory action whereas catecholamines play a minor role, that becomes important when there is glucagon deficiency, as it often happens early during the course of diabetes mellitus. Catecholamines are the warning system in hypoglycemia through the symptoms and signs of adrenergic overactivity. Cortisol and GH play no role in short-term hypoglycemia but have a substantial role in the recovery from long-term hypoglycemia. The relevance of other hormones or neurotransmitters in preventing and correcting hypoglycemia has been debated but it is not definitely established. In type 1 diabetic patients, counterregulation is often altered and, in some patients it may be very deficient. It has been reported that almost all diabetic patients show a deficient glucagon secretory response to hypoglycemia, perhaps as a result of the long-term hyperglycemia (glucose toxicity) or the loss of the regulating effect of insulin on glucagon secretion. In the presence of a defective glucagon secretion, type 1 diabetic patients during hypoglycemic episodes became dependent upon catecholamines to correct low glycemic level, i.e. epinephrine response compensates for deficient glucagon response. Some diabetic patients with long-standing disease have also a deficient catecholamine response to hypoglycemia and this combined disorder impairs glucose counterregulation and represents a high risk of iatrogenic hypoglycemia in these subjects. GH and cortisol responses to hypoglycemia

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Table 1. Causes of hypoglycemia A. Fasting hypoglycemia 1. Reduced glucose production Liver or renal insufficiency Deficiency of counterregulatory hormones Childhood ketotic hypoglycemia (substrate or enzyme deficiency) Drugs (alcohol, salicylates, b-blockers) 2. Increased glucose utilization b-Cell tumor or insulinoma Functional hypersecretion of b-cells Autoantibodies to insulin Autoantibodies to insulin receptors Sepsis Insulin or insulin-releasing drugs (sulfonylureas, pentamidine, quinine) Newborn hypoglycemia (first hours of life, if mother is diabetic) Extrapancreatic non-b-cell tumors Childhood nonketotic hypoglycemia (deficit of carnitine or of enzymes of FFA utilization Exhaustive exercise

B. Postprandial or reactive hypoglycemia Alimentary hypoglycemia (gastrectomy, gastrojejunostomy, pyloroplasty or vagotomy) Hyperthyroidism Obesity with hyperinsulinism Early stage of type 2 diabetes, prediabetes or IGT Idiopathic reactive hypoglycemia Idiopathic postprandial syndrome or pseudohypoglycemia Inherited disorders of carbohydrate metabolism in children Intake of leucine in leucine-sensitive children

3. Factitious or artifactual Factitious hypoglycemia (surreptitious insulin or sulfonylurea administration) Artifactual hypoglycemia (in hemolytic anemia or in leukemia or in hyperlipemia)

in type 1 diabetes are usually not reduced, but deficiency of their secretion may occur.

Classification of Hypoglycemia (see table 1) Postabsorptive or Fasting Hypoglycemia Fasting hypoglycemia may result from impaired hepatic glucose production (involving glycogenolysis or gluconeogenesis) or enhanced peripheral glucose utilization. It can be induced by several causes, listed below. Reduced Glucose Production. This occurs in the following instances: (1) Chronic failure of critical organs such as liver diseases (hepatitis, cirrhosis or hepatoma, severe heart failure with hepatic congestion) which


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impair hepatic glucose production, or conditions of inadequate substrate store and supply (chronic renal failure, malnutrition, starvation or cachexia, anorexia nervosa, late pregnancy). (2) Deficiency of counterregulatory hormones (glucagon and epinephrine, cortisol and GH) that impairs gluconeogenesis, as occurs in hypopituitarism, in adrenal insufficiency and rarely in glucagon deficiency. (3) Ketotic hypoglycemia of infancy and childhood, linked to substrate deficiency or due to defects in one or more of the gluconeogenic or glycogenolytic enzymes, sometimes associated to lactic acidosis. (4) Drugs such as alcohol (which inhibits hepatic gluconeogenesis) especially when associated to fasting, salicylates (a common cause of hypoglycemia in infants) which would increase peripheral glucose utilization and reduce hepatic gluconeogenesis, b-blockers (which reduce the glycogenolytic response to epinephrine). Increased Glucose Utilization. Several causes may lead to increased glucose utilization: (1) Endogenous hyperinsulinism (that causes glucose overutilization) produced by: (a) b-cell tumor or insulinoma (a rare, most often small and single, benign tumor occurring in 1/250,000 adult individuals) or islet cell hyperplasia (nesidioblastosis), a rare syndrome in adult subjects; (b) functional hypersecretion of b-cells; (c) autoimmune hypoglycemia (autoantibodies against insulin, with inappropriate release of antibody-bound insulin in the circulation), common in Japan; (d) rare instances of acanthosis nigricans (insulin receptor autoantibodies, which most often cause insulin resistant diabetes, can in some patients act as insulin-like factors); (e) ectopic insulin secretion. (2) Sepsis (cytokines associated to endotoxinemia increase insulin release). (3) Insulin or drugs that stimulate insulin release, such as sulfonylurea compounds in diabetic patients, pentamidine (which exerts a toxic effect with b-cell cytolysis), and quinine (which induces massive insulin release, although this effect is not well demonstrated). (4) Hypoglycemia of infants born from diabetic mothers, occurring during the first hours of life (provoked by fetal hyperinsulinemia linked to hyperplasia of b-cells induced by maternal hyperglycemia and hyperglucagonemia). (5) Non-b-cell or extrapancreatic large tumors of mesenchymal (50%) or epithelial origin (5–10%) or hepatomas (25%) or other carcinomas (5–10%) or some malignant hematologic diseases (5–10%), in which hypoglycemia is induced by production of insulin-like growth factors such as IGF-2, that interacts with insulin receptors (and may suppress endogenous insulin secretion), or by overutilization of glucose (by the tumoral tissue).

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(6) Nonketotic hypoglycemia due to systemic carnitine deficiency or enzymatic defects which limit the utilization of FFA or ketones (which entails enhanced glucose oxidation for energetic purposes). (7) Prolonged and exhaustive exercise, especially in untrained persons (increased glucose utilization). Factitious or Artifactual Hypoglycemia. Two conditions should be distinguished: (1) Factitious hypoglycemia from deliberate and surreptitious insulin or sulfonylurea assumption (especially in medical people or family members of diabetic patients with psychiatric disturbances). (2) Artifactual hypoglycemia as it may occur in hemolytic anemia or in leukemia and leukemic reactions (due to overutilization of glucose in the test tube by young erythrocytes or leukemic leukocytes) or in the presence of marked hyperlipemia (which may cause a 15% – or more – underestimation of glucose concentration). Postprandial or Reactive Hypoglycemia This form of hypoglycemia occurs within 6 h after a meal, and includes several forms, listed below: (1) Alimentary hypoglycemia (or alimentary hyperinsulinism) caused by gastrectomy, gastrojejunostomy, pyloroplasty or vagotomy, involving about 5–10% of operated patients and developing 30–120 min after ingestion of carbohydrate-containing meals (due to rapid gastric emptying and glucose absorption which stimulate excessive insulin release, and perhaps also to hypersecretion of enterohormones such as enteroglucagon, secretin, GIP, etc.); it may perhaps also occur in patients with hyperthyroidism, or in obesity with hyperinsulinism. (2) Early stage of type 2 diabetes or prediabetes or IGT (deficient earlyphase insulin release leads to higher glucose elevation with subsequent excessive stimulation of insulin secretion). However, it should be mentioned that the relationship between the early stage of type 2 diabetes or prediabetes or IGT and postprandial hypoglycemia is not well established. (3) Idiopathic reactive hypoglycemia or true hypoglycemia (with lowered glucose levels), a rare syndrome characterized by adrenergic symptoms without symptoms of severe neuroglycopenia, probably linked to an increased insulin response or a higher affinity of insulin receptors or to a subtle dysfunction of gastrointestinal tract. (4) Idiopathic postprandial syndrome or pseudohypoglycemia (with a near-normal glycemic value), characterized by adrenergic symptoms and light symptoms of neuroglycopenia, which develop regularly and repetitively during the patient’s life (causes are unknown and might include enhanced


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Table 2. Clinical signs and symptoms of hypoglycemia Sympathetic/parasympathetic activation

Neuroglycopenia

A. Clinical signs and symptoms of adrenergic activation Pallor, tremor, palpitations and anxiety Acute sensation of hunger Occasionally hypothermia, vomiting, fever, moderate tachycardia, crises of systolic hypertension

Clinical signs and symptoms of neuroglycopenia Headache, dizziness, fatigue, irritability or apathy and lethargy Frequent yawning and perioral numbness Disturbed vision and diplopia Paresthesias and motor dysfunction Cognitive impairment, mental confusion and inebriation Personality changes, psychotic behavior Occasionally transient hemiparesis or focal neurologic deficits Convulsions (in children simulating true crises of epilepsy) Semi-coma, coma and even death

B. Clinical signs and symptoms of parasympathetic activation Nausea and eructation Cold sweating Mitigation of expected tachycardia or true bradycardia Mild hypotension

epinephrine release in some subjects, with stress or anxiety contributing in many subjects). (5) Inherited disorders of carbohydrate metabolism in children (hereditary fructose intolerance from deficiency of fructose-1-P aldolase or galactosemia from deficiency of galactose-1-P uridyltransferase). (6) Intake of leucine in leucine-sensitive children (due to increased insulin secretion).

Clinical Signs and Symptoms of Hypoglycemia (see table 2) The clinical manifestations of hypoglycemia are generally nonspecific and varying, not only from patient to patient but also in the same subject from episode to episode. Their development can depend not only on the glycemic value but also on the rate of the fall in blood glucose. Manifestations can be distinguished into adrenergic (due to sympathetic activation) and neuroglycopenic (due to neuronal alterations secondary to glucose deprivation). When glucose drops rapidly, adrenergic symptoms are most evident while when glucose drops gradually neuroglycopenic symptoms may dominate the clinical picture. During a hypoglycemic episode, the response of counterregulatory hormones begins before the symptomatic glucose threshold is reached.

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Neuropenic symptoms may not occur even in the presence of glucose level as low as 25–30 mg/dl (1.4–1.7 mmol/l) due to the ability of normal persons to increase brain blood flow and therefore glucose delivery. This adaptation may be prevented in patients with cerebral atherosclerosis and inelastic vessels, in whom neuropenic symptoms may appear at relatively high glucose levels. It should be pointed out that severe hypoglycemic reactions may occur even in the presence of near-normal or even high glycemic values (pseudohypoglycemia), especially in diabetic patients; on the other hand, there may be no clinical hypoglycemic reactions with very low concentrations of plasma glucose (25–30 mg% or 1.4–1.7 mmol/l). The most important factors probably are the rate of fall in glycemia and the fact that the glucose plasma level may not strictly reflect the glucose concentration in brain tissue. A glycemic range (55–70 mg% or 3.00–3.88 mmol/l) seems to exist in which dysfunction from neuroglycopenia and activation of counterregulatory hormones occur but symptoms are not yet manifest; therefore, the value of 3.88 mmol/l may be a cut-off value of hypoglycemia, useful and safe to consider in the treatment of diabetes mellitus. Adrenergic Symptoms and Signs These are due to catecholamine hypersecretion that develops in response to a blood glucose level =53 mg% or 2.95 mmol/l, and include pallor, anxiety, tremor, palpitations, tachycardia (occasionally with crises of systolic hypertension) and acute sensation of hunger. It is noteworthy that symptoms and signs induced by parasympathetic response can also occur during hypoglycemia, producing nausea, eructation, cold sweating, mitigation of expected tachycardia or true bradycardia, and mild hypotension. Neuroglycopenic Symptoms and Signs These are due to dysfunction of CNS that develops in response to hypoglycemia =45 mg% or 2.50 mmol/l, and include headache, dizziness, fatigue, irritability or apathy, lethargy, frequent yawning, cognitive impairment, mental confusion, inebriation, personality changes and psychotic behavior, disturbed vision and diplopia, perioral numbness, paresthesias, motor dysfunction, convulsions, occasionally transient hemiparesis or focal neurologic deficits (especially in elderly diabetic patients), semi-coma, complete loss of consciousness until hypoglycemic coma and even death. The different neurologic manifestations have been correlated with specific sites of the brain involved in different degrees of hypoglycemia. Clinical hypoglycemic symptoms and signs sometimes suggest true mental disorders, accounting for the frequent reported mistake or delay in diagnosis.


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In children, adrenergic manifestations are near-absent and neuroglycopenic symptoms can predominate with seizures simulating true crises of epilepsy. A failure to develop several adrenergic symptoms before the development of neuroglycopenic symptoms (hypoglycemia unawareness) is observed in 50% of patients with long-standing diabetes (due to the reduced response of sympathetic system to hypoglycemia, secondary to the autonomic neuropathy). However, glucose threshold may also be lowered by hypoglycemia itself which may cause subsequent hypoglycemia unawareness, as it may be observed in patients with insulinoma.

Hypoglycemia Induced by Insulin or Sulfonylurea Treatment The commonest form of hypoglycemia is that induced by insulin or sulfonylureas as well as by ethanol. It accounts for about 60% of patients hospitalized for hypoglycemia, while renal disease accounts for 15%, liver diseases for 15% and malnutrition for 10%. In diabetic patients, hypoglycemic episodes can be isolated or recurrent, and are due to a mismatch of insulin or sulfonylurea therapy to meal pattern or physical activity. In long-standing diabetes, a defective counterregulation with deficiency of glucagon and epinephrine may contribute; these subjects are at 25-fold increased risk for severe iatrogenic hypoglycemic crises during intensive insulin treatment. In type 1 diabetics, mild to moderate symptomatic hypoglycemic crises occur in about 90% of patients (frequently during the night). In insulin-treated diabetics, severe hypoglycemia or hypoglycemic coma was reported in 9–10% of cases in 1 year during conventional insulin therapy, and higher figures most probably apply for patients treated with intensive insulin regimen. The most serious hypoglycemic episodes in diabetic patients can happen with the sulfonylurea compounds. They may occur at any time after ingestion of the drug (from 30–60 min to many hours later) and are characterized by diminished or absent autonomic signs, prolonged or relapsing hypoglycemia and by a response to glucose which is not as prompt as in insulin-induced hypoglycemic episodes. Predisposing factors may hasten the onset or increase the intensity of the hypoglycemic effects of insulin or sulfonylureas (table 3). It is important to avoid hypoglycemia in a diabetic mother in the early period of gestation because maternal hypoglycemia can cause malformations, for a detrimental effect on growth and differentiation of the fetus. Hypoglycemia can have unfavorable long- or short-term effects on vascular complications of diabetes. In fact, it increases systolic and diastolic pressures, glomerular filtration rate, viscosity and platelet aggregation. Repeated episodes

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Table 3. Predisposing factors in drug-induced diabetic hypoglycemia Undernutrition or omission of food or starvation Unexpected exercise Renal or hepatic dysfunction Abuse of alcohol Acute sickness Erroneous high insulin or sulfonylurea doses Increased absorption of insulin from the site of injection

Administration of a b-blocker Defective counterregulation, hypoglycemia unawareness Lowered glycemic threshold for hypoglycemia and counterregulation during intensive insulin treatment (with compromised recognition of developing hypoglycemia)

of hypoglycemia can result in neuropsychologic deficits, especially in younger patients (EEG changes and cognitive impairment) and, if severe, hypoglycemia can be fatal. Related to hypoglycemia is the Somogyi phenomenon, which is a posthypoglycemic hyperglycemia that most often follows a nocturnal fall in blood glucose level (p50 mg/dl) and is due to the response of counterregulatory hormones and the subsequent increase in glycemia. It can be contrasted by reducing the evening doses of drugs. The Somogyi phenomenon should be distinguished from the morning hyperglycemia which may be seen in insulintreated patients, named ‘dawn phenomenon’, linked to the increase in GH secretion normally associated with sleep.

Diagnosis Hypoglycemia in a diabetic patient taking insulin or sulfonylurea drugs is not a diagnostic problem, especially considering that clinical symptoms are most characteristic. Instant glycemic determination (which can be obtained also with a self-blood glucose monitoring device) confirms or excludes the diagnosis of hypoglycemia. In hypoglycemic children, seizures are common and may simulate epilepsy (on the other hand, hypoglycemia may favor or trigger an epileptic focus). An EEG performed successively may help in the diagnosis. Diagnostic problems exist in nondiabetic subjects with symptoms of hypoglycemia because of the several possible causes (factitious or reactive hypoglycemia, insulinoma, extrapancreatic tumors, etc.). In the presence of a patient with suspicion of hypoglycemia, it is crucial to demonstrate the hypoglycemia with a specific determination of blood glucose in specimens obtained during the hypoglycemic event. Very useful in the diagnosis of hypoglycemia is also the assessment of levels of plasma insulin, C-peptide, counterregulatory


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Table 4. Diagnostic tests for hypoglycemia Simultaneous determination of glycemia and insulinemia during hypoglycemic episodes Supervised fasting (the gold standard test) C-peptide suppression test Sulfonylurea assay in plasma or urine 5h-OGTT Insulin tolerance test

Tolbutamide test Glucagon test Vigorous exercise during fasting Proinsulin determination Leucine test Search for antibodies to insulin Search for autoantibodies against insulin or insulin receptors

hormones, drugs or alcohol. It is important to have an accurate history of the patient to distinguish between fasting or postprandial hypoglycemia and to relate hypoglycemic episodes and symptoms and signs. The clinical evaluation should refer to weight loss (extrapancreatic tumor or endocrine deficits) or weight gain (insulinoma or reactive hypoglycemia), presence of autoantibodies against insulin receptors (acanthosis nigricans), hepatomegaly (galactosemia or glycogenosis), and presence of tumoral abdominal masses (of mesenchymal or epithelial origin) localized by CT or abdominal sonography. If an insulinoma is suspected, the tumor should be localized before surgery with ultrasonography (also used intraoperatively), celiac angiography or CT evaluation. Several diagnostic tests can be very helpful (table 4), and are outlined below: (1) Simultaneous determination of glycemia and insulinemia during the hypoglycemic episode and at fasting on 3 consecutive days. (2) Supervised fast, which consists of simultaneous determinations every 4–6 h of glycemia, insulinemia and C-peptide during fasting periods of 24, 48 and 72 h. In insulinoma, glycemia falls while C-peptide and insulinemia remain near-unmodified. Quantitation of plasma cortisol, FFA, glucagon and total ketones can sometimes be useful. In normal male individuals, mean glucose at 72 h is 3.4–3.9 mmol/l (or 62–71 mg%) and in normal female individuals is 2.7–2.9 mmol/l (or 48–52 mg%) while mean insulin is 6 and 4 lU/mL, respectively. A diagnosis of hypoglycemia is probable with values of glycemia =2.5 mmol/l (or 45 mg%) and presence of symptoms which are rapidly relieved by administration of glucose. In the presence of hyperinsulinemia and increase of C-peptide an insulinoma should be suspected, while in the presence of hyperinsulinemia with a low level of C-peptide the possibility of factitious hypoglycemia induced by exogenous insulin (with suppression of C-peptide secretion) should be considered. On the other hand, in factitious hypoglycemia induced by sulfonylureas, both plasma insulin and C-peptide levels are increased.

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(3) C-peptide suppression test, based on the fact that suppression of the release of endogenous insulin and C-peptide during insulin infusion (0.125 U/kg over 1 h or over 3 h) is impaired in about 90% of patients with insulinoma. (4) Assay of sulfonylurea compounds in plasma or urine to diagnose factitious hypoglycemia induced by these drugs. (5) Five-hour oral glucose tolerance test (5h-OGTT), useful for the diagnosis of reactive hypoglycemia in about 50% of cases (it is not a specific test, as it may be positive both in normal persons and in subjects with pseudohypoglycemia). (6) Insulin tolerance test (0.1 U/kg intravenous insulin and determinations of ACTH, cortisol, epinephrine, norepinephrine, GH and glucagon), useful in cases of counterregulatory hormone deficiencies. (7) Intravenous tolbutamide infusion (1 g over 3 min), positive in about 80% of the cases with insulin-secretory tumors (induces a severe hypoglycemia, with average value of glycemic levels at 120, 150 and 180 min p55 mg/dl in lean and p62 mg/dl in obese subjects). (8) Glucagon test (1 mg intravenous glucagon should produce an insulin peak q130 lU/ml), useful in glycogenosis (in this disease, however, enzyme determinations in liver and muscle biopsy are the best diagnostic test). (9) Vigorous exercise in fasted state will provoke hypoglycemia in insulinoma patients (this is not a well-standardized test). (10) Proinsulin determination (?25% of total insulinemia in about 85% of patients with insulinoma, compared to 10–15% of the normal subjects; this proinsulin excess is lacking in factitious hypoglycemia). (11) Leucine test (intravenous L-leucine infusion, 200 mg in 30 min, or an oral load of 0.15 g/kg, with serial samples obtained for 1 or 2 h, respectively), that evokes an excessive insulin response in children susceptible to leucine and in about 70% of patients with insulinoma. (12) Search for antibodies to insulin (if present in persons not receiving insulin therapy can indicate a surreptitious insulin use) or for autoantibodies against insulin or insulin receptors (useful to diagnose acanthosis nigricans and early stage of insulin-resistant diabetes).

Treatment Hypoglycemia in Diabetic Patients The treatment of hypoglycemia depends upon the cause and the severity of the hypoglycemic episode. Diagnosis should be made promptly to select promptly the appropriate treatment. Commonly, episodes of hypoglycemia


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happen in diabetic patients and are treated providing exogenous glucose or stimulating endogenous glucose production with glucagon. When possible, glycemic concentration should be measured before glucose treatment, but this should not be the cause of delay of treatment. Mild to moderate hypoglycemia in conscious and alert patients can be treated orally with foods containing 20–30 g of carbohydrates, eventually followed, after 20 min, by a second smaller assumption of 10–20 g carbohydrates. Suitable foods include honey, sweetened drink, cola beverages, syrups, fruit juices, candies, etc. In unconscious patients with serious hypoglycemia producing confusion, semi-coma or coma (who is not cooperative and cannot take oral feedings), the obligate treatment is intravenous glucose administration as a bolus of about 25 or 50 g (as 33–50% hypertonic glucose solution) followed by a 5–10% dextrose infusion in order to prevent relapse of hypoglycemia, while monitoring frequently the glycemic values during the acute hypoglycemic phase. An effective therapy is also the prompt intravenous glucagon injection (1–2 mg, repeated in 5 min if necessary; in children 0.5–1 mg), even if the time of recovery is longer (6–20 min) than following intravenous glucose (5–10 min). A subcutaneous or intramuscular injection of glucagon is recommended when intravenous administration is not possible or in outpatient treatment, even if the obtained glycemic response is transient and moderate. When a normal consciousness is recovered, oral glucose or carbohydrates can be provided. Glucagon is the ideal agent (safe and efficacious) to keep in medical bags or for use by the family members of the diabetic patient. Glucagon (that mobilizes glucose from liver by stimulating glycogenolysis) has a poor effect or is ineffective in starved or undernourished or uremic or hepatologic or inebriated patients (due to deficiency of hepatic glycogen stores) and in chlorpropamide-induced hypoglycemia (the drug would inhibit glycogenolysis). Adrenaline is rarely used (0.5–1 ml, subcutaneously, repeated eventually after 15 min if no response is observed). Some hypoglycemic patients may require large amounts of glucose to maintain normoglycemia (20–30% dextrose solutions). Sulfonylureainduced hypoglycemia may last for a prolonged time, until 72 h (probably hepatic or renal diseases and interactions with other hypoglycemia-potentiating drugs may play a role in this prolonged effect). In these patients, a constant infusion of hypertonic glucose should not be discontinued until the recovery from hypoglycemia is definitely complete, and clinical surveillance should be continued to notice possible relapse. In patients with prolonged hypoglycemia or retarded recovery from hypoglycemia (particularly if hyperazotemic), 100 mg of hydrocortisone in intravenous bolus may be provided (repeated eventually after 4 h), to facilitate glucose entry into neural cells and to induce gluconeogenesis (hydrocortisone, however, should never be used as the sole treatment in a severe hypoglycemic event or in coma).

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Precautionary Measures In patients at risk for hypoglycemia (diabetics treated with insulin or hypoglycemic drugs, alcoholists, etc.) several precautionary measures must be considered to prevent and minimize hypoglycemic episodes such as adjusted therapeutic regimens, relatively high glycemic goals, etc. In this regard, The Guidelines for Diabetes Care of the European Diabetes Policy Group of IDF (1998) suggest the following principles. Recurrent hypoglycemia at a particular time or times of day implies a mismatch of insulin therapy to meal pattern and/or physical activity. Therefore, it should be reviewed whether a repeated change in meal or activity behavior has occurred, and bear in mind the possibility of changes in underlying insulin sensitivity (age, renal, endocrine). On this basis, the opportunity of specific insulin dose adjustment should be taken into account. In cases of erratic hypoglycemia, the possible causes should be assessed, such as missed or varied meals or snacks, wrong physical activity, abuse of alcohol, injection site abnormalities, errors in insulin doses, gastroparesis, etc. The possibility should be considered of undetected nighttime or other hypoglycemia (especially if HbA1c is lower than average) and the insulin doses or food intake should be modified accordingly (avoiding any glucose excursion to =70 mg/dl or 4 mmol/l). It is especially useful to provide education and training in recognizing early cognitive dysfunction for patients and to advise caution over driving. In nocturnal hypoglycemia, it should be recommended to take the evening NPH insulin and a slowly absorbed carbohydrate snack as late as possible, and to use a rapid-acting insulin analogue before the main evening meal. Hypoglycemia in Insulinoma and Extrapancreatic Tumors In insulinoma patients, surgery is the elective treatment, while medical treatment is indicated only in the presurgical phase (diazoxide in doses of 300–1,200 mg/day, per os, and octreotide in doses of 100–600 lg/day, subcutaneously). Treatment of nonpancreatic insulin-producing tumors is very difficult and unsatisfactory (drugs suggested: streptozotocin plus doxorubicin or fluorouracil, or chlorozotocin). Other Forms of Hypoglycemia In hypoglycemia from intolerance to fructose or galactose, it is mandatory to prescribe a diet low in these sugars. In the intolerance to leucine, a diet deprived of milk (which is rich in leucine) is useful and should be started as soon as possible to prevent the precocious brain damage. Therapy of other forms of hypoglycemia includes hormone replacement in patients with deficiency of counterregulatory hormones and dietary adjustments in reactive hypoglycemia and pseudohypoglycemia (such as avoidance


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of prolonged fasting or simple sugars assumption, restriction of caloric intake, reduction of meal size, consumption of high-protein low-carbohydrate meals and snacks, diets high in fibers, use of b-adrenergic blockers, supply of vitamins and minerals, etc).

Conclusion In conclusion, hypoglycemia is a serious problem in diabetic patients (especially type 1 diabetics) that requires a careful monitoring because it causes morbidity and, directly or indirectly (falls, driving accidents, drowning, status epilecticus, etc.), an increased mortality. It is preventable with an adequate education of both the diabetologist and the patient. The best treatment of hypoglycemia is prevention and, to this end, it is necessary to develop methods to deliver insulin in a physiological manner and to bear in mind that strict euglycemia is not an appropriate objective in diabetic patients with defective counterregulation (to avoid hypoglycemia). Patient education, medical support, self-glucose monitoring and appropriate insulin regimens are helpful to maintain a good glycemic control while minimizing severe hypoglycemic episodes in diabetic patients.

Suggested Reading American Diabetes Association: Clinical practice recommendations 1997. Diabetes Care 1997;20(suppl 1): 1–70. Cryer PE, Fisher JN, Shamoon H: Hypoglycemia. Diabetes Care 1994;17:734–755. Cryer PE, Gerich JE: Hypoglycemia in insulin dependent diabetes mellitus: Insulin excess and defective glucose counterregulation; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and Practice, ed 4. New York, Elsevier, 1990, pp 526–546. Frier BM, Fisher BM, Gray CE, Beastall GH: Counterregulatory hormonal responses to hypoglycemia in type 1 (insulin-dependent) diabetes: Evidence for diminished hypoglycemic-pituitary hormonal secretion. Diabetologia 1988;31:421–429. Gerich JE, Langlois M, Noacco C: Lack of glucagon response to hypoglycemia in diabetes: Evidence for an intrinsic pancreatic a-cell defect. Science 1973;182:171–173. Grunberger G, Weiner GL, Silverman R, Taylor S, Gorden P: Factitious hypoglycemia due to surreptitious administration of insulin: Diagnosis, treatment, and long-term follow-up. Ann Intern Med 1988; 108:252–257. Service FJ: Hypoglycemic disorders. N Engl J Med 1995;332:1144–1152.


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Chapter IX

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Mechanisms of Diabetic Complications (Nephropathy) as Related to Perspectives of Treatment Mark E. Cooper Department of Medicine, University of Melbourne, Austin & Repatriation Medical Centre (Repatriation Campus), West Heidelberg, Vic., Australia

Introduction Diabetic nephropathy (DN) is characterized by a number of functional and structural abnormalitites. Functional changes include initial renal hyperfiltration/hyperperfusion with subsequent development of microalbuminuria which is a modest increase in the urinary excretion of albumin and is not detected by conventional dipstick methods. At this stage, ultrastructural changes including glomerular basement membrane thickening, glomerular hypertrophy and mesangial expansion are present. This is followed by the subsequent development of glomerulosclerosis and tubulointerstitial fibrosis. Overt proteinuria supervenes followed by the development of renal impairment and ultimately renal failure. Although the renal complications of diabetes had already been described in the 18th century, it is only over the last 20 years that the mechanisms linking chronic hyperglycemia to the development of DN have begun to be unravelled (fig. 1). It is likely that DN occurs at least partly as a result of a chronic glucose-dependent process.

Glycation In diabetes, a state of chronic hyperglycemia, there is an acceleration of the Maillard or browning reaction. This is a spontaneous reaction between glucose and proteins, lipids or nucleic acids, particularly on long-lived proteins such as the collagens. There is a sequence of biochemical reactions, many of

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Fig. 1. Schema depicting potential interactions between metabolic and hemodynamic pathways in the pathogenesis of DN. The crosses represent potential targets for intervention. 1>Improved glycemic control, e.g. intensified insulin therapy; 2>inhibitors of advanced glycation formation, e.g. aminoguanidine; 3>cross-link breakers, e.g. PTB, ALT-711; 4> inhibitors of polyol formation, e.g. aldose reductase inhibitors; 5>inhibitors of PKC, e.g. LY-333531; 6>inhibitors of vasoactive hormone formation/action, e.g. ACE inhibitors, AII and ET receptor antagonists; 7>inhibitors of cytokine formation/action. See text for abbreviations.

which are still poorly defined, leading to the formation of a range of advanced glycation end-products (AGEs). These modified long-lived tissue proteins are formed as a result not only of glycation but also oxidative processes and many of these AGEs are now considered glycoxidation products. Over the last decade, an increasing number of AGEs have been identified. However, the identity of the AGEs linked to diabetic complications and in particular to renal disease has not been clearly determined. Various antibodies to AGEs have now been developed and using a variety of immunohistochemical techniques, increased AGE levels have been reported in both human and experimental diabetes. Our own group using a radioimmunoassay has detected increased AGE levels in the diabetic kidney and using immunohistochemistry we have localized this increase in AGE levels to both the glomerulus and tubulointerstitium. Over the last few years, a number of AGE-binding sites have been identified. The first binding site to be cloned has been termed RAGE, this protein having been detected by immunohistochemistry by our group in the kidney, primarily in distal tubules and to a lesser extent in glomeruli. It has been

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suggested that RAGE has a central role in the development of vascular disease in diabetes by influencing various pathological processes including expression of adhesion molecules involved in mononuclear cell recruitment and hyperpermeability. At least three other proteins which bind to AGEs have recently been cloned. It has been postulated that these proteins may mediate a range of functions including clearance of AGEs and activation of intracellular messengers such as protein kinase C. These AGE-binding sites have been identified in cultured mesangial cells. It is still uncertain whether these AGE-binding proteins act primarily to clear AGEs which would be viewed as a beneficial effect or whether they are mainly involved in activating a range of pathological processes which lead to diabetic complications. The importance of the glycation pathway is under further investigation with pharmacological inhibitors of AGE-dependent pathways having now been developed. Aminoguanidine, which prevents AGE formation, has been shown in experimental models of diabetes to not only reduce tissue AGE levels, but also to retard the development of nephropathy and other diabetic microvascular complications. In the diabetic rat, aminoguanidine retarded the development of albuminuria and mesangial expansion. These experimental studies have confirmed that renal accumulation of AGEs in diabetes could be prevented by aminoguanidine treatment. Preliminary results from the Action 1 study suggest that aminoguanidine may have renoprotective effects in man. In this large study in type 1 diabetic patients with overt nephropathy, many of whom were already receiving ACE inhibitor therapy, aminoguanidine treatment was associated with less proteinuria, less decline in creatinine clearance, lower blood pressure and an improvement in various lipid parameters. It remains to be determined if these effects will ultimately be translated to postponement or prevention of end-stage renal failure. Since aminoguanidine also inhibits other biochemical pathways and in particular acts as an inhibitor of inducible NO synthase, it has been difficult to determine if organ protection conferred by this agent is primarily via its action as an inhibitor of AGE formation. New, potent and more specific inhibitors of advanced glycation have been developed recently. Two of these, ALT-462 and ALT-486, are approximately 5 and 20 times, respectively, more potent than aminoguanidine in their ability to inhibit fluorescence generated on reaction of lysozyme with ribose and both are approximately 20 times as potent as aminoguanidine in preventing diabetes-related decreases in rat tail collagen solubility in vivo. Our own group has evaluated 2,3-diaminophenazine, another inhibitor of AGE formation, and observed that this compound is a potent inhibitor of renal AGE accumulation. More recently, a new class of agents known as the thiazolium compounds such as phenacylthiazolium bromide (PTB) have been considered as agents

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which may ultimately inhibit advanced glycation-induced tissue injury. These agents react with and cleave covalent, AGE-derived protein cross-links. Recently, another cross-link breaker, ALT-711, has been reported to improve vascular compliance in diabetic rats. If PTB or related compounds can be shown to be effective in the kidney, this would provide a conceptual basis for the reversal of AGE-mediated tissue damage, which till now has been regarded as irreversible.

Polyol Pathway A role for the hyperglycemia-induced acceleration of polyol pathway metabolism in mediating the development of DN has been suggested by some investigators. In tissues where glucose uptake is independent of insulin such as the kidney, hyperglycemia results in increased levels of tissue glucose. The excess glucose is subsequently reduced to sorbitol by the NADPH-dependent enzyme aldose reductase, the first enzyme in the polyol pathway. The increased formation and accumulation of sorbitol in these tissues is accompanied by a depletion of free myoinositol, loss of Na+,K+-ATPase activity, and increased consumption of the enzyme cofactors NADPH and NAD+, leading to changes in cellular redox potential. These metabolic derangements have been postulated to result in cellular dysfunction and, ultimately, the morphological lesions that characterize diabetic nephropathy. There are some experimental data suggesting that increased polyol pathway metabolism mediates the loss of renal vascular tone in animals with chronic hyperglycemia. Several investigators have demonstrated that glomerular hyperfiltration in diabetic rats could be prevented by treatment with aldose reductase inhibitors. Long-term experimental studies have been conflicting with respect to effects not only on albuminuria but also on glomerular structural injury. Indeed, although inhibitors of this pathway such as aldose reductase inhibitors have now been available for over 20 years, clinical studies on the role of these agents in the prevention and treatment of diabetic nephropathy have been rather disappointing. Hopefully, with newer agents which have better pharmacokinetics and tissue penetration, aldose reductase inhibitors will play a more important role in the prevention and treatment of diabetic microvascular complications including nephropathy.

Protein Kinase C The adverse effects of hyperglycemia have been attributed to activation of protein kinase C (PKC), a family of serine-threonine kinases that regulates

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diverse vascular functions, including contractility, blood flow, cellular proliferation and vascular permeability. PKC activity, especially the membrane-bound form, is increased in the retina, aorta, heart and renal glomeruli of diabetic animals, probably because of an increase in de novo synthesis of diacylglycerol, a major endogenous activator of PKC. It has been postulated that there is preferential activation of the b2 isoform of PKC in diabetes. This led to the synthesis of an orally effective PKC-b-selective inhibitor, LY-333531. LY-333531 is a competitive, reversible inhibitor of PKC-b1 and PKC-b2, with a 50-fold lesser effect on other PKC isoenzymes. In studies over 2–8 weeks in diabetic rats, LY-333531 ameliorated glomerular hyperfiltration, albuminuria and renal transforming growth factor-b overexpression. Further studies including clinical trials are now in progress with this compound.

Hemodynamic Factors Diabetes is associated with elevations of both glomerular filtration rate (GFR) and renal plasma flow (RPF). To explore the underlying intrarenal and in particular intraglomerular hemodynamic changes associated with diabetes, Hostetter and Brenner used micropuncture techniques. The major findings in these landmark studies included the observation of elevated intraglomerular pressure, related to relative afferent versus efferent arteriolar vasodilation in experimental diabetes.

Renin-Angiotensin System It has been suggested that these intraglomerular hemodynamic abnormalities are due to altered vasoactive hormone action. This would imply an imbalance in the actions of vasoconstrictors and vasodilators in the diabetic kidney and has resulted in a large body of research focusing on a range of vasoactive hormones and their receptors in the genesis not only of the initial hemodynamic abnormalities but also on the subsequent glomerular ultrastructural injury. The system most extensively investigated is the renin-angiotensin system (RAS) which involves a series of enzymatic reactions leading to the production of the effector peptide, angiotensin II (AII). This hormone has a diverse range of actions including vasoconstriction, stimulation of sodium reabsorption and of particular interest trophic effects on a range of cells including mesangial cells. These actions are considered relevant to the postulated mode of action of agents which interrupt the RAS such as ACE inhibitors and AII receptor antagonists. All components of the RAS are present in the kidney, consistent


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with the view that this hormone system not only acts as an endocrine system but can also act in a paracrine/autocrine manner. Evidence of a role for the RAS in the genesis of diabetic complications has been provided by a range of studies using different experimental techniques. Although it was initially considered that diabetes was associated with a suppressed RAS, primarily based on studies assessing the systemic RAS, Anderson et al. have identified sites of local activation of the RAS within the kidney including the glomerulus and other renal vessels. Indeed, in a series of experiments using molecular biological and immunohistochemical techniques in an animal model of renal disease, the subtotal nephrectomy model, which has many functional and structural similarities to diabetic nephropathy, our group has shown that with renal injury there is de novo expression of various components of the RAS including renin and AII within the kidney. This local activation of the RAS particularly in the proximal tubule may be particularly important as a potential mechanism for the development of tubulointerstitial fibrosis in advanced diabetic nephropathy. Similar changes have recently been observed by our group in an animal model of advanced DN. To further explore the role of the RAS in the evolution of DN, diabetes has been induced in transgenic Ren 2 rats, a rat strain generated by insertion of the mouse renin Ren 2 gene into their genome. This hypertensive strain has elevated prorenin levels and the induction of diabetes leads to the rapid development of glomerulosclerosis, tubulointerstitial injury and renal impairment which can be attenuated by ACE inhibition. This provides further evidence for a role for the RAS, particularly at the local level, in mediating renal injury in diabetes. The importance of the RAS is of particular relevance to the management of DN. Agents which interrupt the RAS such as ACE inhibitors and AII receptor antagonists have been shown to attenuate the development of experimental DN. These agents normalize intraglomerular pressure, suppress renal cytokine production and prevent extracellular matrix accumulation. These beneficial effects observed in rodents have also been reproduced in man. In various phases of human DN in the presence or absence of systemic hypertension, ACE inhibitors have been shown to reduce urinary albumin excretion and retard the decline in GFR. Whether these drugs are superior to other classes of antihypertensive agents remains controversial. However, a number of studies have suggested that ACE inhibitors have renoprotective effects independent of blood pressure reduction. The status of AII antagonists as renoprotective agents is not as well established with several large clinical studies using these agents now in progress.

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Other Vasoactive Hormones More recent studies have suggested that other vasoactive hormone systems including the natriuretic hormones such as atrial natriuretic peptide, the kallikrein-kinin system and the potent vasoconstrictor, endothelin (ET), may also have important roles in the genesis of the hemodynamic and trophic abnormalities which are observed in organs undergoing diabetic vascular injury such as the kidney. ET antagonists have been reported by several groups to be useful in experimental DN. However, the role of ET antagonists in man in the context of diabetes has not yet been explored. Another class of new drugs to consider are the dual metallopeptidase or vasopeptidase inhibitors. These agents have multiple effects on vasoactive hormone formation and degradation. In a recent study by our group using an agent which not only inhibits ACE but also inhibits the enzyme, neutral endopeptidase (NEP), an enzyme involved in the degradation of vasodilators such as ANP and kinins, it could be demonstrated that this agent reduced blood pressure and was very potent at preventing the development of albuminuria in diabetic, hypertensive rats. The long-term functional and structural effects of these agents in experimental DN and ultimately in man are awaited with interest. Since nitric oxide (NO) is a potent renal vasodilator, it has been suggested that this molecule may be in excess in the diabetic kidney. Indeed, metabolites of NO, nitrate and nitrite, are excreted in excess in the urine of diabetic rodents. Furthermore, several groups have documented that the nonselective inhibitor of NO synthase, L-NAME, can reduce the elevated GFR and RPF in diabetic rats. Further studies exploring in more detail the NO pathway and in particular the use of more specific inhibitors of the various NO synthases are required to delineate more accurately the role of NO in DN.

Extracellular Matrix Accumulation A major feature of diabetic complications is extracellular matrix (ECM) accumulation. Although ECM was originally viewed to be essentially inert, it has now been shown not only to have a structural role but also to be in a dynamic interaction with the surrounding cell population as well as being a reservoir for various cytokines and growth factors. ECM consists of structural proteins such as type IV collagen, cell-associated adhesion molecules such as the integrins, antiadhesins and growth factors. The role of all these proteins and their interactions in the genesis and progression of diabetic complications is now an area of intensive investigation. There are major changes in gene and protein expression of various ECM components in various sites of dia-


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betic vascular injury including activation of a range of growth factors such as the prosclerotic cytokine, TGF-b and matrix proteins such as type IV collagen. Of particular interest are recent findings that various interventions such as inhibition of advanced glycation and the RAS can influence expression of ECM components possibly via effects on cytokines such as TGF-b (fig. 1).

Transforming Growth Factor-b Transforming growth factor-b (TGF-b) has been shown to play a pivotal role in ECM accumulation in the diabetic kidney. Renal expression of this cytokine has been reported to be increased in both experimental and human diabetes. Administration of antibodies to TGF-b prevents diabetes-associated renal hypertrophy. The role of this growth factor is further suggested by both in vitro and in vivo findings indicating that putative mediators of DN such as AII and AGEs promote expression of this cytokine. AII has been shown in vitro to promote collagen IV production via TGF-b in mesangial cells. In the model of subtotal nephrectomy, an animal model of progressive renal injury with many hemodynamic and structural similarities to diabetes, it has been shown that in vivo inhibition of the action of AII, either by ACE inhibition or by AII receptor antagonism, is associated with reduced gene expression of TGF-b1. These treatments lead not only to reduced ECM accumulation but attenuation of glomerular and tubulointerstitial injury and preservation of renal function. More recently, a similar phenomenon has been observed in experimental diabetes with reduced TGF-b1 gene expression after ACE inhibition, particularly in the tubulointerstitium. Reduced TGF-b1 expression after ACE inhibition has also been observed in vessels from diabetic rodents. Exogenous administration of AGEs upregulates a range of cytokines including TGF-b in the kidney. Recent studies have explored the relationship between TGF-b1, collagen and AGEs in diabetic vessels and shown that the increase in gene expression of TGF-b1 in diabetic vessels can be prevented by administration of the inhibitor of advanced glycation, aminoguanidine. Recent studies suggest that these effects of inhibitors of glycation on growth factor and structural protein expression are also observed in the diabetic kidney. At this stage, no specific inhibitors of cytokine formation or action are available for clinical use. Therefore, the major strategy for preventing renal TGF-b overexpression is via inhibition of stimuli of secretion of this prosclerotic cytokine (fig. 1).

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Other Growth Factors Other growth factors have also been studied including IGF-1 and EGF and shown to be increased early after induction of experimental diabetes, but this overexpression, in contrast to TGF-b1, is not sustained. Therefore, the role of these growth factors in the genesis and progression of DN remains to be clearly defined.

Extracellular Matrix Degradation Most studies have focused on factors which influence the formation of the ECM. However, accumulation of ECM involves a balance between matrix protein formation and degradation. In vitro glucose leads to a defect in matrix degradation, most likely due to reduced activity of matrix metalloproteinases (MMPs). These zinc-dependent enzymes are under the influence of a number of tissue inhibitors. In vivo studies suggest that there are changes in the expression and activity of these MMPs and their inhibitors in diabetes. Therefore, it is likely that ECM accumulation in diabetes involves not only an increase in matrix formation but also a defect in matrix degradation. At this stage, no such agents which promote matrix degradation are in clinical use but this represents a potential alternative strategy for the treatment of diabetic complications.

Interactions between Hemodynamic and Metabolic Factors The diabetic state is characterized by a multitude of biochemical and hemodynamic alterations that have been implicated in the pathogenesis of DN (fig. 1). These factors have been shown to modulate the expression of a number of cytokines including TGF-b. It is likely that these cytokines play a pivotal role in orchestrating the accumulation of ECM in the glomerulus and tubulointerstitium which characterizes DN. Such factors include glucose, PKC activation and cell stretch (the in vitro counterpart of hypertension), AGE and AII. Furthermore, specific intervention with reduction of glucose, PKC-b inhibition, reduced cell stretch, aminoguanidine and ACE inhibition have all been shown to reduce TGF-b expression. Since direct inhibition of TGF-b is not currently available as a therapeutic option, current therapy of DN is therefore directed to improving glycemia, lowering blood pressure and blockade of the RAS. In the near future, additional treatments to consider which also prevent renal TGF-b expression include inhibitors of PKC and advanced glycation.


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Suggested Reading Cooper ME: Pathogenesis, prevention and treatment of diabetic nephropathy. Lancet 1998;352:213–219. Cooper ME, Gilbert RE, Epstein M: Pathophysiology of diabetic nephropathy. Metabolism 1998; 47(suppl 1)3–6. Gilbert RE, Cox A, Wu LL, Allen TJ, Hulthen L, Jerums G, Cooper ME: Expression of transforming growth factor-b1 and type IV collagen in the renal tubulointerstitium in experimental diabetes: Effects of angiotensin-converting enzyme inhibition. Diabetes 1998;47:414–422. Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL: Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996;272:728–731. Kelly DJ, Wilkinson-Berka JL, Allen TJ, Cooper ME, Skinner SL: A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (tgr). Kidney Int 1998;54: 343–352. Soulis T, Sastra S, Thallas V, Mortensen SB, Wilken M, Clausen JT, Bjerrum OJ, Petersen H, Lau J, Jerums G, Boel E, Cooper ME: A novel inhibitor of advanced glycation end-product formation inhibits mesenteric vascular hypertrophy in experimental diabetes. Diabetologia 1999;42:472–479. Tikkanen T, Tikkanen I, Rockell MD, Allen TJ, Johnston CI, Cooper ME, Burrell LM: Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme in rats with hypertension and diabetes mellitus. Hypertension 1998;32:778–785. Wolffenbuttel BHR, Boulanger CM, Crijns FRL, Huijberts MSP, Poitevin P, Swennen GNM, Vasan S, Egan JJ, Ulrich P, Cerami A, Levy BI: Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci USA 1998;95:4630–4634.

Assoc. Prof. M.E. Cooper, Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre (Repatriation Campus), West Heidelberg, Vic 3081 (Australia) Tel. +61 3 94962347, Fax +61 3 94974554, E-Mail [email protected]

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Chapter X

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Diabetic Retinopathy Toke Bek ˚ rhus University Hospital, A ˚ rhus, Denmark Department of Ophthalmology, A

Introduction Diabetes mellitus is a systemic disease that affects all parts of the eye. The majority of these changes have a mild course with no permanent influence on visual function. Transitory changes in the refraction of the lens occur secondary to changes in the blood sugar, and can be prevented by optimizing the metabolic control. Diabetic cataract can nowadays be operated with few complications and with a good visual result, and diabetic eye muscle palsy disappears spontaneously within weeks leaving no adverse consequences for the visual function. Diabetic complications in the retina, diabetic retinopathy, is a somewhat different matter. This complication is presently one of the leading causes of blindness in the western world. From a phylogenic point of view, the retina is an advanced part of the brain, and damage to its neuronal tissue is therefore irreversible and leads to permanent reduction of the visual function. This implies that preventive measures are the cornerstone in the clinical management of diabetic retinopathy. However, the preventive efforts should be effective at many levels ranging from elimination of risk factors, initiation of screening programmes, optimization of treatment intervention, and by educating diabetic patients in self-care and good life habits. Once vision-threatening changes have developed the patient should be promptly referred to a specialist for clinical evaluation and initiation of relevant treatment to stop or limit the visual damage. This chapter will present an overview of current knowledge related to the clinical management of diabetic retinopathy. The chapter will be introduced with a brief account of the clinical and epidemiologic characteristics of the disease, followed by a description of the practical management of prevention, screening, diagnostics, and treatment of diabetic retinopathy.

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Table 1. Nomenclature used for diabetic retinopathy Retinopathy

Inside the retina (background retinopathy)

Not vision-threatening

Simple B

Vision-threatening

Maculopathy

In front of the retina (neovascularizations)

7 Proliferative retinopathy

Clinical Appearance The clinical evaluation and classification of diabetic retinopathy is based on inspection of the retina through the optics of the eye. The morphological changes thus observed in the retina are complex and heterogeneous which is reflected in the nomenclature used to describe diabetic retinopathy (table 1). Basically, diabetic retinopathy can be divided into early changes that are not accompanied by reduction in vision and late changes accompanied by visual reduction. Early Changes Not Accompanied by Visual Reduction The most usual name for this retinopathy stage is nonproliferative diabetic retinopathy, but older terms are also used, such as simple retinopathy, or background retinopathy which alludes to the fact that the changes remain inside the ocular background. Nonproliferative diabetic retinopathy is caused by changes in the retinal microcirculation leading to compromised barrier function of the retinal capillaries. The changes first appear temporally from the fovea consisting of capillary microaneurysms and small intraretinal haemorrhages (fig. 1). The increased capillary permeability leads to the development of whitish hard exudates consisting of lipoprotein from the bloodstream (fig. 2). Additionally, cotton-wool spots may develop. These are localized unsharply delimited whitish areas in the superficial parts of the retina representing intracellular material that has accumulated in the nerve fibres because of disturbances in their axoplasmic flow (fig. 3). The retinal changes characterizing nonproliferative diabetic retinopathy are reversible, and often noticeable dynamic changes are seen at repeated examinations, so that the same number of lesions are present, however located in different places. Late Changes Accompanied by Visual Reduction Nonproliferative diabetic retinopathy can develop into one or both of two different types of retinopathy accompanied by visual reduction, namely proliferative diabetic retinopathy and diabetic maculopathy.

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Fig. 1. Minimal nonproliferative diabetic retinopathy in a right eye. A few red dots representing haemorrhages and/or microaneurysms are seen temporally in the macular area which is the dark area surrounding the dark spot in the centre of the image (arrows).

Fig. 2. Slight nonproliferative diabetic retinopathy in a left eye. Several whitish hard exudates have developed inside the macular area.

Proliferative Diabetic Retinopathy Proliferative diabetic retinopathy develops secondary to occlusion of the retinal capillaries in the retinal periphery with a consequent stimulation of vascular new growth. Clinically, both a preproliferative and a true proliferative stage can be differentiated.

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Fig. 3. Moderate nonproliferative diabetic retinopathy in a right eye. Larger haemorrhages and whitish lesions with fluffy borders representing cotton-wool spots have developed.

Fig. 4. Preproliferative diabetic retinopathy in a right eye. Many large haemorrhages are seen temporally in the macular area and there is calibre variation of the lower temporal branch vein (arrow). Hard exudates within one disk diameter of the fovea indicate the presence of clinically significant macular oedema.

Preproliferative diabetic retinopathy is characterized by many cotton-wool spots, larger blot haemorrhages temporally in the macular area, and a variety of vascular abnormalities. These abnormalities are intraretinal microvascular abnormalities (IRMA vessels) often representing arteriovenous shunt vessels, and beading and loop formation on the larger venules (fig. 4). These abnormalities

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Fig. 5. Proliferative diabetic retinopathy in a left eye. A large neovascularization has developed from the optic disk and has given rise to a preretinal haemorrhage that extends arcuately along the lower temporal branch vein.

develop secondary to changes in the retinal haemodynamics that result from occlusion of the capillary bed in the retinal midperiphery and periphery. At this stage the retinopathy will often become proliferative within a few months. Proliferative diabetic retinopathy is characterized by outgrowth of new vessels from the larger venules in the retina and on the optic nerve head (fig. 5). This neovascular process is assumed to be caused by growth stimulation from cytokines released from the ischaemic areas in the retinal periphery where the capillary bed is occluded. However, the newly formed blood vessels do not grow out to replace the occluded retinal vessels. Rather, they grow aberrantly into the vitreous body. Preretinal neovascularizations can lead to visual reduction because of spontaneous haemorrhages into the vitreous body. The cause of this vascular rupture is unknown, but may be caused by attachments of the new vessels to the posterior hyaloid membrane that break secondary to movements of the vitreous body. Finally, neovascularizations may contain connective tissue that shrinks and causes tractional retinal detachment (fig. 6). In some cases the vasostimulatory cytokines released in the retinal periphery diffuse to the anterior eye chamber to cause neovascularization in the iris (rubeosis iridis) (fig. 7) and in the anterior chamber angle. The resulting blocking of the aqueous drainage from the eye will lead to neovascular glaucoma. The high intraocular pressure may endanger the intraocular blood flow and consequently the visual function, and if the rise in intraocular pressure is rapid, severe acute pain may develop.


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Fig. 6. Severe proliferative diabetic retinopathy in a left eye. The new vessels contain whitish fibrous tissue that covers most of the view of the fundus. Shrinkage of this fibrous tissue may lead to tractional retinal detachment.

Fig. 7. Iris rubeosis. New vessels in the iris (arrows) have made the pupil immobile. The small pupil together with the white cataractous lens seen behind the pupil opening makes inspection as well as treatment of the fundus background impossible.

Diabetic Maculopathy Diabetic maculopathy is nonproliferative diabetic retinopathy complicated by retinal oedema. When the oedema area becomes large enough or is too close to the fovea, it becomes vision-threatening (fig. 4) and is termed clinically significant macular oedema (table 2). The oedema may be exudative or ischae-

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Table 2. Clinically significant macular oedema is defined as presence of one or both of the criteria shown 1. Oedema and/or exudates within one-half disk diameter from the fovea 2. Oedema and/or exudates with a size of one disk diameter or more, part of which is located within a zone of one disk diameter from the fovea

mic. The exudative form is most frequent, and it may be both focal or diffuse. Exudative diabetic maculopathy is accompanied by hyperpermeability of the macular vessels. When the oedema, the exudates, and the haemorrhages extend towards the fovea, central vision may become threatened, partly by blocking light access to the retinal photoreceptors, and partly because of a direct destructive effect on the neuronal components of the retina. Ischaemic oedema develops secondary to occlusion of macular capillaries similarly to capillary occlusion in the retinal periphery, with a subsequent fallout of neuronal function in the affected area. If the areas close to the fovea are included, visual acuity may drop. Frequently, mixed types of maculopathy occur with exudative and ischaemic retinal oedema located in different parts of the macular area. Epidemiology Almost all persons having diabetes mellitus will eventually develop nonproliferative diabetic retinopathy. In countries with good diabetes care, retinopathy does not develop until after 10 years of diabetes duration, whereas retinopathy may be present at the time of diagnosis in type 2 diabetes. Nonproliferative diabetic retinopathy can later be complicated by one or both of the two late complications, proliferative diabetic retinopathy and diabetic maculopathy. In type 1 diabetes the most frequent vision-threatening complication is proliferative diabetic retinopathy, whereas in type 2 diabetes the most frequent vision threat is diabetic maculopathy.

Prevention Preventing the development of diabetic retinopathy is one of the basic pillars in the management of diabetic eye complications, since the damage that occurs to the retina is irreversible. The two most significant factors now known to limit the risk of developing diabetic retinopathy are tight regulation of the blood glucose and of the blood pressure. For many years it was suspected that exposition to hyperglycaemia accelerated the development of diabetic retinopathy, but it was not established


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Table 3. Characteristics of diabetic retinopathy

Is frequent Can be prevented Can be detected Can be treated Screening is cost-efficient

until a few years ago in the Diabetes Control and Complications Trial (DCCT) study that the risk of developing retinopathy is considerably lowered by tight glycaemic control. Recently, several studies have been published unanimously showing that the risk of developing retinopathy in type 1 as well as in type 2 diabetes can be considerably lowered by antihypertensive treatment. Furthermore, it has been shown that treatment with especially ACE inhibitors can reduce the risk for developing retinopathy with an effect that adds to the antihypertensive effect. However, these studies have not been conducted far enough to show that this intervention also has an effect on the visual prognosis. Pregnancy is a definite risk factor for the development of diabetic retinopathy. A tight regulation of the blood glucose during pregnancy alone can slow and often halt the development of retinopathy completely, suggesting that the risk of developing retinopathy is to a large extent caused by disturbances in the diabetic metabolism in pregnancy. Since the risk for developing diabetic retinopathy during pregnancy increases with increasing duration of diabetes, diabetic women should be counselled to have children as early as possible in life. A multitude of studies have been conducted to identify new preventive measures for diabetic retinopathy. These studies have for example shown that aspirin and aldose reductase inhibitors have no beneficial effect on diabetic retinopathy. More recent studies have shown that pharmaceutical intervention on second messengers such as protein kinase C might be a future treatment modality for diabetic retinopathy, and these hypotheses are presently under investigation in clinical trials.

Screening Background Even when optimal preventive measures are undertaken, some patients will unavoidably develop vision-threatening retinopathy. Since these changes may not be recognized by the patient before they have advanced to a stage where vision damage is irreversible, early detection is important. Diabetic retinopathy fulfills a number of criteria that makes it appropriate to screen for this complication among the diabetic population (table 3).

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Methods Screening for diabetic retinopathy is performed by inspecting the ocular background through the optics of the eye, supplemented by measurement of the visual acuity. Examination of the Ocular Background Inspection of the ocular background can be done by ophthalmoscopy that enables a qualitative assessment of retinopathy. Alternatively, photography of the ocular background allows a semiquantitative analysis by comparison with standard photographs, or a quantitative computerized analysis of the retinal changes. Examination of the ocular background by ophthalmoscopy has been known for almost 150 years, and this technique is therefore one of the oldest known examination methods in ophthalmology. During ophthalmoscopy the retina is illuminated continuously, and inspection is either done directly or indirectly through a lens positioned with its focal point in the pupil plane of the examined eye. The relevance of doing ophthalmoscopy in diabetic patients was realized during the fifties where it became usual for diabetic patients to survive long enough to develop retinal complications. The advantage of ophthalmoscopy is that only simple equipment is needed for the examination. The disadvantages of this method is that the severity of the retinal lesions cannot be documented in detail, that the retinal changes are difficult to quantify, and that the quality and conclusion of the examination depend on the experience and attitude of the examiner. In spite of these weaknesses, ophthalmoscopy has until now been the most important examination technique for early detection of diabetic retinopathy, and globally it is still the most widely used method. During the last decades, increasing focus has been directed at a different technique to screen for diabetic retinopathy by examination of the ocular background with fundus photography. This method has a number of advantages. Firstly, the retinal changes are documented so that it is possible to re-evaluate the retinopathy, and the grader can consult other specialists at a later time. Secondly, retinal photography enables a standardized and centralized semiquantitative evaluation of the severity of the changes, and thirdly, photography enables an evaluation of even minimal changes in retinopathy. Fourthly, ophthalmologists need not have primary patient contact. Thus, with technicians doing the photography and opthalmologists performing the evaluation of the photographs, more examinations can be carried out with the same specialist resources. Finally, it has been shown that for other than retinal specialists the sensitivity in detecting vision-threatening retinal changes is higher when the retinopathy is evaluated from retinal photographs than by ophthalmoscopy.


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With the current development within computerized image analysis it can be expected that within a few years it will be possible to replace semiquantitative grading of fundus photographs with a fully computerized quantification of the fundus photographic changes. Many initiatives have been taken to start this process, and the results achieved hitherto appear promising. Stereoscopic examination of the ocular background is done by examining the same part of the retina from different angles with the examiner’s two eyes, thus giving an impression of the depth relation of the retinal structures. This can be done directly by binocular inspection of the ocular background, or indirectly by studying stereo photographs of the ocular background. The validity of this technique depends on the examiner’s stereo vision which shows great interindividual variation. The significance of this type of examination lies in its potential for detecting retinal oedema. Until now there has been no documentation of the value of stereoscopic examination of the ocular background for screening for diabetic retinopathy. Measurement of Visual Acuity In most countries there is general agreement that measurement of the visual acuity should be part of the routine screening examination for diabetic retinopathy. The visual acuity may be valuable as a supplement to the inspection of the ocular background, especially if it has to be decided whether the patient should be referred for further evaluation by an ophthalmologist. Thus, in exudative diabetic maculopathy, hard exudates and retinal oedema may be located in the border zone of being clinically significant. A reduced or declining visual acuity in these cases will speak in favour of referral for further evaluation. Similarly, in ischaemic maculopathy with no hard exudates and questionable macular oedema, the visual acuity may be a valuable help in determining whether incipient retinal damage needs referral for further evaluation. Organization In order to ensure that screening efforts are efficient it is necessary that: (1) the health system is organized to permit the establishment of efficient screening programmes; (2) sufficient resources are made available in the short term (they will always pay back in the long term); (3) qualified personnel is available to carry out the screening examinations and evaluations, and (4) patients are taught about the advantages of screening, and are given motivation to participate. Iceland is a positive example of a country where all these factors have been optimal. This country has succeeded in setting up a screening programme where, in principle, all the country’s diabetic patients are known and followed. In most countries, however, screening efforts do not live up to expectations, for the most part due to social or geographic differences. Generally, screening

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is of a high quality near centres with high expertise and impact in the community, and similarly of a poorer quality in peripheral areas. An optimization of screening efforts meets with various barriers in different countries. In some countries it is the structure of the health system that hinders free access to retinopathy screening for the whole diabetic population, whereas in other countries problems inherent in health system structure or geography can be solved within the existing framework. The exploitation of new technology may play a central role for removal of these barriers. For example, it is conceivable that the ongoing developments within teleophthalmology will enable the setting up of decentral screening clinics for diabetic retinopathy from which fundus photographs taken by technicians can be transmitted electronically to a central place for evaluation. Such an organization would be a huge step towards more efficient care in areas where the bottleneck is shortage of qualified specialists, and would solve problems with transportation of patients over long distances. Screening Interval Patients with type 1 diabetes mellitus should be examined at least once a year when diabetes duration is long enough for the development of vision-threatening changes to be conceivable. This critical diabetes duration is only a few years in some societies with poor diabetes care, e.g. in some of the former east block countries, but up to 10 years in societies where diabetes care is optimal. Patients with type 2 diabetes mellitus should be screened at the time of diagnosis, and then every other year if no or minimal retinopathy is found at the initial examination. In both diabetes types the screening interval should be shorter when there is progression of retinopathy or changes appear that possibly in the near future will require treatment. Economy Several health economic analyses have shown that screening for diabetic retinopathy is very cost-efficient. Thus, from a socio-economic point of view, the ability to rescue a few cases from blindness each year is sufficent to balance the total cost of screening efforts in an area with several thousand diabetic patients, not to mention the personal and social consequences for the individual diabetic patient who can preserve visual health.

Diagnostics If a screening examination leads to suspicion of proliferative diabetic retinopathy or maculopathy that potentially threatens central vision, the pa-


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tient should be referred for further evaluation with an ophthalmologist having facilities for fluorescein angiography and photocoagulation treatment. In diabetic maculopathy it is necessary to do fluorescein angiography to distinguish between exudative maculopathy, that can be treated by photocoagulation, and ischaemic maculopathy that is not treatable. Fluorescein angiography is performed by intravenous injection of the tracer compound fluorescein which is transported and distributed in the bloodstream to reach the eye in a few seconds. Under normal circumstances, fluorescein cannot pass the bloodretina barrier and therefore remains inside the bloodstream. However, in exudative diabetic maculopathy the blood-retina barrier is broken down and areas where fluorescein leaks out of the bloodstream into the retinal tissue and the vitreous can be recognized. In ischaemic maculopathy, however, areas with focal occlusion of retinal capillaries are seen in the macular area. When the ocular background is inspected by ophthalmoscopy or by evaluation of fundus photographs, the type of maculopathy can often be diagnosed. Thus, exudative maculopathy is almost always associated with hard exudates, while the ocular background in ischaemic maculopathy almost always appears slightly yellowish combined with many intraretinal haemorrhages and no exudates. However, since mixed types with both exudative and ischaemic maculopathy may occur, angiography is an important tool to differentiate and locate leakage and capillary occlusion. Exudative diabetic maculopathy should be treated with retinal photocoagulation when there is clinically significant macular oedema (table 2), or when exudates or oedema are otherwise suspected to threaten central vision. Clinically significant macular oedema has previously been difficult to describe quantitatively since no technique was available to quantify retinal thickness. However, in recent years this has changed, and several new methods making this possible have now been developed. One of the most promising of these methods is optical coherence tomography that detects the phase shift of light reflected from different surfaces in the retina and transforms this signal to a colour code that expresses the reflectivity and depth of different retinal levels. The method has a depth resolution of approximately 10 lm and gives a precise indication of whether there is retinal oedema, and the method can be used to quantify the effect of therapeutic intervention. When the diagnosis of proliferative diabetic retinopathy is certain, no more diagnostic evaluation is required and retinal photocoagulation can be initiated immediately. In less clear cases, differential diagnostic alternatives should be carefully considered, the most frequent being shunt vessels or other intraretinal microvascular abnormalities. On the basis of the criteria shown in table 4, the presence or not of neovascularizations requiring photocoagulation treatment can almost always be established clinically.

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Table 4. Characteristics of new vessels in proliferative diabetic retinopathy requiring photocoagulation treatment and intraretinal microvascular abnormalities not requiring treatment New vessels requiring photocoagulation treatment

Intraretinal microvascular abnormalities not requiring photocoagulation

Preretinal May cross their feeder vessel Always emerge from larger venules Are recursive back to venule of origin Displays extensive branching

Intraretinal Do not cross their feeder vessel Connect venules and arterioles Are not recursive Branching pattern normal

In proliferative diabetic retinopathy complicated with vitreous haemorrhage it may be difficult to get a view of the ocular background. In these cases ultrasound B-scan examination is useful to establish whether the vitreous opacities are associated with retinal detachment, in which case operation will give no benefit for vision.

Treatment Retinal Photocoagulation Retinal photocoagulation is the only known treatment modality with a documented effect on diabetic retinopathy. The treatment itself, however, may incur impairment of vision and should therefore only be performed by ophthalmologists with special interest and training within this field. The mechanism of action of retinal photocoagulation is unknown, but the effect can be achieved with any light source that destroys the outer retinal layers after absorption in the retinal pigment epithelium. Retinal photocoagulation is usually performed using the blue line of an argon laser which is mounted on a slit lamp so that treatment can be applied through a contact glass. The contact glass enables the viewing of the ocular background by eliminating the corneal refraction, enables treatment of the retinal periphery through built-in angled mirrors, and dampens voluntary or reflectory eye movements. The treatment is done by applying burns with a distance of one burn in between but avoiding retinal vessels, and the energy of the burns is adjusted to produce a distinct retinal whitening. Proliferative Diabetic Retinopathy In proliferative diabetic retinopathy, treatment should be panretinal, meaning that the whole retina peripherally from the temporal arcades should be


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treated. In most cases, this treatment will arrest the neovascular growth, and often lead to a regression of the new vessels. This effect is assumed to be a result of a destruction of the peripheral parts of the retina. The elimination of the ischaemic retinal areas that release the vasostimulatory factors eliminates the stimulus for neovascular growth. For panretinal photocoagulation a spot size of 300–500 lm is usually employed with which approximately 2,500–3,500 applications are needed to fill out the retinal periphery. The treatment is applied in at least two sittings, partly because the redistribution of the choroidal blood flow induced by the treatment may impair central retinal function, and partly because sittings lasting more than 15 min are tiring for both the patient and the treating ophthalmologist. The risk to consider with this treatment is accidental photocoagulation in the foveal area, which is less likely to occur when treatment is done through angled mirrors. During treatment the patient’s eye is subjected to a strong blaze, and there may occasionally be a distinct stinging pain when the laser treatment is applied to the retinal areas along the vertical and horizontal meridians. After treatment the patients often experience a shrinkage of the peripheral visual field and impaired night vision which can be directly attributed to the destructive effect of the laser applications in the retinal periphery. In more rare cases, retinal photocoagulation applied to the retinal periphery may, for unknown reasons, lead to a lowering of central vision. Exudative Diabetic Maculopathy In diabetic maculopathy, laser treatment is applied corresponding to the lesions in the macular area. The treatment is performed differently dependent on the individual appearance and location of the lesions, but also dependent on varying ideas of how diabetic maculopathy should be interpreted. The principle of the treatment strategy is to apply a laser grid pattern corresponding to the area with retinal oedema, however sparing a central zone out to approximately 500 lm from the fovea. In some centres, treatment is only applied in a horseshoe temporally around the centre, thus sparing the papillomacular bundle. If the papillomacular bundle is treated, one should be careful not to apply burns with so high an energy that they extend transretinally to cause destruction to the nerve fibres coursing to the fovea. If the oedema area is small, as for example inside circinate conglomerates of hard exudates, the treatment grid becomes small, perhaps consisting of single points, and treatment becomes focal. The mechanism of action of macular laser photocoagulation is unknown, but the treatment leads to disappearance of hard exudates and oedema. The total resolution of these lesions is slow, however, and it may take from weeks to years. The treatment causes blazing, but is not otherwise associated with

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any appreciable discomfort. The risk involved with macular photocoagulation is that the applications can accidentally be given in the foveal area with a consequent reduction in central vision. Even when treatment is applied safely outside the foveal area, there may be a risk of visual reduction. Thus, if the patient has excentric fixation due to lowered visual acuity, treatment may unwittingly be applied corresponding to the new fixation area resulting in a further reduction of vision. When there is coexistence of proliferative diabetic retinopathy and diabetic maculopathy, both panretinal photocoagulation and macular photocoagulation should be given. There is no conclusive documentation for whether panretinal or macular photocoagulation should be given first. A suggestion that diabetic maculopathy should be worsened when panretinal photocoagulation is done first has received some focus, but the issue has not been finally clarified since there is evidence in support of both this and the opposite view. Vitrectomy When proliferative diabetic retinopathy has resulted in vitreous haemorrhage or retinal traction from connective tissue in the new vessels, there is indication for vitrectomy. During vitrectomy, thin instruments are introduced through the sclera in order to cut and remove fibrous strings and opaque vitreous, and to apply laser treatment. With modern techniques this operation can be done in local anaesthesia in an outpatient setting with no appreciable discomfort. When the purpose of the operation is only to remove a vitreous haemorrhage, full restitution of the visual function to the level before the haemorrhage developed will often result, while permanent damage to the visual function will most often have developed when there is tractional retinal detachment. Neovascular Glaucoma Proliferative diabetic retinopathy that has progressed to neovascular glaucoma should be treated immediately with panretinal photocoagulation. Most often, neovascular glaucoma is associated with severe visual reduction and if vascular new growth has immobilized the iris, perhaps combined with cataract, the disease has come beyond therapeutic reach with laser and vitrectomy (fig. 7). The therapeutic goal in this situation is to keep the intraocular pressure normal primarily in order to preserve residual vision, but also to keep the patient free of pain and thereby avoid a cosmetically disfiguring enucleation. The primary treatment is administration of local or systemic drugs to lower the intraocular pressure. Destruction of the ciliary body by transscleral heating or freezing reduces aqueous production, or alternatively an artificial outflow channel can be made to replace the trabecular meshwork channel closed by new vessels.


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Psychosocial Aspects Diabetes mellitus is a burdening chronic disease with profound influence on daily life. The disease is associated with many contacts to the health-care system and the necessary routine eye controls combined with the threat of losing vision may be an additional burden. Consequently, some patients may need to repress or forget their disease for periods, during which they drop out of the diabetes care system. For these patients there may be a risk of developing vision-threatening retinal changes, in spite of the fact that the organization of retinopathy screening to detect early changes has been set up optimally. This risk is so much higher because the patients who drop out of the eye controls often also neglect the metabolic regulation, which further increases the risk of developing vision-threatening complications. The problem is not easy to solve, but resources should be used to give appropriate information about adverse consequences of disease neglect, and ideally psychological assistance should be offered. Impairment of vision secondary to diabetes mellitus often affects younger persons of family supportive age. Therefore, in addition to the personal consequences, diabetic retinopathy also has great social and economic implications for the patients’ relatives and for the society as a whole. Preserved vision may make the difference that enables self-monitoring of blood glucose or home dialysis, enables daily doings, and enables the filling out of a job position. Therefore, it is of paramount importance that visual loss is prevented, but also, that diabetic patients who have already experienced visual reduction are offered help to come to terms with their situation, to manage their daily life, and perhaps be rehabilitated to fill out a job with demands that match the visual ability.

Conclusion It appears from the foregoing account that in most countries there are significant unexploited potentials for reducing the risk of visual loss secondary to diabetic retinopathy. Presently, the most remarkable shortcoming is the lack of detection of vision-threatening retinopathy in the diabetic population, largely caused by organisational limitations and lack of long-term health economic thinking. An optimization of this field requires that patients and medical personnel bring this problem to the attention of health politicians. Another significant limitation for initiating a rational fight aginst visual loss secondary to diabetic retinopathy is the limited knowledge of the pathophysiology of the disease. Huge and significant research efforts have been initiated

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to solve this puzzle, and major advances have been made. A detailed account of this field, however, is beyond the scope of this chapter. In most recent years much attention has been directed at the importance of systemic factors for the development of diabetic complications, inclusively diabetic retinopathy. It is now well established that a tight glycaemic regulation can delay the development of diabetic retinopathy, and lately focus has been given to the effect of reducing the blood pressure. The diabetologic expertise has thus become one of the cornerstones in the preventive efforts against diabetic eye disease, signalling that optimal diabetes care of the future will probably depend on a close cooperation between diabetologists and ophthalmologists. With such a collaboration, the ophthalmological evaluation of retinopathy might be an effective measure for the diabetological regulation of systemic factors such as blood glucose, blood pressure, or other metabolic parameters. Together with an optimized education and motivation of the diabetic patient, and appropriate treatment of already developed visionthreatening retinopathy, it can be hoped that once in a not too far future diabetic retinopathy will be demoted to a rare cause of visual impairment and blindness.

Suggested Reading Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL, Klein R: Diabetic retinopathy. Diabetes Care 1998;21:143–159. Diabetes Control and Complications Trial Research Group: The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. Arch Ophthalmol 1995;113:36–51. Early Treatment Diabetic Retinopathy Study Research Group: Report No 1: Photocoagulation for diabetic macular oedema. Arch Ophthalmol 1985;103:1796–1806. Kohner EM, Bek T, Aldington S: Diabetic Retinopathy. Diagnosis, Management and Reference Images (CD-ROM). Amsterdam, Elsevier, 1999. Kohner EM, Porta M: Screening for Diabetic Retinopathy in Europe: A Field Guide Book, Geneva, WHO, 1992, pp 1–51.

˚ rhus University Hospital, Dr. Toke Bek, Department of Ophthalmology, A ˚ rhus C (Denmark) DK–8000 A Tel. +45 89493223, Fax +45 86121653, E-Mail [email protected]


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Chapter XI

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Nephropathy and Hypertension in Diabetic Patients Carl Erik Mogensen Medical Department M (Diabetes and Endocrinology), Kommunehospitalet, ˚ rhus University Hospital, A ˚ rhus, Denmark A

Introduction Strict and steady near normoglycemia over many years is of paramount importance for the prevention and postponement of renal disease, as well as other complications in most patients with type 1 and type 2 diabetes. Later, several other factors appear to affect progression in renal disease of which blood pressure (BP) elevation seems most important. This seems also to be the case for macrovascular complications along with dyslipidemia, smoking and, as mentioned, hyperglycemia. Incipient renal disease in diabetes, as judged by the occurrence of microalbuminuria, is frequently characterized by hypertension starting with increase in BP from a normal level. The increase, however, is often subtle and may only be detectable by careful and continuous monitoring, e.g. by 24-hour ambulatory recordings. Elevation of BP is found in both types of diabetes, but there appear to be several distinctions between type 1 and type 2 diabetes; some of these variations are clearly explained by the different etiology and nature of the diabetic state. In type 2 diabetic patients, higher age, increased body weight, as well as syndrome X abnormalities are important factors. Though hypertension secondary to renal dysfunction is also frequently seen in type 2 diabetic patients, the renal genesis of hypertension is much clearer and more common in the relatively younger type 1 diabetic patients. Indeed a vicious circle seems to be operating in both types of diabetes and differences between type 1 and type 2 diabetes regarding nephropathy are far fewer than reported earlier. It should be noted that dietary protein intake may also be a modulating factor, but further studies on intervention are needed. These factors – glycemic control, BP elevation and to some extent

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dietary proteins, and the modification by treatment – will be the main issues for discussion here.

BP, Glomerular Pressure and Potential Genetic Factors In the past decades there has been a growing interest in the nature of diabetic renal disease, mainly focusing on BP, glomerular pressure and protein leakage as related to structural and biochemical abnormalities. A recently published volume intends to cover almost every aspect of renal disease and hypertension in diabetes. One key point is interesting here; in general, two or more risk factors must coincide to provoke fast and serious organ damage. In terms of diabetic nephropathy this means that some degree of poor glycemic control may not always be clinically noxious enough per se, unless some other risk factors, especially elevated BP or possibly poorly defined genetic elements coexists. However, increased glomerular pressure seems to be a decisive factor, whether caused directly by poor glycemic control, dietary proteins or systemic hypertension, in particular with loss of renal vascular autoregulation that may be seen in diabetes. Other risk factors may contribute to renal and especially vascular damage in diabetes, e.g. smoking, lipid abnormalities or obesity, again highlighting the importance of the metabolic syndrome, or syndrome X mainly in type 2 diabetes. Diabetic renal disease may tend to cluster in families, possibly partly reflecting that poor metabolic control also predominates in certain families. This could also relate to ACE gene or other gene polymorphism, but genetic association to diabetic renal disease and its progression may not be strong and has recently been challenged. From a clinical point of view, ACE genotyping is hardly relevant. Based on a meta-analysis, Tarnow et al. concluded that the ACE/ID polymorphism may contribute to the genetic susceptibility to diabetic nephropathy in Japanese type 2 diabetic patients, whereas it does not play a major role in the initiation of diabetic nephropathy in Caucasian type 2 patients. In Caucasian type 1 diabetic patients, comparison of data is complicated by differences between study populations, but a trend towards a protective effect of the II genotype on the development of increased urinary albumin excretion rate was observed, but there is considerable overlap between genotypes. However, a progression also during antihypertensive treatment is somewhat faster with the DD genotype. Whether this is related to actual BP during treatment is unclear. Comparing the different risk factors – apart from poor metabolic control – BP elevation seems to be not only the most important index of actual or subsequent organ damage, but also the most readily measurable (sometimes

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Fig. 1. Interplay of genetics and risk factors.

with 24 h ambulatory BP) as well as modifiable risk factor (fig. 1). Virtually all studies agree that standard medical antihypertensive treatment is able to reduce BP in diabetes, and many studies have confirmed the original observations of a beneficial impact of antihypertensive treatment on the course of renal disease, both in incipient and overt type 1 diabetic patients. Interestingly, ACE inhibitors may be particularly beneficial, although this has been questioned by some. Certainly, the side effect profiles usually favor the use of these agents often combined with diuretics both in incipient and overt nephropathy. These considerations also apply to cardiovascular events in hypertensive type 2 diabetic patients. Combination therapy including b-blockers often has to be used to reduce BP as well as albuminuria efficiently.

Changing Cumulative Incidence of Renal Disease in Diabetes The cumulative incidence of diabetic nephropathy used to be high (B35%) but seems to have declined over recent years, especially in certain areas where only very few patients in a given cohort developed nephropathy. However, this observation could not be confirmed by other groups. The explanation is not clear, but certainly the so-called natural history may be considerably modified by more intensive intervention throughout the course of diabetes. To a large extent, this relates to metabolic control and BP elevation as major factors, but other issues are of importance, e.g. smoking, that may vary considerably. Also race is of importance and diabetic nephropathy is more commonly seen in African-Americans. Indeed new studies among the Pima Indians suggest that with long follow-up periods practically all patients will develop renal

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disease. This information is important because it has been suggested that there may be important susceptibility factors that could relate to genetics. Comparison has been made to eye diseases where practically all patients sooner or later develop lesions. However, there are important modifications since usually renal disease is judged by albuminuria and not by morphology, e.g. on biopsies, and in fact the cumulative incidence of diabetic retinopathy and nephropathy could be almost the same, if histological as well as ophthalmologic examinations are used. It has also been discussed why some people seem to escape diabetic nephropathy even if they are in poor control. A feasible explanation is that in order to produce important clinical disease two factors must be present, namely high BP as well as high glucose. If the combination of high BP and high blood glucose is present the clinical experience is that almost all patients will develop clinically relevant nephropathy and also retinopathy. Recent studies underscore the role of good metabolic control also in more advanced nephropathy. This has been documented in several studies, and also recently by Mulec et al. These results are in concert with information from Denmark, Gothenburg and London. Clearly with advanced nephropathy elevated BP is of importance, and combining the two risk factors in overt nephropathy, huge differences in progression may be observed. With poor control of glycemia and especially poor BP control, the fall rate is high (B10–12 ml/min/year or even more), but with efficient control of blood glucose and BP fall may be close to 1–2 ml/year which is close to the age-related reduction. Obviously, it is not possible to obtain perfect metabolic control in all patients, especially in those at risk or with nephropathy because the very background for developing complications is the poor control which may not be easy to modify even after development of complications. This is exemplified in a study from the UK, The Microalbuminuria Collaborative Study. The combined deleterious effect of poor glycemic control and BP control is indeed also clear from the important UKPDS intervention study in type 2 diabetes. In summary, one could argue that the concept of ‘natural history’ may be wrong unless it is used specifically in patients who are in specifically defined glycemic control. However, if risk factors such as hyperglycemia and BP elevation can be controlled, few patients may actually develop proteinuria and eventually end-stage renal disease both in type 1 and type 2 diabetes. Also with advanced nephropathy, glycemic control seems very important. However, an intensified strategy requires considerable resources not only from the health-care providers but also from the patients. The recent Steno Study used the new concept of multifactorial intervention with a good result on renal and retinal diseases. It may be easier to implement long-term treatment with ACE inhibitors or other antihypertensive agents, also in the normoalbumi-


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nuric state as recently proposed by Ravid et al. However, both strategies should be exercised in the clinical setting as discussed below. Notes on Key Risk Factors: Blood Glucose Perfect metabolic control, that is blood glucose as well as concentrations of other metabolites and hormones within normal range, is presently almost impossible to obtain in the majority of diabetic patients. Even in the DCCT (The Diabetes Control and Complications Trial Research Group) optimized management in type 1 diabetic patients only rarely resulted in perfect glycemic control. The same may be the case in type 2 diabetes, where a somewhat better control may be possible. Under standard care conditions, HbA1c values may be 50% or most often even higher than normal reference values in most patients. However, good metabolic control remains a key factor in preventing retinopathy and nephropathy, and progression of nephropathy, also when severe damage is present after fall in GFR. Further long-term studies are needed in type 2 diabetic patients but the same relation seems to exist here, especially early in the course of the renal disease. Long-term renal data from the UKPDS would be highly interesting. Notes on Key Risk Factors: BP Level in Treated Diabetes Nowadays very high BP levels are rarely observed in the clinic in treated diabetic patients. High pressures are most often encountered in populations without any structured care for complications. With appropriate antihypertensive programs the degree of elevation of BP is usually not very pronounced at least when compared to the past. This is for instance corroborated by new studies where 24hour BP recordings in diabetics are carefully compared to nondiabetics. When diabetics who do not receive antihypertensive treatment are selected, it is obvious that BP elevation is not pronounced, around 5 mm Hg on average in microalbuminuric patients. Clearly such data are biased, because patients who are already in treatment are excluded. On the other hand, even minor BP elevation may lead to vascular and glomerular damage, especially when accompanied by other risk factors, e.g. hyperglycemia. A correlation exists between albuminuria and BP and the association is amplified when 24 ambulatory BP values are used rather than conventional BP measurements. Diabetic patients may be exquisitely susceptible to systemic BP elevation because the normal protection exerted by the afferent renal arteriolar vasculature is likely to be compromised in many diabetic patients, and a vicious circle will develop in such conditions. A few decades ago, BP elevation was usually much higher. A very pronounced fall in recorded BP has been observed in diabetes clinics during recent years, as evidenced by a Danish study, where BP levels in cohorts of patients in the 1960s were compared to patients in the 1980s.

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Interesting differences exist between the two types of diabetes. In type 1 diabetes the prevalence of hypertension is strongly correlated with the degree of albuminuria. With normal albumin excretion rate, BP is close to normal which has been confirmed in recent studies using 24-hour BP recordings. With the occurrence of microalbuminuria there is a considerable increase in the prevalence of elevated BP, and even more marked changes are seen with overt diabetic nephropathy. In type 2 diabetes the situation is more variable, although there is usually some association between albuminuria and BP level. However, the correlation is weaker, and it is also important to recognize that the prevalence of BP elevation is much higher in the elderly type 2 diabetic patients; even at the time of clinical diagnosis about 40% of patients had elevated BP or were receiving antihypertensive treatment. In a control population without diabetes this figure may be 20%. Interestingly BP elevation in type 2 diabetic patients is usually of systolic nature, at least in some studies. Effective treatment may be difficult with high initial values and therapeutic goals should be modified, with a stepwise reduction in BP. Without treatment the rate of increase in BP with time is recorded to be high in type 1 diabetic patients with microalbuminuria or overt proteinuria, supporting the idea that a self-perpetuating process exists. This increase is most pronounced in type 1 diabetic patients; clear data are more difficult to obtain in type 2 diabetes, because so many patients are treated with antihypertensive drugs and discontinuation of treatment is not justifiable. Still an increase is seen, especially with 24-hour monitoring. In type 1 diabetes, BP may increase by 3–4 mm Hg/year with microalbuminuria, and around 6 mm Hg/year with overt renal disease. Such data may be difficult to reproduce today, simply because so many patients are early and effectively treated. Notes on Key Risk Factors: Dietary Proteins With some variations from country to country, traditional diabetic dietary management often results in a high protein intake (sometimes 50% higher than the average background population). This may not be an appropriate strategy because a dietary pattern like that may aggravate the course of renal disease.

Microalbuminuria as an Important Intermediary Endpoint A major question in all types of clinical management is to define parameters that can be considered important markers in terms of disease activity. This is of special importance in intervention trials, but also in the treatment


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of patients, where results from already conducted trials are rapidly reflected in practical management. An outline of the natural history of renal disease in type 1 diabetic patients is given in table 1. Hypertensive and proteinuric diabetic patients usually carry a very poor prognosis. It has also become clear that abnormal albuminuria in the microalbuminuric range (20–200 lg/min) is an important long-term predictor for poor outcome. A decisive parameter is the fall rate of GFR as measured by exact and reproducible techniques. Doubling of S-creatinine has also been used. Obviously, an even more solid endpoint is end-stage renal failure (ESRF) and/or death, but in patients with early clinical proteinuria or microalbuminuria, this is (fortunately) a distant endpoint since the development of ESRF may last at least one or two decades, especially after it has been shown that antihypertensive treatment postpones end-stage renal disease. Strong evidence suggests that abnormal albuminuria (even slight elevation) is a key parameter and an important intermediary endpoint in the monitoring of all diabetic patients, not only because it relates so closely to the more advanced endpoints, but also because this parameter can be used both in the treatment strategies in controlled clinical trials, and in the day-today management of patients. Importantly, new studies show that glomerular structural damage can be arrested by early antihypertensive treatment (b-blockers or ACE inhibitors) in microalbuminuric patients. This is an extremely important finding again supporting the use of early antihypertensive medication.

GFR Fall in Type 1 Diabetes Related to Abnormal Albuminuria and/or BP Elevation Patients with completely normal albumin excretion rate usually preserve normal renal function (GFR) over many years, at least one or two decades. It should be noted here that there may, however, be a small probably agerelated reduction in GFR. Also patients with persistent microalbuminuria usually maintain intact GFR, though a subsequent fall in GFR can be predicted, with progression to macroalbuminuria and possibly partly related to previous hyperfiltration. Only with the development of proteinuria (macroalbuminuria) is there a significant decline in GFR. Antihypertensive treatment may reduce or even normalize albumin excretion, and thus lead to misclassification of patients. Albumin excretion may again increase if treatment is stopped for some reason. Feldt-Rasmussen et al. observed a significant drop in GFR with the development of clinical nephropathy but most of their patients received antihypertensive treatment which modifies the level of UAE

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Table 1. Stages in the development of renal changes and lesions in diabetes mellitus (mainly type 1 or younger type 2) Stage

Chronology

Main structural Glomenular changes or lesions filtration rate

Dextran clearance Albumin exception (% of GFR) baseline UAEa

exerciseinduced UAE Increased, but reversible

Blood pressure

Reversible by strict insulin treatment

Arrestable or reversible by AHTb

Normal

Yes

No hypertension present Microcirculatory changes modifiable

1

Acute renal hypertrophyhyperfunction

Present at diagnosis of diabetes (reversible with good control)

Increased kideney size Increased glomerular size

Increased by 20–50%

Normal

May be increased, but reversible

2

Normoalbuminuria (UAE=20 lg/ min)

Almost all patients normoalbuminuric in first 5 years

On renal biopsy, increased BM thickness

Increased by 20–50%

Normal

Normal by definition May be Normal (BP as (15–20 lg/min may abnormal after in background be abnormal) a few years population) Increase by 1 mm Hg/year

Hyperfiltration reduced

Filtration fraction and UAE may be reduced

3

Incipient diabetic nephropathy, UAE 20–200 lg/ min

Typically after 6–15 years (in B35% of patients)

Further BM thickening and mesangial expansion, arrestable with AHT

Still supraNormal normal values, predicted to decline with development of proteinuria

Increase B20%/year (of glomerular origin)

Abnormal aggravation of baseline UAE, related to BP increase

Incipient increase, B3 mm Hg/year (if untreated)

Microalbuminuria stabilized, GFR also stable (if HbA1c is reduced). Structural damage slower

Microalbuminuria reduced Prevention of fall in GFR

4

Proteinuria, clinical overt diabetic nephropathy

After 15–25 years (in B35% of patients)

Clear and pronounced abnormalities

Decline B10 ml/min/year with clear proteinuriac

Abnormal to high molecular dextrans (nonspecific and only with low GFR)

Progressive clinical proteinuriac of glomerular origin

Pronounced increase in BP

High BP, increase by B5 mm Hg/year (if untreated)

Higher fall in GFR with poor control

Progression reduced (aiming at 135/85 mm Hg)

5

End-stage renal failure

Final outcome, after 25–30 years or more

Glomerular closure and advanced glomerulopathy

=10 ml/min

Not studied

Often some decline due to nephron closure

Not studied

High (if untreated)

No

No

BM>Basement membrane; UAE>urinary albumin excretion rate; AHT>antihypertensive treatment. a The best clinical marker of early renal involvement. b Mostly ACE inhibition + diuretics. c Without antihypertensive treatment.


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and slightly lowers GFR, again a confounding factor. In patients with more advanced renal disease and proteinuria, it was documented long ago that the fall rate in GFR is at an average of 10 ml/min/year. Already this study suggested glomerular hyperfiltration still to be present in microalbuminuric type 1 patients, without any time-dependent decline in GFR, since these patients had not yet developed proteinuria. In some type 1 diabetic patients with elevated BP (or white-coat hypertension?), but with normal albumin excretion rate, Nørgaard et al. documented a well-preserved renal function. It is postulated that these patients may have essential hypertension together with diabetes. In conclusion, it is likely that abnormal albuminuria is the main predictor – or perhaps even a determinant – of future decline in renal function, although the nature of the initial permeability defect in glomeruli is not yet explained. Pressure dependency may play an important role. The underlying mechanism may either be an increased transglomerular traffic of proteins leading to further glomerular damage or an increased tubular reabsorption rate of albumin. The latter may cause interstitial damage, which in turn, may lead to structural damage in glomeruli. Another hypothesis for this self-perpetuating process involves glomerular hyperfiltration. Patients with a decline in GFR due to nephron closure are likely to show single nephron hyperfiltration in the remaining glomeruli. On the other hand, patients with microalbuminuria usually do not exhibit any decline in GFR but some compensatory hyperfunction may still prevail on top of the usual diabetic hyperfiltration. Abnormal albuminuria is clearly associated with vascular damage in other organs.

Elevated BP and Relation to Kidney Function and Structural Damage The exact mechanism behind the increase in BP related to renal impairment is not clear. It is well established that BP increases with reduction of GFR in most glomerular diseases, but in diabetic patients elevated BP is seen prior to this reduction of renal function. Mesangial expansion observed in diabetic nephropathy, already at the microalbuminuria stage, could be of importance, but this is not yet clarified. The BP elevation may also relate to sodium retention associated with renal disease. In type 2 diabetics the relationship between elevated BP and impaired renal function is also present, but less clear due to many confounding factors. Usually there is a correlation between the mainly systolic BP elevation and the degree of abnormal albuminuria but the correlation is not very striking.

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Retention of Sodium, BP Elevation and Local Pressures There is an association between exchangeable sodium and elevated BP in microalbuminuric patients suggesting that sodium excess may be of importance. The sodium excess may be explained by increased tubular reabsorption of sodium, possibly stimulated by exogenous or endogenous hyperinsulinemia. However, the association is mainly empiric and there may be common underlying mechanisms that explain both sodium retention and elevated BP. In type 1 diabetes there is a correlation between cardiac contractility and degree of microalbuminuria, suggesting that increased cardiac contractility in diabetes may produce increased output and thus contribute to hyperfusion in diabetes. However, with the transition to overt proteinuria a decrease in contractility is observed. Besides generalized hyperfusion, there may be evidence of increased localized pressure not only in the kidney, but also in the peripheral circulation. This abnormality may possibly parallel the increase of glomerular pressure in the kidney, but it is not observed in type 2 diabetes, where only a minor degree of hyperfiltration exists.

Arterial Disease In type 2 diabetes there is evidence of increased arterial stiffness. This phenomenon may explain why the BP elevation is predominantly of systolic nature in these patients. Diastolic BP is usually also elevated, but often to a lesser extent unless overt renal damage is present. The hypothesis that large vessel disease produces systolic elevation of BP, which in turn increases albuminuria and provokes renal damage, is intriguing. BP reduction may reduce albuminuria but could also potentially provoke ischemia in other organs, e.g. the brain or the heart. Treatment therefore may often be difficult and stepwise reduction is recommended. These limitations clearly support the concept of early antihypertensive treatment in these individuals, e.g. in patients with microalbuminuria long before too severe hypertension. Of note, patients with essential hypertension do show insulin resistance and/or hyperinsulinemia. Since insulin resistance is also a mechanism involved in the pathogenesis of type 2 diabetes, insulin resistance may also contribute to BP elevation in diabetes. Indeed, elevated BP is found early in the course of type 2 diabetes right from the time of diagnosis, where insulin resistance probably is an important phenomenon. There are other abnormalities that may be involved in the genesis of hypertension in diabetes, such as increased sympathetic nervous activity producing increased vascular reactivity. This may also be related to obesity. How-


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Table 2. How antihypertensive agents may be combined in diabetes b-Blockers

Yes (diuretics often required)

ACE inhibition Yes (diuretics or angiotensin often required) receptor blockers

Yes

Yes (theoretically interesting combination, results promising)

Ca blockers1

Yes (diuretics often required)

Yes (rarely used) Yes (rarely used)

Yes (often used; also with diuretics)

Diuretics

b-Blockers

ACE inhibition

b-Blockers + diretics

Careful clinical metabolic and BP monitoring always required, including control of serum electrolytes and serum creatinine of GFR index (combination therapy used in more than 50% of patients). 1 Some results suggest cardiovascular long-term effect less favorable than with ACE inhibition in type 2 diabetes.

ever, since these phenomena may not point clearly to specific modalities of treatment, they will not be further discussed.

Treatment of BP Elevation Mechanisms of BP Elevation and Choice of Therapy in Nephropathy Based upon the known mechanisms operating in the genesis of hypertension, some interesting concepts regarding selection of antihypertensive treatment are evolving in diabetes. The abnormalities in renal function, where hyperfusion, hyperfiltration and increased glomerular pressure may be important mediators, favor the use of ACE inhibitors, since these agents tend to reduce efferent glomerular resistance. This effect, operating by reducing glomerular pressure, may even to some extent be independent of systemic hypertension or systemic BP level. The sodium retention evident in both type 2 and type 1 diabetes supports the use of diuretics and sodium restriction in antihypertensive programs in diabetes. The early cardiac hyperfunction in microalbuminuric patients may suggest the use of cardioselective b-blockers to reduce this hyperfunction. Obviously, the generalized BP reduction seen with all these agents may be of prime importance, but these mechanisms could also favor the use of combined treatment: ACE inhibitors, diuretics and possibly b1-blockers (or other agents) in diabetic patients (table 2). Calcium blockers reduce BP, and may be important in therapy although some, but decreasing, controversy exists.

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Table 3. Diabetes-related side effects and favorable effects related to antihypertensive treatment in diabetics (mainly type 1 diabetes) Diuretics (thiazide Noncardioor loop) selective b-blockers

Cardioselective b-blockers

ACE inhibitors

Triple treatment: diuretic b1-blockers/ ACE inhibitors

Calcium blockers Angiotensin receptor blockers

Glucose intolerance Yes, type 2, but related strongly to hypokalemia)

No problem

No problem

No side effects Limited or no change No Insulin sensitivity (with small dosages) not changed clinically

No

Hypoglycemic masking

No

Yes, mainly in type 1 diabetes

A problem, but limited, seen in few patients

Not seen

Limited or no change No (with small dosages)

No

Unfavorable lipid profits

Yes, but not with small doses

Likely

Limited or nonexisting

No side effects

?

No

No

Other unfavorable effects

May cause sodium depletion

Less physical exercise capacity

Less physical exercise capacity

Coughing and drug-related side effects (uncommon)

Limited (with small dosages)

Foot edema seen No in few patients

Favorable effects (apart from BP reduction)

Elimination of edema

Reduction of cardiovascular morbidity/ mortality Normalization of cardiac arrhythmias?

Reduction of cardiovascular morbidity/ mortality Normalization of cardiac arrhythmias?

Elimination sodium excess and possibly restoration of glomerular pressure gradients

Probably also combination of favorable effects (stable GFR?)

No potentiation of peripheral ischemia?

Effect on abnormal albuminuria

Not well documented

Not well documented

Yes, but relatively Very consistent few studies exist finding

Addition of ACE Related to BP inhibition reduces reduction abnormal albuminuria

Reducing fall rate of GFR

Not documented

Not documented

Yes

GFR stable on this program

Yes

Yes

Not documented Ungoing studies

Obviously, from a theoretical point of view, potential additional beneficial effect should be considered (table 3). For example, ACE inhibitors may as suggested specifically reduce the localized increased pressures seen in these patients, as originally observed in animal studies. The presence of edema of course favors the use of diuretics. It is suggested that arrhythmias may play a role in the early mortality, especially in type 2 diabetic patients, and the observation that in trials in patients at risk b-blockers are especially effective in diabetic patients points to additional beneficial effects of b-blockers in the management of hypertension in diabetics where cardial disease and silent myocardial infarctions are not uncommon. Importantly, in heart failure bblockers are increasingly being used according to new trials, e.g. the Merit HF Study. Clearly, side effects are important and these are usually dose related. For example, the well-known diabetogenic effect of diuretics may be dose dependent with sufficient BP reduction with small doses that are not diabetogenic. Potassium loss is important but can readily be restored by potassium supplementation or by the use of ACE inhibition. Also small doses of diuretics may


Under investigation

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not impair lipid parameters. A side effect that has caused some concern is hypoglycemic unawareness. This was previously reported with unselective bblockers but is only of minor importance with cardioselective b-blockers and the phenomenon is not important in type 2 diabetics that may especially benefit from cardioprotection by b-blockers. Most ACE inhibitors do certainly not possess any diabetogenic effects, rather they are neutral. Thus there is no negative effect on glucose metabolism or lipid homeostasis; a positive effect has in fact been observed in some studies. This positive or rather neutral pattern may therefore favor the use of ACE inhibitors in diabetic patients. Importantly, no increased frequency of hypoglycemia is seen in clinical practice. Coughing as a side effect is surprisingly rare in diabetic patients, possibly due to diabetic neuropathic changes. The new angiotensin II receptor antagonists could be considered in this situation, also with other side effects caused by ACE inhibitors. Problems of Optimized Glycemic Control During Antihypertensive Treatment In recent years it has become increasingly clear that good glycemic control is of clear importance in the prevention and postponement of diabetic renal disease. As documented in the DCCT, good glycemic control can reduce the number of patients that develop advancing renal disease. Improved metabolic control seems also to protect against deterioration in renal function in patients with microalbuminuria. However, it is important to stress that it is quite often difficult to obtain good metabolic control, especially in patients with incipient or overt renal disease. There are no formalized long-term trials with a sufficient number of patients on the effect of optimized diabetes care in patients with overt renal disease. However, new studies strongly suggest a correlation between progression in renal disease, as measured by fall rate of GFR and level of HbA1c. If HbA1c is satisfactory, with values around 7–8% (reference value 5.5%), progression is slow. This observation was recently confirmed. In patients with type 2 diabetes, progression can be reduced by early intervention. With overt nephropathy there is no correlation between progression and HbA1c. The UKPDS clearly documented the role of good glycemic control in preventing microvascular complications. Intervention Trials in Normoalbuminuria Even in type 1 diabetic patients with normal BP and normal albumin excretion, renal hemodynamics may be beneficially influenced by ACE inhibition. This study was of experimental nature and treatment of such individuals cannot be recommended, although a trial should be conducted in high-risk normoalbuminuric patients (high normal UAE (?12 lg/min), high HbA1c

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(?9–10%)). However, the Euclid Study did not document any clear effect in normoalbuminuria in a 2-year trial, but longer intervention is likely to be positive, according to unpublished studies from Denmark.

Microalbuminuria and Antihypertensive Treatment Several intervention studies have been published, some with self-controlled or crossover design, some double-blinded without being long term and some long term and randomized without being blinded. All these trials generally showed a reduction or a stabilization in microalbuminuria. In a recent randomized double-blind large-scale placebo-controlled study, the effect of an ACE inhibitor was investigated with respect to progression to clinical nephropathy in normotensive type 1 diabetic patients with microalbuminuria. The major endpoint was the progression to persistent proteinuria (UAER ?200 lg/min). In this large study, treatment delayed the progression to overt renal disease in normotensive, type 1 diabetic patients with microalbuminuria. Interestingly, in all these studies confirmed from 1985 to 1999, patients were included purely on the basis of microalbuminuria and indeed in most studies patients should not be hypertensive (often an exclusion criterion for participation). Therefore, in most studies BP was close to normal, and in some of the patients BP was in the middle of the range as seen in healthy young individuals (mean arterial pressure B90 mm Hg). There seems to be a tendency towards a correlation between reduction in BP and reduction in albuminuria. The clinical consequence is that the indication for antihypertensive treatment should be microalbuminuria (as in the clinical trials) rather than some elevation of BP (fig. 2). Obviously any elevation of BP or any increasing BP would further strengthen the indication, because there is a correlation between rate of progression of microalbuminuria and BP; still the conclusion from these studies would mean that antihypertensive treatment should be initiated whenever microalbuminuria is consistently found. A more cautious view would be to start antihypertensive treatment if microalbuminuria is clearly increasing (5–10% per year), but the variability in UAE makes this approach somewhat difficult in the practical clinical setting. All studies document a reduction or stabilization in microalbuminuria, irrespective of the treatment used; however, most studies were conducted with ACE inhibitors as the principal agent with few or no side effects. Diuretics were systematically added in one important study. Thus the scenario for the use of antihypertensive treatment, in particular ACE inhibitors, is moving from the indication of elevated BP to the indication of increased or increasing UAE as proposed in recently published guidelines. Combination therapy is also very useful in such patients.


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Fig. 2. Microalbuminuria (MA) in type 1 diabetic patients below 60 years of age. New studies suggest similar effects in the relative young and lean type 2 diabetic patients. A/C>Albumin/creatinine ratio. Modified from Mogensen et al.

In type 2 diabetic patients, microalbuminuria can be reduced by ACE inhibition and two long-term studies suggest a beneficial effect on GFR. The fall rate of GFR correlates to BP. This important topic has recently been reviewed by Cooper and McNally, and ACE inhibition as early treatment seems equally important in type 1 and type 2 diabetes.

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Table 4. ACE inhibitors in type 1 diabetic patients: observed effects in clinical trials (stages as described in table 1) 1

No trials in newly diagnosed patients

2

Normoalbuminuria reduced BP not significantly changed Filtration fraction reduced (in normoalbuminuria)

3

Microalbuminuria reduced BP reduced (diastolic and systolic) Fall in GFR prevented or postponed

4

Proteinuria reduced BP reduced (diastolic and systolic) Fall rate of GFR reduced

5

End-stage renal disease and mortality postponed

Trials in Patients with Proteinuria or Overt Diabetic Nephropathy In the untreated situation there is a correlation between the fall rate of GFR and BP, but interestingly the correlation between the fall rate of GFR and albuminuria is equally strong. It has been suggested that a pronounced fall in proteinuria after start of antihypertensive treatment predicts a more benign course of renal disease in type 1 diabetic patients, compatible with an important role for the level of albuminuria in the rate of progression in renal disease. Several studies have documented that antihypertensive treatment unequivocally reduces the fall rate of GFR. This is invariably accompanied by reduction of albuminuria. Therefore, antihypertensive treatment is the major therapeutic option for these patients. The use of ACE inhibitors often with diuretics is popular, though antihypertensive programs, e.g. with b1-blocker, have been reported equally effective, but possibly with more side effects. The recent important study by Lewis et al. showed that the number of patients with doubling of S-creatinine could be reduced by ACE inhibition, thus confirming earlier studies. However, BP was 3–4 mm Hg lower in the ACE-I group. A beneficial effect of ACE inhibition when combining ESRF and mortality was noted however. Thus, ACE inhibitors work in all stages of diabetic renal disease (table 4). Pregnant diabetic patients require special attention and ACE inhibitors are contraindicated here. In proteinuric type 2 diabetic patients it has also been shown that during treatment there is a correlation between BP elevation and the rate of decline in GFR, suggesting that elevated BP in type 2 diabetic patients is also important for the rate of progression in renal disease. When these patients exhibit overt


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proteinuria, they generally have a poor prognosis. No very long-term intervention trials over several years with the fall rate of GFR as endpoint have been conducted recently in type 2 diabetes. Fall rate is generally high, and in some patients even dramatic, and ACE inhibition and b-blockers seem to have a similar effect on outcome. Important large-scale studies are now ongoing using angiotensin II receptor antagonists and results are keenly awaited in this highrisk population. Protein-Reduced Diet In normoalbuminuric type 1 diabetic patients, hyperfiltration can be reduced by normalizing dietary protein intake, a potential beneficial effect. Studies suggest that microalbuminuria can be reduced on a 2-year intervention basis by a low protein diet, but so far, no long-term results are available, and compliance may pose a problem. In diabetic nephropathy, new data have recently been published indicating that the rate of decline of GFR can be reduced by a low protein diet. Patients were monitored on their usual dietary intake of proteins and thereafter patients were put on a low protein diet. A remarkable reduction in the fall rate of GFR was observed, although the response varied considerably. Patients served as their own controls without a parallel nontreated group and it cannot be excluded that late or long-term action of antihypertensive treatment may explain at least part of the observed beneficial effect. In a randomized parallel study, Zeller et al. also documented beneficial effect on the fall rate of GFR in these patients. The MDRD Study was not convincingly positive but this trial only included few diabetics. Nyberg et al. did not find correlation between dietary protein intake and status of renal disease in type 1 diabetic patients. At this point, the general consensus may be to prescribe a protein intake of approximately 0.8 g/kg body weight per day (D10% of daily calories) in the patient with overt nephropathy. However, it has been suggested that once the GFR begins to fall, further restriction to 0.6 g/kg/day may prove useful in slowing the decline of GFR in selected patients. On the other hand, nutrition deficiency may occur in some individuals and may be associated with muscle weakness. Protein-restricted meal plans should be designed by a registered dietitian familiar with all components of the dietary management of diabetes.

Cardiovascular and Cerebrovascular Trials Along with Renal Endpoints Cardio- and also cerebrovascular diseases are important causes of death in both type 1 and type 2 diabetes, especially when the kidney is affected. Although the concept of controlled clinical or therapeutical trial has evolved

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Table 5. Positive effect on cardiovascular endpoints in type 2 diabetes by antihypertensive treatment Favors 1. 2. 3. 4. 5. 7. 8. 9.

Shep [Curb et al.] ABCD [Estacio et al.] Facet [Tatti et al.] HOT [Hansen et al.] UKPDS [Turner et al.] CAPP [Hansson et al.] Syst-Eur [Toumilehto et al.] Hope-study [Yusef et al.]

Diurectics vs. placebo ACE-I vs. CCB ACE-I vs. CCB Strict control (CCB-based) Strict control (ACE-I +b-blocker-based) ACE-I vs. conventional CCB vs. placebo ACE-I vs. placebo

CCB>Calcium channel blockers.

over the past 50 years, only a few large trials have been conducted in diabetes, the first being the UGDP (University Group Diabetes Program) which now after the UKPDS, is mainly of historical interest. No real large-scale controlled trials were done when introducing sulfonylureas, biguanides or insulin, but this has changed now with the UKPDS. There has therefore been an increasing interest in cerebro- and cardiovascular endpoints, especially in type 2 diabetes with respect to effective modulation, mainly with antihypertensive treatment strategies, which show a beneficial effect (table 5). Most studies employ ACE inhibitors but it is noteworthy that any reduction of BP seems to be important. Certain trials show ACE inhibitors to be superior to calcium blockers and also conventional treatment. Importantly, the UKPDS showed a similar outcome using ACE inhibitors and b-blockers. Fewer side effects occurred with the use of ACE inhibitors. This study also clearly showed that careful BP monitoring and effective treatment reduced cardio- and microvascular endpoints very considerably (around 30%). Therefore, antihypertensive treatment should be given a great priority in the management of patients with type 2 diabetes. The UKPDS showed some effect of optimal glycemic control, but due to the nature of the trial this was not so evident. However, combined euglycemia (HbA1cB6–7%) and normotension is highly protective when BP is around 130–135/80–85 mm Hg.

Guidelines with Origin in Pathophysiological and Clinical Trials The World Health Organization-International Society of Hypertension (WHO-ISH) Liaison Committee on Hypertension was established in the mid-


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Table 6. Suggested target BPs during antihypertensive treatment (systolic and diastolic should be attained, e.g. =140/85 mm Hg means =140 systolic and =85 diastolic) Clinic BP no diabetes Titrate to diastolic BP p85 Optimal BP =140/85 Suboptimal BP p150/90

ABPM or home BP 1

diabetes

no diabetes1

diabetes

p80 =130/80 p140/85

p80 =130/80 p140/85

p75 =125/75 p130/80

ABM>Ambulatory blood pressure monitoring. In those with high cardiovascular risk and initial BP 140–159/90–99 mm Hg there could be a case for adopting the targets for diabetic patients (British Hypertension Society 1999). 1

1970s and has subsequently produced several guidelines, the first in 1975. New guidelines have recently appeared also related to hypertension in diabetes. Several of these new guidelines have a similar approach. There is a clear emphasis on early and effective antihypertensive treatment in patients with diabetes suggesting a lower threshold for the start of the treatment and also a lower goal during treatment. ACE inhibitors are often preferred as initial agents but combination therapy is often warranted. In view of the recent observation that different types of drugs (ACE-I, b-blockers, calcium channel blockers and diuretics) reduce cardiovascular risks in type 2 diabetes, there are different treatment options. In diabetic renal disease, ACE-I is however preferred. We should aim to achieve a BP around 135/85 mm Hg during treatment, or lower. The British Hypertension Society proposes: (1) ‘ The threshold for antihypertensive treatment in type 1 diabetes is q140/90 mm Hg. The target BP is =130/80 mm Hg, or lower (=125/75 mm Hg) when there is proteinuria q1 g/24 h’. And (2): ‘Trials support treatment of all patients with type 2 diabetes and BP q140/90 mm Hg, aiming for a target BP =130/80 mm Hg. BPs p140/85 mm Hg on treatment should be considered suboptimal.’ (3) ‘ Thus there is evidence from outcome trials in hypertensive patients with diabetes for the efficacy and safety of ACE inhibitors, b-blockers, dihydropyridines, and low-dose thiazides. The choice among these drug classes should be made using the criteria set out for nondiabetic patients. BP control will usually require more than one antihypertensive drug, and about 30% of hypertensive patients with diabetes need three or more agents in combination.’ A similar approach is seen in table 6.

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The problem is that it may be difficult to achieve such BP with patients with proteinuria and overt renal disease and also in others with cardiovascular problems. Therefore, it is strongly advocated to start treatment early, e.g. with development of microalbuminuria, even in patients with normal BP. It has also been proposed to start treatment even before microalbuminuria. Since complications are so closely associated with BP increase (also in the normal range) this could easily be recommended in future guidelines as we now have effective treatment modalites with rather limited side effects.

Summary Notes This chapter clearly documents that excess albuminuria, often accompanied by increased BP, is associated with actual or subsequent organ damage, not only in the kidney but also in other organs, especially in the eyes and in the heart. In the kidney, abnormal albuminuria starting in the microalbuminuric range reflects more advanced glomerular structural lesions, although the exact location of the permeability defect has not been defined at an ultrastructural level. BP elevation may not initiate the glomerular permeability defect but high systemic BP aggravates the course of established lesions and clinical disease. Transition from micro- to macroalbuminuria is associated with a reduction in GFR, the key parameter in evaluation of renal function. Biochemical and hemodynamic hypotheses have been put forward supported by animal models, but these notions are difficult to substantiate in humans, where isolated phenomena cannot be studied, and direct measurement of e.g. glomerular wall charge and intraglomerular pressure is not feasible. A unifying concept would be attractive, comprising biochemical aberrations, such as charge defects, changes in enzymatic activities and glycation phenomena as well as hemodynamic changes such as hyperfiltration with elevated glomerular pressure, aggravated by early systemic BP rise. This may be seen along with vascular and endothelial changes, reflected by increases in von Willebrand factor, circulating prorenin as well as increased transcapillary escape rate of albumin and dyslipidemia. Antioxidant status may also play a role. A common pathway explaining all or most of these abnormalities should be pursued, with the basis in prolonged hyperglycemia and related biochemical changes, characteristic for the diabetic state. However, when diabetic complications are evolving as a consequence of hyperglycemia, increasing BP remains a decisive factor in promoting organ damage in the kidney, and antihypertensive treatment seems to be the therapeutic cornerstone in ameliorating deterioration in organ function. A low protein diet may also reduce albuminuria and the fall rate in GFR. However,


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strict antihypertensive therapy may limit the need for any dramatic reduction of the protein content of the diet.

Suggested Reading American Diabetes Association: Diabetic nephropathy. Diabetes Care 2000;23(suppl 1): 69–72. Charurvedi N: HOPE and extension of the indications for ACE-inhibitors? Lancet 2000;355, in press. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, et al: Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA 1996;276:1886–1892. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW: The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998;338:645–652. Feldt-Rasmussen B, Mathiesen ER, Jensen T, Lauritzen T, Deckert T: Effect of improved metabolic control on loss of kidney function in type 1 (insulin-dependent) diabetic patients: An update of the Steno studies. Diabetologia 1991;34:164–170. Forsblom C, Trenkwalder P, Dahl K, Mulder H, on behalf of the Multicenter Study Group: Angiotensin II receptor blockers in type 2 diabetic patients with microalbuminuria. Nephrol Dial Transplant 1998;13:1069. Gæde P, Vedel P, Parving HH, Pedersen O: Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: The Steno type 2 randomised study. Lancet 1999;353: 617–622. Guidelines (1999) for the management of hypertension: Memorandum from a World Health Organization/ International Society of Hypertension Meeting. J Hypertens 1999;17:151–183. Hansson L , Lindholm LH, Niskanen L, et al: Effect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) Randomised Trial. Lancet 1999;353:611–616. Hansson L, Zanchetti A, Carruthers SG, et al, for the HOT Study Group: Effects of intensive BP lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatmen (HOT) randomised trial. Lancet 1998;351:1755–1762. Jacobsen P, Rossing K, Rossing P, Tartow L, Mallet C, Poirier O, Cambien F, Parving HH: Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy. Kidney Int 1998;53:1002–1006. Lewis EJ, Hunsicker LG, Bain RP, Rhode RD: The effect of angiotensin-converting-enzyme inhibition on nephropathy. N Engl J Med 1993;329:1456–1462. Mathiesen ER, Hommel E, Hansen HP, Parving HH: Preservation of normal GFR in type 1 diabetic patients with microalbuminuria under long-term (8 years) ACE inhibition. Nephrol Dial Transplant 1998;13:1062. Microalbuminuria Collaborative Study Group, UK: Intensive therapy and progression to clinical albuminuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. BMJ 1995;311: 973–977. Mogensen CE: Combined high BP and glucose in type 2 diabetes: Double jeopardy (editorial). BMJ 1998;317:693–694. Mogensen CE (ed): The Kidney and Hypertension in Diabetes mellitus. Boston, Kluwer Academic, 2000. Mogensen CE: Microalbuminuria, blood pressure and diabetic renal disease: Origin and development of ideas. Diabetologia 1999;42:263–285. Mogensen CE, Keane WF, Bennett PH, Jerums G, Parving HH, Passa P, Steffes MW, Striker GE, Viberti GC: Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet 1995; 346:1080–1084.

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Mogensen CE, Mau Pedersen M, Ebbehøj E, Poulsen PL, Schmitz A: Combination therapy in hypertension-associated diabetic renal disease. Int J Clin Pract 1997;90(suppl):52–58. Nørgaard K, Rasmussen E, Jensen T, Giese J, Feldt-Rasmussen B: Essential hypertension and type 1 diabetes. Am J Hypertens 1993;6:830–836. Nyberg G, Norde´n G, Attman PO, Aurell M, Uddebom G, Lenner RA, Isaksson B: Diabetic nephropathy: Is dietary protein harmful? J Diabetes Complications 1987;1:37–40. Østerby R, Schmitz A, Nyberg G, Asplund J: Renal structural changes in insulin-dependent diabetic patients with albuminuria. Comparison of cases with onset of albuminuria after short or long duration. APMIS 1998;106:361–370. Parving HH: Renoprotection in diabetes: Genetic and non-genetic risk factors and treatment. Diabetologia 1998;41:745–759. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R: Use of enalapril to attenuate decline in renal function in normotensive patients with type 2 diabetes mellitus. A randomized controlled trial. Ann Intern Med 1998;128:982–988. Tarnow L, Gluud C, Parving HH: Diabetic nephropathy and the insertion/deletion polymorphism of the angiotensin-converting enzyme gene. Nephrol Dial Transplant 1998;13:1125–1130. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco RG, Strollo G, Strollo F: Outcome results of the fosinopril versus amlodipine cardiovascular events randomized trials (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21:597–603. Turner R, Holman R, Stratton I, Cull C, Frighi V, Manley S, et al, for United Kingdom Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: United Kingdom Prospective Diabetes Study 38. BMJ 1998;317: 703–713. UKPDS 34: Effect of an intensive blood glucose control policy with metformin on complications in type 2 diabetic patients. Lancet 1998;352:854–865. Zeller K, Whittakerm E, Sullivan L, Raskin P, Jacobson HR: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 1991;324:78–84. Carl Erik Mogensen, Medical Department M (Diabetes and Endocrinology), ˚ rhus University Hospital, DK–8000 A ˚ rhus C (Denmark) Kommunehospitalet, A Tel. +45 89492011, Fax +45 86137852, E-Mail [email protected]


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Chapter XII

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Lipid Abnormalities and Lipid Lowering in Diabetes E. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Pathophysiology The metabolism and function of the various lipoproteins (VLDL, LDL and HDL) is quite complex. Here a brief summary will be given, referring to the various steps illustrated in figure 1. Metabolism of Lipoproteins in the Normal State VLDL are produced by the liver and secreted into circulation (step 1 in figure 1). In the liver they are formed by assembling TG, formed through the esterification of FFA (coming from adipose tissue, where they are released through lipolysis effected by the hormone-sensitive lipase), C, and the apoprotein B-100 (ApoB-100), besides other components such as phospholipids. The VLDL particles can be distinguished into two subclasses, VLDL1 and VLDL2, with Svedberg flotation (Sf) rates of 60–400 and 20–60, respectively. After secretion, VLDL reach ‘peripheral tissues’, i.e. adipose tissue and muscle (step

Abbreviations Apo>Apoproteins; C>cholesterol; CAD>coronary artery disease; CE>cholesteryl esters; CETP>cholesteryl ester transfer protein; CHD>coronary heart disease; CVD>cardiovascular disease; FFA>free fatty acids, HDL-R>high-density lipoprotein receptor; HDL>high-density lipoproteins; HL>hepatic lipase; HMG-CoA>hydroxy-methyl-glutaryl-CoA; IDL>intermediate density lipoproteins; LCAT>lecithin:cholesterol acyltransferase; LDL-R>LDL receptor (ApoB/ApoE receptor); LDL>low-density lipoproteins; Lp(a)>lipoprotein(a); LPL>lipoprotein lipase; LRP> LDL receptor-related protein; TG>triglycerides; UC>unesterified cholesterol; VLDL>very low-density lipoproteins.

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Fig. 1. Simplified scheme of the metabolism of lipoproteins involved in plasma TG and C transport. In addition to the abbreviations used in the text (see p. 1), the following ones are also used: AI>ApoA-I; AII>ApoA-II; B-100>ApoB-100; CII>ApoC-II; CIII> ApoC-III; E>ApoE.

2 in figure 1) where they are subjected to the action of LPL. While in the circulation, VLDL are enriched with ApoC-II, ApoC-III and ApoE, which are transferred to VLDL from the HDL. ApoC-II is the cofactor required for the activity of LPL (ApoC-III would inhibit LPL). This enzyme is produced by the cells of adipose tissue and muscle, and then transferred to the endothelial capillary surface, where it hydrolyzes the TG in VLDL, thus releasing FFA. The latter are taken up by cells and then re-esterified and stored as TG (in the adipose tissue) or mainly oxidized (in the muscle). The action of LPL profoundly alters the structure of the VLDL, with collapse of the TG-containing core. The excess surface components, including UC and phospholipids, are transferred to HDL. ApoC and ApoE are also transferred back to HDL. Through this process, the original VLDL particle is first converted into IDL, containing ApoB-100 and ApoE (step 3 in figure 1), and then into LDL, which are mainly composed of C and ApoB-100 (step 4 in figure 1). LDL

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particles are taken up and degraded by the liver (and other tissues) through the LDL receptors (fig. 1, step 5 for extrahepatic tissue, step 6 for the liver), which recognizes ApoB-100 and ApoE. When LDL-lipid peroxidation occurs (such as in diabetes), LDL are taken up by endothelial cells and macrophages through an alternative ‘scavenger pathway’ (not shown in figure 1). In the artery wall this may contribute to the genesis of the atherosclerotic lesions. IDL are in part converted into LDL (step 4 in figure 1) but in part are taken up and degraded by the liver (step 7 in figure 1) through another receptor (the remnant receptor) which is specific for ApoE, and is thought to be the LDL LRP. Thus, the VLDL-IDL-LDL pathway (steps 1–5 in figure 1) can be regarded as a pathway conveying C to peripheral tissues (including arteries), even if some amount of LDL-C is returned to liver (steps 1–4, 6 in figure 1). HDL, produced by liver (step 10 in figure 1) as well as by intestine (step not shown in figure 1) as native particles, are composed primarily of phospholipid, ApoA-I and ApoA-II, and other apoproteins. In the circulation, HDL can be distinguished into the larger and less dense HDL2 and the smaller and more dense HDL3. HDL serve important functions. They provide apoproteins (ApoC and ApoE) to VLDL (and chylomicrons) to allow the TG hydrolysis by LPL, and take up UC, phospholipid, and various apoproteins which form excess surface material in VLDL, after VLDL-TG hydrolysis by LPL. It seems probable that during the catabolism of VLDL effected by LPL, HDL3 is converted into HDL2. Moreover, HDL take up UC from tissues and esterify it through the action of the enzyme LCAT. Part of CE so formed is transferred to TG-rich lipoproteins (while these are being hydrolyzed), in exchange for TG, through the action of CETP, while the remaining is transported with the HDL to the liver, where the HDL particles may be taken up through a not yet well-defined HDL-R. Thus, the HDL-LCAT-CETP system or pathway (steps 8, 9, 12 in figure 1) can be regarded as a pathway for removing excess cellular C and for its transferring to the liver for excretion (reverse C transport). This may results in protection against CAD. Recently, antioxidant and antithrombotic properties have been attributed to HDL. In addition to LPL, a major role is also played by HP. This lipase, whose expression is regulated by hormones and nutritional state, is secreted by the hepatocytes and remains on the surface of hepatic endothelial cells and hepatocytes and (like LPL) acts on circulating lipoprotein particles. HL is thought to act on the uptake of CE from IDL and HDL (and also from chylomicron remnants), and may be involved in the conversion of HDL2 to HDL3. HL also participates in the VLDL to IDL and LDL cascade by contributing to the conversion of IDL into LDL (deficiency of HL is associated to accumulation of IDL).

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Comment on Normal Lipoprotein Metabolism Hepatic production of VLDL is regulated by insulin (and the anti-insulin hormones) at different sites. In fact, insulin, by inhibiting lipolysis at adipose tissue level, refrains the afflux of FFA to the liver, which is one of the factors stimulating VLDL production. Moreover, insulin (although favoring FFA esterification to TG in the liver) exerts a direct suppressive effect on the production of VLDL-ApoB in the liver and decreases the production of large TG-rich VLDL1 particles, independently of the availability of FFA. On the other hand, acute lowering of FFAs (acipimox administration, which inhibits lipolysis) does not change the overall production rate of VLDL particles, but shifts the production towards to smaller and denser VLDL2 particles, without changing the amount of total VLDL particles secreted. ApoE is the ligand required for lipoprotein binding to ApoB/ApoE receptors in liver (as well as for the binding of chylomicron remnants). The gene for ApoE is polymorphic and includes three common alleles designated E2, E3 and E4. Type 3 hyperlipidemia may occur only in the subjects who are homozygous for the E2 allele, i.e. with the genotype E2/E2. It has also been suggested that the ApoE phenotype may modulate the response of LDL to diet or drug therapy. It has been suggested that ApoE4 is associated with elevation of TG and decrease in HDL-C both in nondiabetic and diabetic populations. On the other hand, the frequency of ApoE alleles was found not significantly different in type 1 or 2 diabetic patients compared to nondiabetic population. ApoA-IV is considered to play a role in TG-rich lipoprotein metabolism, in reverse C transport, and in facilitation of CETP activity. Moreover, ApoAIV is genetically polymorphic in humans, in whom two major isoproteins (ApoAIV1 and ApoA-IV2) are known to occur. In the normal population, a potential protective lipid profile (characterized by increased HDL- and HDL2-C levels) is related to the Apo-A-IV1/ApoA-IV2 phenotype. Lp(a) is a lipoprotein particle similar to LDL in which, however, the ApoB-100 is linked to a glycoprotein named Apo(a). Lp(a) shows size heterogeneity, which is genetically determined, and has been identified as an independent risk factor for atherosclerotic vascular disease in nondiabetic populations. In the clinical setting, determination of plasma total-C, LDL-C, HDL-C and TG has an established diagnostic value. Recently, measurement of apoproteins has become feasible and may result in additional useful information. Considering that each lipoprotein particle has only one apoprotein molecule, measurement of ApoB and ApoA-I allows the assessment of the number of LDL and HDL particles, respectively. Moreover, simultaneous determination of lipid concentration (C and TG) allows detection of changes in lipoprotein


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composition. However, the use of apoprotein determination in the clinical setting is limited by the lack of standardized procedures. As a whole, it is still uncertain whether the determination of ApoB and ApoA-I has diagnostic advantage over the measurement of LDL-C and HDL-C.

Diabetes mellitus Diabetes affects most lipoprotein classes, including VLDL, LDL, HDL and Lp(a). As a rule, both in type 1 and type 2 diabetes, the total plasma C and TG are usually within normal limits when the blood glucose is controlled, but elevation occurs with metabolic decompensation. In addition, qualitative alterations of lipoproteins (mainly LDL) do occur in diabetic patients, including glycation, oxidation and peroxidation as well as composition abnormalities consisting of smaller and more dense LDL. It has been reported that when TG are ?200 mg/dl, LDL particles are small and dense whereas when they are =90 mg/dl, the particles are of the large, light variety. These changes are potentially atherogenic, as the small, dense and peroxidized LDL are taken up in reduced amount by the specific LDL receptors, whereas they are susceptible to uptake by the macrophage scavenger receptors, thus leading to foam cell formation in the arterial wall. Thus, glycated/oxidized lipoproteins induce CE accumulation in human macrophages and may promote platelet and endothelial cell dysfunction. Furthermore, these modified lipoproteins have the ability to trigger an autoimmune response that leads to the formation of autoantibodies and subsequently to the formation of immune complexes containing LDL. These immune complexes, in turn, promote macrophage activation accompanied by release of cytokines, thus initiating a sequence of events leading to endothelial cell damage. Considering the dangerous effects of increased oxidative stress combined with oxidized lipoproteins, an antioxidant combination therapy of vitamin E and vitamin C might be beneficial, but this needs to be further investigated. Finally, it should be considered that long-term hyperlipidemia may exert direct inhibitory effects on b-cell function (lipotoxicity), which should form the basis of a more active approach to lipid screening and pharmacological treatment of hyperlipidemia in diabetes patients. Type 1 Diabetes In insulin-treated type 1 diabetic patients in good metabolic control and without micro- and macrovascular complications, the plasma levels of VLDLTG, LDL-C and HDL-C are near normal. Indeed, a favorable pattern may

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often occur, as tight control in IDDM usually reduces LDL and VLDL to normal (or even subnormal) levels and may raise HDL above the normal range, although lipoprotein composition abnormalities can persist despite intensified insulin treatment. However, with the loss of glycemic control, marked elevation in TG and C can develop and is often due to superimposed genetic abnormalities in lipoprotein metabolism. Moreover, it has been shown that the development of microalbuminuria or overt diabetic nephropathy is associated with increased concentrations of C, TG and of atherogenic lipoprotein species, including IDL as well as Lp(a), and low levels of HDL-C, and hence with increased cardiovascular risk. Notably, there are no differences between patients with microalbuminuria and those with overt albuminuria. Lp(a) has been found elevated also in diabetics with both nephropathy and retinopathy. It is uncertain whether the increase in Lp(a) is secondary to diabetic nephropathy or is a genetic marker of susceptibility to this diabetic complication. The relationship between glycemic control and the Lp(a) level has not been fully resolved. In addition, increase in HL activity has been found in microalbuminuric and albuminuric type 1 diabetics. Concerning apoproteins, it is noteworthy that in type 1 diabetic patients with good metabolic control, although the level of LDL is often normal, the ratio LDL-C/ApoB is elevated, suggesting changes in the composition of the LDL particles. Depletion of the choline-containing phospholipids in the ApoBcontaining lipoprotein particles has also been reported, suggesting an alteration of the surface components of atherogenic particles. With worsening of the glycemic control, ApoB increases roughly correlated with HbA1c. On the other hand, insulin treatment seems to suppress the production of VLDLand LDL-ApoB. With regard to ApoA, it has been observed that the elevation of HDL, which may occur in insulin-treated type 1 diabetic patients, is mainly due to increase in ApoA-I (rather than ApoA-II), suggesting that the change concerns mainly HDL2. This may result from increased activity of LPL and reduced activity of HL. Type 2 Diabetes Lipid changes in type 2 diabetes include particularly elevated levels of total and VLDL-TG and reduced levels of HDL-C, and may be minimal in compensated patients but become more pronounced when glycemic decompensation develops. Total and LDL-C levels also are usually normal if glycemic control is adequate, but show increase with worsening of glycemic control. These changes may be even stronger risk factors for CHD in type 2 diabetic patients than in nondiabetic individuals. Hypertriglyceridemia is often associated with the accumulation of IDL, abnormal postprandial lipid


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metabolism and small, dense LDL and HDL (which are also enriched with TG as compared with C). Both low HDL-C and mild to moderate elevations of VLDL-TG are more frequent in type 2 diabetics when proteinuria is also present. Lipid abnormalities may be associated with coexisting visceral obesity and insulin resistance. Fasting TG and visceral obesity appear to independently predict mortality from CAD in glucose-intolerant and diabetic subjects. The predominance of small, dense LDL was found to be one of the interrelated risk factors that characterize the insulin resistance syndrome. The trend towards increased VLDL and reduced HDL has been found to be present already in first-degree relatives of type 2 diabetic patients with normal glucose tolerance. These lipid abnormalities therefore may represent early markers of insulin resistance. Concerning the underlying mechanism, a contributory factor to hypertriglyceridemia in type 2 diabetes may be the inability of insulin to inhibit the release of VLDL1 from the liver, despite efficient suppression of serum FFA. Indeed, in type 2 diabetes, secretion of VLDL in the postabsorptive state is higher than in normal, possibly because of impaired ability of insulin to inhibit lipolysis and to reduce hepatic VLDL secretion. Recent data suggest that TGrich lipoproteins in the range Sf 12–60 may be associated with angiographic severity in both diabetic and nondiabetic individuals. A study in people with type 2 diabetes found that patients with moderate CAD had higher levels of both Sf 12–60 and 60–400 fractions. Multivariate analysis showed that this association was independent of both low LDL and HDL. Moreover, the risk correlated positively to the postprandial levels of ApoB-48 in the Sf 20–60 fraction. This suggests that elevated levels of chylomicron remnants are involved in progression of CAD. Postprandial hyperlipidemia has been shown to be atherogenic. In type 2 diabetes patients, lipid intolerance (a greater increase of postprandial TG and a slower return towards basal levels) was almost always present. An increased supply of glucose and FFA contributes to overproduction of VLDL, increasing the burden of TG-rich lipoproteins on the common lipolytic pathway at the level of LPL. In addition, the capacity of LPL to minimize postprandial hyperlipidemia may be reduced. The clearance of atherogenic remnants is also delayed in type 2 diabetes mellitus. There is evidence that a relative hepatic removal defect exists, secondary to impaired remnant-receptor interaction and increased competition with VLDL remnants. Concerning apoproteins, increased ApoB and ApoC-III concentration has been reported in type 2 diabetic patients. Moreover, enhanced production of VLDL-ApoB may be a main contributing factor of elevation in plasma VLDL in these patients, who also show increase in the ApoE content of VLDL. The

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mechanism of these changes is not fully understood, but insulin resistance together with the enhanced afflux of FFA to liver may play a significant role. On the other hand, the reduction in HDL level is associated with decrease of ApoA-I (while ApoA-II is often little changed) and therefore mainly concerns the HDL A-I particles (rather than the HDL A-III ones), i.e. the HDL2 fraction. Considering that hypertriglyceridemia has been reported to be associated with increased clearance of HDL, these data might be secondary to enhanced VLDL-TG. In type 2 diabetes, decreased ApoA-I has been reported, whereas ApoAIV levels are often increased, mainly related to hypertriglyceridemia and to a lesser extent to HDL-C level. On the other hand, ApoA-IV phenotype distribution is not changed. It has been reported that the potential protective lipid profile (characterized by increased HDL- and HDL2-C levels) related to the ApoA-IV 1-2 phenotype, is no longer found in type 2 diabetic patients. In these patients, plasma ApoA-IV levels are associated with increased prevalence of macrovascular disease. Finally, in type 2 diabetes treated with insulin, ApoA-IV levels are increased and not related to hypertriglyceridemia. Studies in different ethnic groups have suggested that type 2 diabetic patients carrying the ApoE 2 allele may be more susceptible to develop hypertriglyceridemia in some populations but not in others, which suggests that the effect of ApoE2 is population-specific. It has also been reported that CHD shows higher prevalence among type 2 diabetic patients with phenotype E4/E4 compared to those with different ApoE phenotypes. In addition, ApoE2 may be overrepresented in diabetic populations. In type 2 diabetes, Lp(a) levels are not significantly changed and not related to the degree of glycemic control. An association has been reported between elevated Lp(a) and macrovascular disease in type 2 diabetes (this link has not been found with type 1 diabetes). As a whole, the role of Lp(a) as a risk factor for CHD in diabetic patients remains uncertain.

Lipid-Lowering Intervention in Diabetes It is now well established that hyperlipidemia is a risk factor for CVD in the diabetic population. In type 2 diabetes, lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. On the other hand, it has been demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. However, it should be stressed that the rationale for treatment of lipid disorders in diabetes mellitus


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is based upon results of trials conducted primarily in nondiabetic populations. Indeed, no trials of lipid-lowering therapy in the primary or secondary prevention of CVD have been targeted specifically to the diabetic population, and available data have been obtained through post-hoc subgroup analyses. However, four important multicenter studies are currently in progress. American Diabetes Association guidelines call for aggressive treatment of high TG and LDL-C. TG should be =200 mg/dl, are considered borderline high between 200 and 400 mg/dl, and high when ?400 mg/dl. Low HDL is defined as =35 mg/dl. Control of obesity with diet and exercise and reduced intake of saturated fat and C are important first steps. If needed, drug therapy is appropriate to lower TG and, specifically, to reduce LDL-C to levels =130 mg/dl in all adult diabetics and =100 mg/dl in those with CVD. The lipid profile should be monitored at beginning and during treatment, including TG and total and LDL-C. The therapeutic interventions to reduce body weight, increase physical activity and control the glycemic condition are described in chapters II–VI. Here we recall that the National Cholesterol Education Program guidelines suggested a dietary two-step approach. Step 1 consists of reduction of % calorie assumption to =10% from saturated fat, =10% from polyunsaturated fats and 10–15% from monounsaturated fats, while C assumption should be =300 mg/day. If the therapeutical goals are not reached, then step 2 should be adopted, which consists in further reduction of saturated fat to =5% of total calories and C intake to =200 mg/day. When dietary measures (plus exercise) and hypoglycemic agents have failed to achieve acceptable lipid levels, drug therapy should be prescribed. Drugs currently in clinical use for the treatment of hyperlipidemias are listed in table 1, in which the distinction is made between drugs mainly lowering C, represented by the HMG-CoA reductase inhibitors statins (besides bile acidbinding resins and niacin) and drugs primarly lowering TG, consisting of the group of fibrate derivatives (besides niacin and fish oil). As a rule, the treatment in the diabetic patients should be based on the use of statins or fibrates (ciprofibrate and fenofibrate appearing more effective than bezafibrate), whereas other drugs are in general not recommended, unless severe hyperlypidemia or intolerance to statins or fibrates is present. Intensive treatment with lipid-regulating agents is often necessary to normalize diabetes-associated dyslipidemias. HMG-CoA reductase inhibitors are the only agents thus far shown in prospective multicenter trials to reduce the risk of coronary events in diabetic patients. Long-term statin treatment of coronary patients significantly lowers the recurrence of coronary events, in addition to improving the lipid disorder. However, no information is available concerning the preventive effect of long-term improvement of lipid disorders

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Table 1. Lipid-lowering drugs Drug

Mechanism

Effects

BBA reabsorption; CBA synthesis; CLDL receptors

BLDL-C; CHDL-C; BTG

BVLDL synthesis

BTG; BVLDL- & LDL-C; CHDL

BCholesterol synthesis; CLDL receptors

BLDL-C; BVLDL secretion; BTG

Probucol4 (500 mg b.i.d.)

BLDL Antioxidant

BLDL-C BAtherosclerosis

Fibric acid derivatives5

See below

See below

CLPL; CHPL; BVLDL production; BApoC-III synthesis; CLDL clearance

BTG; CHDL; KCLDL-C a

Niacin2

See above

See above

Fish oil6 (4 g t.i.d. or q.i.d.)

BVLDL product

BTG

Hypercholesterolemia Bile acid (BA) binding resins1 (Cholestyramine, 8–12 g b.i.d. or t.i.d.) (Cholestipol, 10–15 g b.i.d. or t.i.d.) Niacin2 (Niacin, starting; 100 mg t.i.d., then up to 1–2 g t.i.d.) (Niacin (extended release) 0.5–3 g/day)

HMG-CoA reductase inhibitors3 (Lovastatin, 10–80 mg/day) (Pravastatin, 10–40 mg/day) (Simvastatin, 5–40 mg/day) (Fluvastatin, 20–40 mg/day) (Atorvastatin, 10–80 mg/day) (Cerivastatin, 0.1–0.3 mg/day)

Hypertriglyceridemia Fibric acid derivatives5 (Gemfibrozilb, c 600 mg b.i.d.) (Fenofibrate, 100 t.i.d. or q.i.d.) (Fenofibrate, micronized 200–250 mg/day) (Bezafibrate6, 400 mg/day or 200 mg t.i.d.) (Ciprofibrate, 100 mg/day)

a

Fenofibrate may be an exception, producing a decrease in LDL-C. Long-acting formulations of these fibrates are also available. c This fibrate increases LDL particle size. 1 Resins may cause gastrointestinal symptoms (nausea, constipation, hemorrhoidal bleeding); contraindicated in biliary obstruction and in hypertriglyceridemia. 2 May cause various symptoms: cutaneous (flushing, dry skin), cardiac (tachycardia, arrhythmias), gastrointestinal (nausea, diarrhea, peptic ulcer, hepatic dysfunction), metabolic (insulin resistance, glucose intolerance, hyperuricemia); contraindicated in peptic ulcer, cardiac arrhythmias, liver diseases, hyperuricemia, diabetes mellitus. 3 May cause abnormal liver function tests and myopathy; contraindicated in myopathies, renal failure, or in association with fibrates or niacin. 4 May reduce HDL-C. 5 May favor bile stone or cause nausea, abnormal liver function tests or myopathy; contraindicated in hepatobiliary disease. 6 Usually a mixture of eicosapentaenoic acid (D58-64%) and docosahexaenoic acid (D36–42%); may be associated with a slight increase in LDL-C. b


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in type 2 diabetic patients without CHD, or in patients with the ‘classical’ type of diabetic lipid disorder (hypertriglyceridemia with low HDL and normal LDL-C levels). In these latter patients, beneficial lipid effects can be obtained (although perhaps not normalization) with fibrates alone or, especially, in combination with current statins. Recent data showed that the risk reduction was 22–50% with statins and approximately 65% with fibrates (relative to placebo). Preliminary results indicate that fenofibrate treatment in type 2 diabetes under optimized metabolic control improves not only fasting lipid levels but also postprandial lipemia and associated abnormalites in lipoprotein levels and composition. However, it was pointed out that the statins should be regarded as the current lipid-lowering drugs of choice because the change in LDL-C to HDL-C ratio is better than with fibrates (gemfibrozil). According to the IDF guidelines (1999) to type 2 diabetes, drugs for lowering lipids should be prescribed according to the following scheme. A statin should be used when LDL-C ?115 mg/dl (q3.0 mmol/l) or, in subjects at low risk (including the thin elderly), when LDL-C ?155 mg/dl (4.0 mmol/l). A fibrate should be used when TG are ?200 mg/dl (?2.2 mmol/l) and LDL-C =115 mg/dl (=3.0 mmol/l). Atorvastatin should be used when TG are 200–400 mg/dl (2.3–4.5 mmol/l) and LDL-C q115 mg/dl (q3.0 mmol/l). When TG are markedly elevated, i.e. ?600 mg/dl (?6/8 mmol/l), a fibrate should be first used, and thyroid, renal, and liver function, and ApoE fenotype should be checked; if LDL-C levels remain elevated, combined fibrate-statin therapy should be advised. Combined therapy (beginning with a statin) is also suggested when both LDL-C and TG are markedly elevated. Finally, it is noteworthy that antiproteinuric and lipid-lowering therapy can be expected to reduce vascular damage and the progression of diabetic nephropathy.

Suggested Reading Austin MA, Edwards KL: Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol 1996;7:167–171. Coppack SW: Postprandial lipoproteins in non-insulin-dependent diabetes mellitus. Diabet Med 1997; 14(suppl 3):67–74. De Man FH, Cabezas MC, Van Barlingen HH, Erkelens DW, de Bruin TW: Triglyceride-rich lipoproteins in non-insulin-dependent diabetes mellitus: Post-prandial metabolism and relation to premature atherosclerosis. Eur J Clin Invest 1996;26:89–108. Groop PH, Elliott T, Ekstrand A, Franssila-Kallunki A, Friedman R, Viberti GC, Taskinen MR: Multiple lipoprotein abnormalities in type I diabetic patients with renal disease. Diabetes 1996;45:974–979. Gylling H, Miettinen TA: Treatment of lipid disorders in non-insulin-dependent diabetes mellitus. Curr Opin Lipidol 1997;8:342–347. International Diabetes Federation (IDF), 1998–1999 European Diabetes Police Group: A Desktop Guide to Type 2 (Non-Insulin-Dependent) Diabetes mellitus. Brussels 1999.

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Jeakins AJ, Best JD: The role of lipoprotein(a) in the vascular complications of diabetes mellitus. J Intern Med 1995;237:359–365. Kreisberg RA: Diabetic dyslipidemia. Am J Cardiol 1998;82:67U–73U, 85U–86U. Laakso M: Dyslipidemia, morbidity, and mortality in non-insulin-dependent diabetes mellitus. Lipoproteins and coronary heart disease in non-insulin-dependent diabetes mellitus. J Diabetes Complications 1997;11:137–141. Lopes-Virella MF, Virella G: Modified lipoproteins, cytokines and macrovascular disease in non-insulindependent diabetes mellitus. Ann Med 1996;28:347–354. Malmstrom R, Packard CJ, Caslake M, Bedford D, Stewart P, Yki-Jarvinen H, Shepherd J, Taskinen MR: Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects. Diabetes 1998;47:779–787. Steiner G: Clinical trial assessment of lipid-acting drugs in diabetic patients. Am J Cardiol 1998;81: 58F–59F. Taskinen MR: Lipoproteins and apoproteins in diabetes; in Belfiore F, Bergman RN, Molinatti GM (eds): Current Topies in Diabetes Research. Front Diabetes. Basel, Karger, 1993, vol 12, pp 122–134.



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Chapter XIII

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Cardiovascular Disease and Diabetes Giulio Zuanetti Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italia and Adis International, Auckland, New Zealand

Epidemiological Evidence for Increased Risk of Cardiovascular Disease in Diabetic Patients It has been known for many years that diabetes mellitus is a potent independent risk factor for cardiovascular disease (CVD). In the Framingham Study the risk of CVD for diabetic subjects at baseline was higher by about 2 times for men and 3 times for women after adjustment for other risk factors (dyslipidemia, hypertension and smoking). More recently, the NAHANES 1 (for acronyms, see table 1) also showed that the diabetic population was twice as likely to develop coronary artery disease as the nondiabetic population, with 75% of the excess mortality in men with diabetes due to coronary artery disease. These data indicate that the diabetic population should be a prime target for all efforts toward primary prevention of CVD, and this attitude has been clearly taken by the new European guidelines for prevention of CVD, in which distinct risk charts for nondiabetic and diabetic patients have been prepared, with diabetic patients consistently considered at higher risk than nondiabetics.

Pathophysiology of Risk of CVD in Diabetic Patients Four main factors contribute to the increased incidence of CVD in diabetic patients: the acceleration of the atherosclerotic process (leading to macrovascular disease), the development of specific diabetic cardiomyopathy, the occurrence of progressive microvascular disease and the development of autonomic neuropathy. Dissecting the relative role of these four factors in increasing

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Table 1. Significance of acronyms of trials quoted AIRE ALLHAT BARI BIP CABRI CASS CARDS CARE CCS-1 CONSENSUS-II DIGAMI EAST EPILOG EUCLID FINMONICA GISSI-2 GISSI-3 GUSTO-1 HOPE ISIS-2 LIPID MIDAS MOCHA NAHANES 1 PURSUIT RITA SAVE SHEP SOLVD SYST-EUR TAMI TIMI-2 TRACE 4S

Acute Infarction Ramipril Efficacy Anti-Hypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial Bypass Angioplasty Revascularization Investigation Bezafibrate Infarction Prevention Coronary Angioplasty vs Bypass Revascularization Investigation Coronary Artery Surgery Study Collaborative Atorvastatin Diabetes Study Cholesterol and Recurrent Events Chinese Cardiac Study 1 Cooperative New Scandinavian Enalapril Survival Study II Diabetes mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction Emory Angioplasty vs. Surgery Trial Evaluation of PTCA to Improve Long-Term Outcomes by c7E3 GPIIb/IIIa Receptor Antagonist Eurodiab Controlled Trial of Lisinopril in Insulin-Dependent Diabetes mellitus Finnish Contribution to the WHO Multinational Monitoring of Trends and Determinants of Cardiovascular Disease Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico 2 Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico 3 Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries 1 Heart Outcomes Prevention Evaluation International Study of Infarct Survival 2 Long-Term Intervention with Pravastatin in Ischemic Disease Multicenter Isradipine Diuretic Atherosclerosis Study Multicenter Oral Carvedilol Heart Failure Assessment First National Health And Nutrition Survey Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy Randomized Intervention Treatment of Angina Survival and Ventricular Enlargement Systolic Hypertension in the Elderly Program Studies of Left Ventricular Dysfunction Systolic Hypertension in Europe Thrombolysis and Angioplasty in Myocardial Infarction Thrombolysis in Myocardial Infarction 2 Trandolapril Cardiac Evaluation Scandinavian Simvastatin Survival Study

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cardiovascular risk in diabetic patients has been, and still is, an ambitious task of experimental and clinical results. Today, it is still impossible to evaluate which pathophysiological mechanism/s is/are most important in the single diabetic patient: some of these factors may be identified at an early stage with noninvasive techniques (for example, retinopathy may be identified by an eye fundus examination and autonomic neuropathy may be quantified by heart rate variability), whereas other would require more invasive techniques. Also, diabetes is often associated to other risk factors such as dyslipidemia, hypertension, obesity which all act synergistically in favoring CVD.

Natural History of Coronary Artery Disease in Diabetes The incidence of many manifestations of coronary artery disease (angina, myocardial infarction (MI) and sudden death) is increased in patients with type 1 and type 2 diabetes. These manifestations are more marked in women than men and CVD may be present at diagnosis of diabetes before other macro- or microvascular complications are evident. Data on the development of clinically evident atherosclerotic disease in diabetic compared with nondiabetic subjects are somewhat controversial; in general, studies have shown that diabetics usually have more diffused disease with higher degree of coronary atherosclerosis with more triple vessel disease and fewer normal vessels. This more severe coronary artery disease may not lead to an increased incidence of anginal symptoms because ischemia in diabetic patients may be more often silent and only discovered at exercise testing or nuclear medicine imaging. In general, patients taking insulin or with signs of organ damage (i.e. retinopathy) are at greater risk of silent ischemia: diabetic autonomic neuropathy may be one of the major factors involved. Diabetic patients with silent ischemia have a worse prognosis than nondiabetics (for example, 6-year survival was 59 vs. 82% in the CASS study).

Clinical Manifestations of CVD in Diabetic Patients Acute Myocardial Infarction (MI ) The difference in post-MI survival between diabetic and nondiabetic patients, documented by several studies performed before the introduction of fibrinolysis, remains mostly unaffected, despite the widespread use of fibrinolytic agents and aspirin, which led to a marked improvement in the prognosis of acute MI patients. Data from the GISSI-2 and GUSTO-1 trials, in which

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Fig. 1. Factors contributing to increased mortality in diabetic patients with acute MI.

all patients received fibrinolytic agents, show a 30–100% higher in-hospital mortality in diabetic patients compared to nondiabetics. It appears that, although concomitant risk factors such as advanced age, history of hypertension, hyperlipidemia and increased body mass index may exert a confounding effect and contribute to a decreased survival post-MI, diabetes per se exerts an independent negative role, as consistently documented in all studies. Mechanisms for increased mortality are shown in figure 1. Interestingly these data obtained in multicenter randomized studies, where selected patients usually receive state-of-the-art treatment, leading often to mortality rates well below the one observed in the general population, have been confirmed by observational studies where mortality rates more closely reflect those observed in current clinical practice. In the Finmonica study, 45.1% diabetic men and 38.8% diabetic women with their first MI died within 1 year, as compared to 32.6 and 20.2% in nondiabetic patients. A substantial proportion of these deaths occurred out of hospital soon after the onset of symptoms. Survival is closely linked to residual left ventricular pump function following acute MI. The increased susceptibility to cardiac failure (a 4-fold increase for women in the Framingham Study) is an important factor in reducing survival in diabetics. Two factors may explain the increased incidence of heart failure post-MI. First, more severe and diffuse coronary disease limits the coronary reserve causing noninfarcted segments to be rendered more ischemic by an infarct of comparable size. Secondly, coexistent diabetic cardiomyopathy, which is independent of the coronary disease, impairs myocardial relaxation and contractility.


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Fig. 2. Event-free survival curves in the BARI trial for diabetic (TDM) and nondiabetic (all others) patients.

Unstable Angina There are few conclusive data concerning the impact of diabetes on the prevalence or outcome of unstable angina. However, patients with diabetes who have unstable angina have increased morbidity compared with their nondiabetic counterparts. The suggestion that diabetes worsens the prognosis of unstable angina, but does not increase the incidence, is supported by other data that examine diabetic patients as subgroups in studies of unstable angina. Coronary Angioplasty (PTCA) and Coronary Bypass Grafting (CABG ) A history of diabetes is associated with a higher incidence of complications during PTCA and CABG and to increased morbidity and mortality during follow-up. The mechanisms responsible for an increased incidence of restenosis after PTCA are several. Interestingly, in the BARI trial comparing PTCA and CABG in patients with multivessel disease, diabetic patients treated with PTCA had a higher incidence of mortality (35 vs. 19%, p=0.02) as compared with CABG, whereas no difference was observed in nondiabetic patients (fig. 2). A further analysis of the data indicated that the difference was mainly due to a lower mortality for the patients undergoing internal mammary grafting, whereas patients with saphenous vein grafts only had a similar mortality compared to patients treated with PTCA. In contrast, data from a large consecutive series of patients in one center did show that diabetics (24% of the total population) had a worse outcome after both PTCA and CABG, with an effect that was similar in both treatment groups, thus questioning the data

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from the BARI trial. Finally, older data derived from the TIMI-2 trial showed that primary PTCA in patients with acute MI (a rapidly emerging new treatment of acute MI patients) was associated with a higher mortality than in patients treated with a more conservative strategy although newer data suggest the opposite to be true. All these data may be already outdated due to the tremendous evolution in the technique for PTCA, so that a prospective reassessment of the use of PTCA in diabetic patients with newer techniques is warranted. Specifically the role of stent implantation after direct PTCA is not yet fully defined. Heart Failure Several studies documented an increased incidence of heart failure even in the absence of overt ischemic heart disease. Epidemiological data from the Framingham Study show that diabetic subjects have a much higher risk of developing heart failure. Men aged 45–74 had a 2-fold increased risk and women had a 5-fold increase in risk. Diabetic cardiomyopathy presents with features of systolic and diastolic dysfunction, although the diastolic filling defect predates the development of systolic ventricular dysfunction. Diastolic dysfunction is related to the duration of diabetes. As already discussed, heart failure is also common in patients with diabetes mellitus and is more common than expected following MI. Two reasons which have been postulated to explain this are, firstly, the extent and severity of the occlusive coronary artery disease and secondly, the presence of a specific diabetic heart muscle disease.

Management of CVD in Diabetic Patients Treatment of Diabetic Patients with Acute MI So far, only one prospective study, the DIGAMI trial (see below) evaluated specifically the effect of pharmacological treatment on prognosis of diabetic patients after acute MI, while most of the information on the effect of commonly used cardiovascular drugs in diabetics with MI has been obtained only from retrospective subgroup analyses of some large trials or as nonrandomized comparisons between control and drug-treated patients. The evidence for several classes of drugs will be discussed below. Insulin-Glucose Infusion. In the DIGAMI study, 620 diabetic patients were randomized to receive either standard treatment (n>314) or an intensive treatment (n>306) with insulin-glucose infusion targeted to achieve a tight control of glycemic levels. The insulin treatment was then continued long term. Data showed that this ‘intensive’ hypoglycemic treatment was associated with


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Fig. 3. Mortality curves in the DIGAMI trial.

a lower 1-year morbidity and mortality (8.6 vs. 18.0% intensive vs. traditional treatment, p>0.020) and that the beneficial effect was even more evident during long-term follow-up (fig. 3). The effect was most pronounced among the predefined group (n>272) without previous insulin treatment and at a low cardiovascular risk (RR>0.49, p>0.004). Fibrinolytic Agents. For many years diabetes represented a relative contraindication to the use of fibrinolytic agents, based on the fear their use would lead to an unacceptable rate of hemorrhages (cerebral and retinal). However, the relative decrease in mortality of diabetics with fibrinolytic treatment has been at least similar to that observed in nondiabetics: the overview of fibrinolytic trials in acute MI found that fibrinolytic treatment was associated with a 35-day mortality of 13.6 vs. 17.3% in diabetics (–21.7%) and 8.7 vs. 10.2% in nondiabetics (–14.3%). Of note, the incidence of stroke in diabetics is doubled that of nondiabetics (1.0 vs. 0.6%, respectively); however, this increased risk is by far outweighed by the beneficial effect on mortality. The relative efficacy of newer fibrinolytic treatment regimens in this population remains to be determined. Aspirin and Other Antiplatelet Agents. Aspirin’s effect in primary prevention trials has been investigated in a subgroup analysis of the Early Treatment Diabetic Retinopathy Study which showed a nonsignificant reduction in MI but no conclusive impact on all-cause mortality.

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The role of aspirin as first-line therapy in the treatment of patients with acute MI has been firmly established. However, the optimal dosage in the diabetic population remains unclear. Interestingly, in ISIS-2 there was no reduction in mortality among diabetic patients receiving aspirin 160 mg daily compared with a 20% reduction in nondiabetic patients. On the other hand, aspirin 325 mg in the GISSI-3 trial (a nonrandomized treatment) was associated to an independent beneficial effect on 6-week mortality. Increased platelet turnover may be one explanation for this disparity, as 300 mg of aspirin may be necessary to effectively suppress thromboxane A. The antiplatelet trialists collaboration overview on patients with unstable angina, acute MI, prior MI, stroke or transient ischemic attack indicate a similar benefit (38 vs. 36 vascular events saved/1,000 treated patients) in diabetics vs. nondiabetics. Taken together, these data would suggest that the beneficial effect of aspirin is maintained in diabetics, but the optimal dosage remains speculative. Attention has recently shifted toward selective antiplatelet agents, such as the glycoprotein IIb/IIIa antagonists. Preliminary data from subgroup analysis of the several trials in acute coronary syndromes recently completed suggest that these agents are as effective in diabetic as in nondiabetic patients. b-Blockers. b-Blockers are able to reduce mortality post-MI in diabetic patients, with an absolute and relative beneficial effect in most cases larger than that observed in nondiabetics. The pooled data indicate a 37% mortality reduction during the acute phase (13% in nondiabetics) and a 48% mortality reduction postdischarge (33% in nondiabetics). Since all these studies have been performed before the advent of fibrinolytic therapy, they would need confirmation with current therapy. Data from a subgroup analysis of the DIGAMI study showed a relative risk of dying for patients on b-blockers of 0.62 (95% CI 0.39–0.98). Also, data from the GISSI-3 trial in a total of 2,553 diabetic patients discharged alive from the hospital (25% of them on b-blockers) showed a survival benefit in diabetic patients taking b-blockers at discharge (3.6 vs. 7.6% mortality). These data point to a protective effect of b-blocker treatment even in the fibrinolytic era. ACE Inhibitors. Recent trials used ACE inhibitors as a new therapeutic strategy in an attempt to reduce mortality and morbidity after acute MI. In the GISSI-3 study, treatment with lisinopril was associated with a decreased 6-week mortality in both type 1 (11.8 vs. 21.1%, p=0.05, n>496) and type 2 (8.0 vs. 10.6%, p=0.05, n>2294) patients corresponding to a 44.1 and 24.5% reduction, respectively. The beneficial effect of the early use of an ACE inhibitor was mostly maintained at 6 months and after 4 years despite withdrawal of the treatment at 6 weeks. The metaanalysis by the ‘ACE inhibitor in MI Collaborative Group’ including data from GISSI-3, CCS-1 and CONSENSUS-II trials, confirmed that the subgroup of diabetic patients experi-


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enced a 30-day lower mortality (10.3 vs. 12.0 %, or 17.3 lives saved per 1,000 patients) when treated early with an ACE inhibitor. Data on ACE inhibitors in the prevention of cardiovascular events in patients with diabetics at risk of ischemic heart disease are still controversial but the completion of some large studies such as HOPE and PEACE will clarify their role in this clinical setting. Calcium Antagonists. Calcium antagonists have always been considered as a rather homogeneous class, despite the well-known pharmacodynamic and pharmacokinetic differences, particularly between nondihydropiridines and dihydropiridines. These differences are most apparent in terms of the relative action of these agents at myocardial vs. vascular level, but may include effects also at renal level that can be important particularly for the diabetic patient. For example, a recent study has shown that diltiazem, but not nifedipine, is able to reduce microalbuminuria in diabetic patients. Several trials have been performed with calcium antagonists in acute MI and, in general, nondihydropiridine (‘heart rate lowering’) calcium antagonists proved to be neutral or effective in patients recovering from acute MI, short-acting dihydropiridines were detrimental in the acute MI setting and long-acting dihydropiridines were neutral in patients with congestive heart failure. Data in the diabetic subpopulation seem to mirror those obtained in nondiabetics. Statins. Three recent studies, the 4S, CARE and LIPID trials, evaluated the effect of statins in reducing morbidity and mortality in patients with a history of ischemic heart disease (mainly previous MI). The main difference between these trials lies in the cut-off cholesterol level for enrollment, that was much tighter for 4S than for CARE or LIPID. In all the trials diabetics had a worsened outcome compared to nondiabetics; also the reduction in mortality was proportionally at least similar to that observed in nondiabetics. In the 4S study a 42% reduction in the incidence of death was observed in diabetic patients compared to 27% in nondiabetics; in the CARE study mortality reductions were –25% nondiabetics and –23% diabetics. Despite the obvious limitations of this post-hoc analyses, these data suggest that statins confer long-term protection from cardiovascular events in diabetic patients recovering from MI at least to the same extent as in nondiabetics. In summary, there appears to be compelling evidence for the use of statin therapy post-MI in diabetic subjects. There is also growing evidence for lipidlowering therapy in the primary prevention of CVD, although we are restricted to drawing conclusions from subgroup analyses of large trials. Treatment of Diabetic Patients with Chronic Ischemic Heart Disease As discussed earlier, diabetic patients with ischemic heart disease have a higher prevalence of silent ischemia and a more diffuse pattern of atheroscle-

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rotic lesions than nondiabetic patients. However, when the severity of the anatomical damage is similar, the clinical picture of chronic myocardial ischemia is considered to be superimposable to that of nondiabetic patients and the management of these patients is therefore very similar. Drugs commonly used in the treatment of chronic myocardial ischemia include b-blockers, nitrates and calcium antagonists. Surprisingly, data on morbidity and mortality in diabetic patients are available only for b-blockers: a post-hoc analysis of the BIP Study showed their usefulness in patients with diabetes and coronary artery disease. Total mortality during a 3-year followup was 14% in patients who were not on b-blockers and 7.8% in those patients receiving b-blockers (a 44% reduction). After multiple adjustment, RR of bblocking treated patients were 0.58 (95% CI 0.46–0.74). Overall, the striking beneficial effect of b-blockers in diabetic patients with ischemic heart disease challenges the view that these drugs are not a first choice in these patients because of their ‘detrimental’ effect on the glycolipidic metabolism and the risk of masking hypoglycemic episodes Data on the effect of calcium antagonists on ‘hard endpoints’ in diabetic patients with ischemic heart disease are still missing; however, very recent data from trials performed in hypertensive type 2 diabetics such as ABCD and FACET raised an alarm bell concerning morbidity due to ischemic heart disease in patients treated with dihydropiridines since in several instances the incidence of cardiac events such as acute MI was documented to be significantly higher than that observed in patients treated with other cardiovascular drugs such as ACE inhibitors or diuretics. On the other hand, data with nitrendipine obtained in the SYST-EUR trial lead to a major protective effect in diabetic elderly with isolated systolic hypertension. Treatment of Diabetic Patients Undergoing PTCA or CABG So far, no conclusive data are available to indicate the best pharmacological treatment to prevent restenosis in these settings. Studies with ACE inhibitors, calcium antagonists or statins usually failed to show any consistent effect of these agents in reducing the incidence of restenosis or morbidity during long-term follow-up. Recent data from the EPILOG study indicate that the antithrombotic agent abciximab is effective in preventing restenosis in nondiabetic, but not in diabetic patients. All other available data do suggest that the efficacy (or lack of efficacy) of different agents is similar irrespective of the diabetic status of patients. Thus, currently the treatment of diabetic patients undergoing PTCA and also CABG mirrors that of nondiabetic patients. In particular, no data are available to indicate whether a careful control of blood glucose during the peri-intervention period would decrease morbidity and mortality.


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Treatment of Diabetic Patients with Heart Failure As for data after MI, all available data on diabetic patients with heart failure are available from post-hoc subgroup analyses. The main data are reviewed here. ACE Inhibitors. The landmark ramdomized studies in the evaluation of the efficacy of ACE inhibitors were performed in the eighties and early nineties, when the CONSENSUS, SOLVD treatment and SOLVD prevention trials were completed. A subanalysis of the SOLVD trial and registry showed that ACE inhibitors are as effective in diabetics as in nondiabetics in reducing mortality and hospitalization rates. The attention of researchers then shifted toward testing ACE inhibitors in patients with left ventricular dysfunction resulting from acute MI. All the studies have shown a significant benefit of ACE inhibitor therapy, with a risk reduction in mortality of 19–27% over a 2.5- to 4-year follow-up. The meta-analysis of the major trials in this setting, including SAVE, AIRE and TRACE studies, indicate that the beneficial effect of ACE inhibitors documented in the overall population is present also when limiting the analysis to patients with a history of diabetes. Mortality was 36.4% in control and 31.6% in ACE inhibitor-treated patients, respectively, corresponding to an RR of 0.81; 95% CI 0.68–0.97. b-Blockers. For many years b-blockers have been contraindicated in chronic heart failure (CHF) patients, and even more so in diabetic patients; however, the pioneering work performed in the seventies and eighties, particularly by Scandinavian groups, led the way to their targeted use in patients with asymptomatic or overt CHF. A retrospective analysis performed by Kjekshus et al. showed that diabetic patients with CHF post-MI benefited even more than those with preserved left ventricular function. The MOCHA trial, a randomized study comparing different doses of carvedilol with placebo, reported that the treatment was associated to a dramatic decrease in mortality, that was most evident in diabetic patients, with a 6.1% mortality after a median of 6 months, compared to a 30% mortality in the control group. These data would suggest that diabetic patients with CHF are among the ones who benefit most from a treatment with b-blockers.

Conclusions and Implications for Clinical Practice CVD in diabetes is a critical area where research effort should be focused. Patients with diabetes have a much higher risk of developing coronary artery disease, including stable and unstable angina and MI, leading also to an increased occurrence of heart failure. Prognosis of diabetic patients with CVD is poor. The specific problems of diabetic subjects suggest that a universal

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Table 2. Effect of different drug classes in diabetic patients with CVDs

Aspirin ACE inhibitors a-Blockers Angiotensin II antagonists b-Blockers Calcium antagonists (dihydropiridines) Calcium antagonists (non-dihydropiridines) Nitrates Statins

Acute MI

Post-MI

Heart failure

++ +++ ? ? ++ – × × NA

++ ++ ? ? ++ – × × ++

NA +++ ? ? +++ × ? + NA

+++>Highly effective; ++>effective; ×>controversial; –>deleterious; ?>unknown; NA>not applicable.

management plan cannot be applied to all patients. Diabetic patients may need specific interventions which may differ from current practice in nondiabetic subjects. Evidence supports the use of many drugs and procedures in diabetic subjects, often in cases where there appears to be more benefit in diabetic compared to nondiabetic subjects, but where usage is not as high as it perhaps could be. In fact, the rate of morbidity and mortality of diabetic patients has now been shown to be beneficially affected by a variety of interventions. Several issues however should be underlined. First, most of the data have been obtained as post-hoc subgroup analysis of trials performed in a general population of patients with CVD. This would imply the need to confirm these findings in appropriate prospective studies; however, no further studies are ongoing or planned with most of the agents reviewed in this chapter, indicating that the evidence so far gathered will be the one to rely upon. Second, the application of these research findings in clinical practice remains a major challenge, since drugs consistently documented to be effective in specific patient populations are often underused in clinical practice. As shown in table 2, strong evidence is available only for ACE inhibitors and b-blockers and for statins in the postMI setting while question marks remain for several commonly used drugs. Finally, the burden of morbidity and mortality of diabetic patients with CVD remains high and deserves testing novel therapeutic approaches targeting the several pathophysiological alterations present in diabetic patients with CVDs.


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Suggested Reading Malmberg K for the DIGAMI (Diabetes mellitus Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group: Prospective randomised study of intensive insulin treatment on long-term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997;314:1512–1515. Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G, The Scandinavian Simvastatin Survival Study (4S) Group: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20:614–620. The BARI Investigators: Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI). Circulation 1997;96:1761–1769. Zuanetti G, Latini R, Maggioni AP, Franzosi MG, Santoro L, Tognoni G, on behalf of GISSI-3 Investigators: Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: The data from the GISSI-3 study. Circulation 1997;96:4239–4245.

Giulio Zuanetti, MD, Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62, I–20157 Milano (Italy) Tel. +39 02 39014407, Fax, +39 02 33200049 E-Mail [email protected]/[email protected]

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Chapter XIV

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Diabetic Neuropathy Andrew J.M. Boulton a, b, Rayaz A. Malik b a b

University of Manchester and Manchester Royal Infirmary, Manchester, UK

Introduction and Classification Diabetic neuropathy is one of the commonest late complications of diabetes and the international recognized definition is ‘the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes, after exclusion of other causes’. Of all the long-term complications of diabetes, none affects so many organs or systems of the body as those conditions included under the term ‘diabetic neuropathies’. Neuropathies have been described in patients with type 1, type 2 and secondary diabetes of differing causes, suggesting a common aetiological mechanism based upon chronic hyperglycaemia. All the neuropathies are characterized by a progressive loss of nerve fibres that can be assessed noninvasively by a variety of methods varying from a simple clinical neurological exam through more detailed quantitative sensory and autonomic testing to detailed electrophysiology. The accurate assessment of symptoms, signs and objective manifestations of peripheral nerve dysfunction are of course essential in the diagnosis and management of neuropathy, though the approach will vary according to need. Thus whereas longitudinal clinical trials of putative new therapies require a detailed and structured approach as outlined above, such comprehensive investigation is not necessary for day-to-day clinical management. The natural history of diabetic neuropathy remains ill defined, partly because of poor patient selection and variable criteria for the definition of neuropathy employed in previous studies. However, neuropathies many give rise to much suffering amongst diabetic patients, especially those with painful symptomatology and/or foot ulceration. The late sequelae of neuropathy include Charcot neuroarthropathy, foot ulceration and even amputation, although many of these are potentially preventable.

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Table 1. Clinical classification of diabetic neuropathies Polyneuropathy

Mononeuropathy

Sensory

Chronic sensorimotor Acute sensory

Cranial

Autonomic

Cardiovascular Gastrointestinal Genitourinary Other

Isolated peripheral

Proximal motor (amyotrophy)

Mononeuritis multiplex

Truncal

Truncal

Table 2. Prevalence of diabetic peripheral sensorimotor neuropathy Study/country

Patients, n

Type of diabetes

Prevalence, %

Clinic-based studies Tesfaye et al., 1996/Europe Cabezas-Cerrato et al., 1998/Spain

3,250 2,644

1 1, 2

28 22.7

380 811 133

1, 2 2 2

47.6 41.6 41.9

Population-based studies Dyck et al., 1993/USA Kumar et al., 1994/UK Partanen et al., 1995/Finland

Definitions and Classification As the precise pathogenesis of neuropathy remains enigmatic, a classification based upon clinical manifestations is generally acceptable. A clinically descriptive classification will be used in this chapter as outlined in table 1. A brief description of the main subgroups of neuropathy then follows, but thereafter, the rest of this chapter will focus mainly on the symmetrical polyneuropathies, particularly the commonest variety, distal symmetrical somatic polyneuropathy. A brief description of certain aspects of the autonomic neuropathies will also be included, although erectile dysfunction is covered in chapter XV.

Epidemiology of Diabetic Neuropathies A summary of some recent epidemiological reports on the prevalence of diabetic neuropathy is provided in table 2. As can be seen, these studies, all

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of which report on chronic peripheral sensory motor neuropathy, show how common neuropathies are, and it must be remembered that up to 50% of older type 2 diabetic patients have clinical evidence of peripheral neuropathy on examination. Risk factors for the development of neuropathy include hyperglycaemia, age, height and duration of diabetes. The studies of epidemiological features of autonomic neuropathies are less consistent and give conflicting data for the prevalence of autonomic dysfunction and also predictive factors.

Clinical Features of Diabetic Neuropathies Mononeuropathies Isolated peripheral nerve lesions are recognized as being more common in diabetic patients, particularly in older individuals with type 2 diabetes. These mononeuropathies occur not infrequently in the absence of other complications but as with all neuropathic syndromes, may be the presenting feature of type 2 diabetes. Cranial Mononeuropathies The nerves supplying the extraocular muscles (particularly the third nerve) are most commonly affected: these ophthalmoplegias tend to be of relatively rapid onset and not infrequently are associated with some pain. Diplopia is the usual presenting feature, and exclusion of other causes, particularly spaceoccupying or vascular lesions, is essential, usually by computerized tomography. The natural history of the cranial mononeuropathies is of spontaneous recovery in a matter of months. Isolated and Multiple Mononeuropathies Almost any peripheral nerve may be affected but those particularly likely to be involved include the median nerve (carpal tunnel syndrome), the peroneal nerve (foot drop) and the lateral cutaneous nerve of thigh (meralgia paraesthetica). Mononeuritis multiplex simply describes the occurrence of more than one isolated mononeuropathy at the same time in an individual patient. Truncal Mononeuropathy This rare neuropathy is characterized by pain occurring in a band distribution around the chest or abdomen in a dermatomal pattern. It typically occurs in isolation, but truncal polyneuropathy is recognized that is also rare, but tends to occur in association with other long-term complications.

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Polyneuropathies Diabetic Amyotrophy (Proximal Motor Neuropathy) This typically affects older male type 2 diabetic patients and presents with pain, wasting and weakness in the proximal muscles of the lower limb, either unilaterally or with symmetrical bilateral involvement. These patients invariably have evidence of a peripheral sensory motor neuropathy in addition, and weight loss may be an accompanying feature. As in all neuropathies, the diagnosis is one of exclusion of nondiabetic causes and a thorough search for internal malignancy may be required. Autonomic Neuropathies Involvement of the autonomic nervous system in diabetes can affect any area receiving autonomic innervation, but although dysfunction can frequently be found using sophisticated autonomic function tests, severely symptomatic autonomic neuropathy remains relatively rare. Symptoms and signs of autonomic dysfunction may typically involve the cardiovascular, gastrointestinal, urogenital, thermoregulatory and sudomotor function. Cardiac autonomic neuropathy is rarely symptomatic, although an increase in heart rate secondary to vagal denervation may be found with no response to respiration or the Valsalva manoeuvre. Similarly, although a postural drop in systolic blood pressure is a not uncommon finding in diabetic patients with neuropathy, it is rarely symptomatic. Gastrointestinal autonomic dysfunction may be manifested by abnormalities in motility and secretion. The two major clinical problems are diabetic gastroparesis which may present with nausea, postprandial vomiting, and diabetic diarrhoea which tends to be worse at night and interspersed by periods of normal function or even constipation. Abnormalities of sudomotor function are common but are often neglected. Reduced sweating in the feet due to sympathetic denervation is a contributory factor in the pathogenesis of diabetic neuropathic foot problems. In contrast, truncal sweating, particularly at night, can be troublesome and gustatory sweating (profuse sweating in the head and neck region on eating certain foods) is a highly characteristic symptom of autonomic dysfunction which is also seen in patients with diabetic nephropathy. Peripheral Sensory Neuropathies Chronic distal sensorimotor is the commonest of all these syndromes that may have very diverse clinical features. At one extreme patients may have severe symptoms of pain (characteristically worse at night), paraesthesiae,

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Table 3. Stages of diabetic peripheral sensory neuropathy Stage of neuropathy

Characteristics

No neuropathy

No symptoms or signs

Clinical neuropathy Chronic painful

Acute painful

Painless with complete/ partial sensory loss Late complications

Burning, shooting, stabbing pain × pins and needles; increased at night; absent sensation to several modalities; reduced/absent reflexes Severe symptoms as above (hyperaesthesia common); may follow initiation of insulin in poorly controlled diabetes; signs minor or absent Numbness/deadness of feet or no symptoms; painless injury; reduced/absent sensation; reduced thermal sensitivity; absent reflexes Foot lesions; neuropathic deformity; nontraumatic amputation

Types of diabetic neuropathy: frequent, sensorimotor symmetrical neuropathy (mostly chronic, sensory loss or pain), autonomic neuropathy (history of impotence and possibly other autonomic abnormalities); rare, mononeuropathy (motor involvement, acute onset, may be painful), diabetic amyotrophy (weakness/wasting usually of proximal lower limb muscles). Staging does not imply automatic progression to the next stage. The aim is to prevent, or at least delay, progression to the next stage. From Boulton et al. [1998], with permission of J. Wiley & Sons.

allodynia and pins and needles, usually most predominant in the feet and lower legs. Motor manifestations include small muscle wasting in the more severe cases, and absent ankle reflexes. The onset of these symptoms is insidious or gradual and should be contrasted with the much rarer acute sensory neuropathy in which patients have very severe symptoms, but few signs: this type of neuropathy frequently follows a period of metabolic instability. At the other extreme some patients may never experience neuropathic symptoms, but gradually lose sensation in the feet to such an extent that the presenting feature may be insensitive trauma to the feet. It is therefore essential that all diabetic patients have their feet examined on a regular basis, as diabetic peripheral neuropathy cannot be diagnosed without such a thorough examination. These stages of diabetic peripheral sensory neuropathy are summarized in table 3.

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Table 4. Annual review: screening for neuropathy History

Exam

Presence/absence of neuropathic symptoms

Pin-prick test

Use a disposable instrument, e.g. a disposable dressmaker’s pin Do not use a hypodermic needle Ask ‘Is it painful?’ not ‘Can you feel?

Light touch

Use a consistent method, ideally a cotton wisp

Duration/progression of symptoms

Vibration test

Use a 128-Hz tuning fork, initially on the big toe

Nocturnal exacerbation?

Ankle reflex

Compare the ankle reflex with the knee reflex

History of insensitive injury/ulcers?

Pressure perception

Absence of sensation in the foot to a 10 g monofilament may be used to assess the risk of foot ulceration

Nature of symptoms (positive/negative?)

Measurement of Neuropathy In clinical practice, all diabetic patients should be assessed for evidence of peripheral neuropathy at least annually. The necessary constituent features of the annual review for neuropathy are summarized in table 4. A more detailed assessment may include quantitative sensory tests for modalities such as vibration perception, thermal discrimination, and pain threshold. Electrophysiological tests may also be used and are highly reproducible, but it must be remembered that whereas they might demonstrate or confirm a peripheral neurological abnormality, these tests cannot differentiate between diabetic and other peripheral neuropathies. Autonomic function tests might include assessment of cardiovascular reflexes such as beat-to-beat variation of heart rate, Valsalva manoeuvre, lying/standing blood pressure drop and so on. A number of detail-specific tests of gastrointestinal autonomic function are also available.

Diagnosis and Treatment As noted above, the diagnosis of all the diabetic neuropathies is always one of exclusion of other nondiabetic causes. It is important to exclude non-

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Table 5. Management of the stages of neuropathy Stage

Objectives

Key elements

Referral

No clinical neuropathy

Education to reduce risk of progression; maintenance of nearnormoglycaemia

Education; glycaemic control; annual assessment

As required

Clinical neuropathy

Management of symptoms; prevention of foot ulceration

Acute/chronic painful

Stable glycaemic control; symptomatic treatment (simple analgesics or tricyclic drugs or carbamazepine). Consider referral of acute sensory neuropathy

Diabetologist/neurologist

Painless/loss of sensation

Education, especially foot care; glycaemic control according to needs


Other types of diabetic neuropathy

Early referral


Late complications

Prevention of new/ recurrent lesions and amputation

Emergency referral if lesions Diabetologist/neurologist/ present; otherwise referral chiropodist/podiatrist/ within 4 weeks diabetes specialist nurse/ diabetes foot clinic if available

From Boulton et al. [1998], with permission of J. Wiley & Sons.

diabetic neurological disease which may be responsible for up to 5% of neuropathy in diabetic individuals. These include malignant disease, HIV, metabolic conditions including vitamin B12 deficiency, hypothyroidism, drug therapy, exposure to toxins and alcoholic polyneuropathy. Atypical features that might alert the clinician to the possibility of a nondiabetic neuropathy would include rapid progression, foot drop, back or neck pain, family history, weight loss and asymmetrical clinical features. The management of the different stages of peripheral sensory neuropathy is summarized in table 5. Of all the treatments, tight and stable glycaemic control is probably the only one that might provide symptomatic relief as

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Table 6. Drugs for symptomatic (painful) neuropathy Class

Drug

Dose/day

Comments

Tricyclic drugs

Imipramine Amitriptyline Desipramine

25–150 mg 25–150 mg 25–150 mg

Anticonvulsants

Carbamazepine Gabapentin

200–800 mg 900–3,600 mg

CNS AEs

Centrally acting

Tramadol

50–400 mg

CNS AEs

Other therapy

Topical capsaicin (0.075% cream)

Up to 4¶daily topically

H

Troublesome AEs limit dosage

Acupunctue Opsite AEs>Adverse events; CNS>central nervous system. These agents are used, if required, in addition to stable glycaemic control.

well as slowing the relentless progression that typifies the natural history of neuropathy. It is likely that unstable blood glucose control induces neuropathic pain, so stability rather than the actual level of glycaemic control is most important in pain relief. A large number of drugs have been reported to be useful in the relief of neuropathic pain: these are summarized in table 6. Until we have a greater experience with some of the newer therapies, the tricyclic drugs remain the first-line medications for painful neuropathic symptoms: they have been proven to be effective in several randomized controlled trials. Thus the order of listing of drugs in table 6 is normally the order in which these drugs would be used. The newer agents such as Gabapentin and Tramadol (table 6) are promising and already have proven efficacy in randomized controlled trials. The limitations of all the drugs listed in table 6 relate to adverse effects which tend to be dose related and predictable. Other therapies such as capsaicin, acupuncture and Opsite may be useful in some cases. Capsaicin is a topical application and tends to be more helpful in localized pain. Acupuncture has been shown to be efficacious in several uncontrolled studies, with reported efficacy in up to 70% of treated cases. As this is without side effects, it is a useful therapy for diabetic neuropathy. Opsite is a transparent dressing which has reported efficacy in an uncontrolled study: it is reported to work through the gate control mechanism of pain.

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None of the above listed agents has any affect on the natural history of diabetic sensory-motor neuropathy which, as noted above, is one of slow progression. A number of agents are under investigation that might slow or halt progression in diabetic neuropathy and these include the antioxidant a-lipoic acid, a number of aldose reductase inhibitors, and essential fatty acids such as c-linolenic acid. Finally, all patients with diabetic sensory peripheral neuropathy must be considered as being at risk of insensitive foot ulceration and should receive education on foot care and if necessary a podiatry referral. These patients require more frequent follow-up, always paying particular attention to foot inspection to reinforce the educational message of the need for regular foot care.

Suggested Reading Boulton AJM, Malik RA: Diabetic neuropathy. Med Clin North Am 1998;82:909–929. Boulton AJM, Gries FA, Jervell JA: Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Diabet Med 1998;15:508–514. Cabezas-Cerrato J: The prevalence of clinical diabetic polyneuropathy in Spain: A study in primary care and hospital clinic groups. Neuropathy Spanish Study Group of the Spanish Diabetes Society (SDS). Diabetologia 1998;41:1263–1269. Dyck PJ, Kratz KM, Karnes JL, et al: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: The Rochester Diabetic Neuropathy Study. Neurology 1993;43:817–824. Gries FA, Koschinsky T, Tscho¨pe D, Ziegler D: Current state and perspective of diabetes research: Chronic complications. Diabetes 1997;46(suppl 2): 1–134. Kumar S, Ashe HA, Parnell LN, Fernando DJ, Tsigos C, Young RJ, Ward JD, Boulton AJ: The prevalence of foot ulceration and its correlates in type 2 diabetic patients: A population-based study. Diabet Med 1994;11:480–484. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M: Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:89–94. Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M, Ionescu-Tirgoviste C, Nuber A, Pozza G, Ward JD: Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: The EURODIAB IDDM Complications Study. Diabetologia 1996;39:1377– 1384. Veves A (ed): Clinical Management of Diabetic Neuropathy. Totowa/NJ, Humana Press, 1998.

Prof. A.J.M. Boulton, Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL (UK) Tel. +44 161 276 4452, Fax +44 161 274 4740, E-Mail [email protected]

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Chapter XV

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Foot Problems in Diabetes Jonathan E. Shaw, Andrew J.M. Boulton Department of Medicine, Manchester Royal Infirmary, Manchester, UK

Introduction The diabetic foot can present with a variety of problems, but the most important clinically are ulceration, amputation and Charcot neuroarthropathy. These will be the focus of this chapter. Many diabetic complications have a great impact on the foot and it is therefore not surprising that diabetic foot problems account for more hospital inpatient days than any other diabetic problems. Diabetic neuropathy and peripheral vascular disease are the main aetiological factors in foot ulceration and may act alone, together or in combination with other factors such as microvascular disease, biomechanical abnormalities, limited joint mobility and increased susceptibility to infection. A thorough understanding of the contributory factors that lead to foot ulceration and amputation is essential for successful treatment of established pathology. Perhaps more importantly, as the role of education and appropriate footwear in preventing ulceration and amputation is now established, accurate identification of high-risk patients on whom these services can be focused is vital.

Peripheral Vascular Disease Atherosclerotic vascular disease is probably present (at least in a subclinical form) in all patients with long-duration diabetes. Like other forms of macrovascular disease, peripheral vascular disease (PVD) is more common in diabetes. Using clinical techniques of palpation of foot pulses, the Framingham Study found a 25–50% excess of PVD in people with diabetes, but using Doppler pressures, PVD can be found in up to 3 times as many diabetic as nondiabetic people.

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The distribution of vascular disease in the lower limb is thought to be different in diabetes, with more frequent involvement of vessels below the knee. This is somewhat similar to the distal pattern of disease that is often seen in the coronary circulation, and may partly explain the fact that PVD is frequently asymptomatic in people with diabetes, and may present with ischaemic foot ulceration or gangrene, with no previous claudication. Distal disease may allow a reasonable blood supply to be maintained to the large muscles involved in walking, whilst critically impairing the supply to the skin of the feet. Co-existent neuropathy and exercise limitation due to other diseases may also mask the symptoms of PVD. Thus, regular screening by physical examination is necessary to identify people with PVD. Although PVD is more prevalent amongst the diabetic population, once established it does not progress any more rapidly than does PVD in the nondiabetic population. Furthermore, its treatment should follow similar lines. Exercise can improve claudication distances, and revascularization procedures are frequently successful, although may require a more distal anastomosis. In the pathogenesis of diabetic foot ulcers, ischaemia is a major factor in a third to a half of all cases, and approximately 50% of amputations can be attributed to ischaemia. In a prospective study of type 2 diabetes, PVD (measured by Doppler techniques) nearly doubled the risk of developing a foot ulcer – an effect that was independent of a wide range of other risk factors.

Diabetic Neuropathy Somatic Neuropathy Chronic sensorimotor peripheral neuropathy is one of the commonest long-term complications of diabetes affecting at least a third of older diabetic patients in the UK according to a large study of hospital outpatients. Its onset is insidious and data suggest that only about a third of patients with objective evidence of neuropathy actually have neuropathic symptoms. Thus progression to the insensitive foot at high risk of ulceration can occur without the patient being aware of any disorder. Identification of the neuropathic foot at risk of ulceration therefore relies on careful examination. Typically, the sensory defect predominates, but a motor component is often present, and its distal nature leads to small muscle wasting in the foot with a consequent imbalance of flexor and extensor muscles resulting in clawing of the toes and prominence of the metatarsal heads, which then become potential sites of ulceration. Peripheral somatic neuropathy has been clearly associated with foot ulceration in several cross-sectional and prospective studies. The risk of ulcera-

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tion attributable to neuropathy ranges between 2- and 10- fold, and is independent of the presence of PVD. Sensory neuropathy is most easily determined by measuring vibration perception thresholds (using a bio- or neurothesiometer), pressure perception thresholds (using monofilaments) or by clinical examination. These methods have been validated in their ability to predict ulceration. Autonomic Neuropathy Sympathetic dysfunction affecting the lower limbs leads to reduced sweating and results in dry skin that is prone to crack and fissure. It also increases blood flow (in the absence of large vessel PVD) with arteriovenous shunting leading to the warm foot. The insensitive foot is therefore often warm resulting in a false sense of security, as the patient perceives that because the circulation is intact, the risk is minimal.

Other Risk Factors for Foot Ulcers Biomechanical Aspects The neuropathic foot does not ulcerate spontaneously. It is the combination of neuropathy and trauma that results in tissue breakdown. The trauma required to ulcerate the neuropathic foot can take several different forms. Sometimes it is a single event such as standing on a nail, but more frequently it occurs as repeated minor trauma such as unperceived shoe rubbing to the toes or increased pressure beneath the metatarsal heads during walking. A number of studies have clearly demonstrated that dynamic plantar foot pressures are elevated in diabetic neuropathy and especially in patients with a history of plantar ulceration. More importantly, a prospective study has shown that elevated plantar pressures are predictive of ulceration, with 17% of patients with high foot pressures developing plantar ulcers during a 30-month followup period, whilst no plantar ulcers developed in patients with normal pressures. The presence of callus (produced in response to pressure) may exacerbate the problem both by acting as a foreign body and by increasing plantar pressures. Amongst those with diabetic neuropathy, the presence of callus is a strong and important predictor of subsequent ulceration at the site of the callus. The simple removal of the callus significantly reduces foot pressures, and presumably, therefore, also reduces the risk of ulceration. Most studies on foot pressure have simply looked at the highest instantaneous pressure measured during a single foot step. However, evidence from in vitro studies indicates that the rate of increase of applied pressure is more important than the peak pressure achieved in causing cellular damage. If this

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could be confirmed in vivo, it would have important implications for the design of pressure-relieving orthoses which may need to control the rate of descent of the forefoot (increased in the ‘footslap’ caused by motor neuropathy), as much as redistribute load and lower the peak pressure. The main cause of increased pressure is thought to be the alteration in foot shape resulting in prominent metatarsal heads. Atrophy of the intrinsic muscles of the foot (predominantly plantar flexors of the toes) alters the flexor/ extensor balance at the metatarso-phalangeal joints and causes clawing of the toes, and prominence of the metatarsal heads. A further contributing factor to elevated plantar pressure is limited joint mobility. Glycosylation of collagen results in thickening and cross-linking of collagen bundles. This is manifested clinically as thick, tight, waxy skin and restriction of joint movement. Limited joint mobility of the subtalar joint alters the mechanics of walking and is strongly associated with high plantar pressure. Other Long-Term Complications Patients with retinopathy and nephropathy have been shown to have an increased risk of foot ulceration and amputation. The pathogenic mechanisms by which other complications lead to ulceration and amputation are not entirely clear, but visual impairment makes it more difficult for patients to identify a lesion at an early stage, and tissue repair is slow in nephropathy, because of oedema, the frequent co-existence of macrovascular disease and immunological abnormalities. Thus, such patients must always be regarded as being at high risk. Previous Foot Ulceration Several studies have confirmed foot ulceration is more common in those patients with a past history of ulceration or amputation and in patients with a poor social background. Diabetes Control Poor glycaemic control as measured by HbA1c, fasting and even a single random blood glucose is a strong risk factor for subsequent amputation. Chronic hyperglycaemia increases the risk of developing complications such as neuropathy, and impairs the wound healing capacity, thus setting the scene for ulceration and amputation. Ethnicity Lower extremity amputation rates have been shown to be high amongst several groups of American Indians and may be as much as 4 times greater


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than in the general US diabetic population. Amputation rates also appear to be higher amongst Black than Europid people with diabetes. Studies in the UK have shown lower incidences of amputation and foot ulceration in the Asian than the White population. The reasons for different amputation rates among different ethnic groups are unclear. Access to health care (ranging from detection and early treatment of diabetes to availability of specialized foot services) is likely to be important, but biological variation between ethnic groups may also play a role. Cardiovascular Factors Evidence would suggest that hypertension is probably a moderately important risk factor for amputation, but neither lipid abnormalities nor surprisingly smoking predict amputation. Behavioural/Psychological Factors Despite the fact that causal pathways to ulceration are well recognized (predominantly involving neuropathy and PVD), and many high-risk patients receive education on footcare, ulceration remains common. It has been suggested that denial of risk is the main reason for this and indeed extreme denial has been reported in some foot ulcer patients. However, in our own prospective study of psychological factors in foot ulceration, measures of denial have failed to predict ulceration. In contrast, neuropathic patients developing ulcers showed a more negative attitude to the feet, and their belief in the efficacy of advice (as provided in footcare education) was lower than that of patients who did not develop ulcers. Wound Healing Slow wound healing and increased susceptibility to infection increase the problems of foot ulceration and may predispose to amputation. A number of inherent immunological abnormalities have been documented in diabetes and these may explain the increased infection rates that are seen in postoperative wounds of diabetic patients. Amongst other abnormalaties, neutrophil function is impaired, with abnormalities of adherence, chemotaxis, phagocytosis and killing ability, and these may be partly due to ascorbic acid transport defects. Microcirculation and Endothelial Dysfunction Diabetes is associated with microcirculatory abnormalities, which are accentuated in the presence of long-term complications, including diabetic neuropathy. Typically, in the neuropathic foot, resting skin blood flow is elevated, but there is a marked blunting of the hyperaemic reserve, and of the postural vasoconstriction that should reduce limb blood flow on standing. The vasodila-

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Table 1. Foot ulcer risk factors and relevant measurement techniques; all people with diabetes should be screened for these risk factors annually Risk factor

Screening method

Abnormal result indicating increased risk of foot ulceration

Neuropathy

Vibration perception threshold 1 Pressure perception threshold 1 Clinical examination1

Greater than 25 V at the great toe Insensitivity to a 10-gram monofilament on the plantar surface of the foot Absent ankle reflexes or sensory loss

Peripheral vascular disease

Clinical examination Doppler pressures1

Less than 2/4 palpable foot/ankle pulses Systolic ankle pressure less than 90% of brachial pressure

Previous foot lesion

Self-report1

Previous ulcer or amputation

1

Screening methods that have been shown to predict subsequent foot ulceration.

tory response is mediated by both endothelium-dependent and endotheliumindependent mechanisms, both of which appear to be impaired in neuropathy. Whilst the direct causal connection between these abnormalities and foot ulceration is attractive, since a failure to respond appropriately to tissue injury could lead to chronic ulceration, the possible association is as yet untested. Another related factor which may be important in the development of ulceration is capillary fragility. Recent work has shown the presence of microhaemorrhages in the feet of neuropathic patients with a history of ulceration. As haemorrhage into callus commonly precedes ulceration, this may be an important finding.

Management of Ulcers The first principle of foot ulcer management is prevention. Regular screening for the presence of risk factors (table 1) requires only very simple skills, and when combined with education (table 2) about footcare for those identified as being at risk, the likelihood of foot ulceration can be significantly reduced. The management of diabetic foot ulcers relies on relief of pressure, debridement of necrotic tissue, aggressive treatment of infection when present and restoration of normal circulation if PVD is present. All people presenting with foot ulcers should have an examination of the peripheral sensation and


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Table 2. Principles of footcare education Target the level of information to the needs of the patient. Those not at risk require only general advice about foot hygiene and footwear Make positive rather than negative recommendations Do inspect the feet daily Do report any problems immediately – even if painless Do buy shoes with a square toe box and laces Do inspect the inside of shoes for foreign objects every day before putting them on Do attend a fully trained podiatrist regularly Do cut your nails straight across and not rounded Do keep your feet away from heat (fires, radiators, hot water bottles) and check the bath water with your hand or elbow Do always wear something on your feet to protect them and never walk barefoot Repeat the advice at regular intervals and check for compliance Disseminate the advice to other family members and other health-care professionals involved in the care of the patient

circulation to classify the ulcer as neuropathic, neuroischaemic or ischaemic. Most neuropathic ulcers are due to repetitive pressure either from tight-fitting shoes (on the dorsum of the toes) or from walking (over the metatarsal heads). Pressure must be relieved in order to heal the ulcer. Poorly-fitting shoes need to be replaced by shoes with a better fit, while pressure on the plantar surface of the foot usually requires some form of walking cast (such as a total contact cast) to redistribute the load away from the ulcer. If there is any clinical evidence of PVD, Doppler pressures must be measured to determine if angiography is required. If revascularization is possible (by surgery or angioplasty), it should be performed, both to aid healing and to prevent recurrence. An infected diabetic foot ulcer can lead to limb loss in a matter of days, but by no means are all ulcers infected, although bacterial colonization is almost universal. The distinction between colonization and infection can be difficult and is not usually aided by microbiological investigations. Clinical signs are the most reliable indicators of infection. Evidence of systemic upset (e.g. fever, leukocytosis) is usually absent and signs of local inflammation and the presence of pus usually confirm the diagnosis. Infections are usually polymicrobial, and so broad-spectrum antibiotics (such as clindamycin, or amoxycillin combined with clavulanic acid) are required. Osteomyelitis should be suspected in any nonhealing ulcer, and in all ulcers in which it is possible to ‘probe to bone’. While it is often apparent on plain X-rays, CT, MRI or isotope scanning may be needed for the diagnosis.

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Recent studies have opened up the possibility of manipulating the wound environment in order to accelerate healing. These interventions have sprung from a clearer understanding of the complex processes that underlie normal and delayed wound healing, much of which is orchestrated by growth factors. A topically applied ‘bioengineered human dermis’ which consists of neonatal dermal fibroblasts cultured on a bioabsorbable mesh is thought to promote healing by the production of growth factors and of matrix elements such as collagen and fibronectin. Evidence suggests that healing rates of neuropathic ulcers can be significantly improved with this material, although this conclusion relied on a post-hoc analysis, which excluded a number of subjects who were judged to have received a product of low metabolic activity. The direct application of growth factors to foot ulcers is another area of rapid progress. The underlying assumption is that chronic diabetic foot ulcers are slow to heal, at least in part because of a failure to produce adequate amounts of growth factors. Platelet-derived growth factor has now been shown to improve the ulcer healing rate from 35 to 50% at 20 weeks, but a small pilot study of fibroblast growth factor found no benefit. During the American Civil War, maggot-infested wounds were noted to be cleaner and to heal better than other wounds. This observation has recently been applied therapeutically to a variety of other wounds, and anecdotal reports suggest a beneficial effect in diabetic foot ulcers. The larvae selectively ingest necrotic slough leaving healthy tissue alone, and possibly also produce substances that directly stimulate wound healing. Hyperbaric oxygen therapy increases tissue oxygenation, inhibits anaerobic microorganisms and promotes macrophage activity. It is therefore a candidate for treatment of diabetic foot ulcers. In a small trial of limbthreatening (predominantly ischaemic) diabetic foot lesions, a significant reduction in the rate of major amputations was seen in the group randomized to receive hyperbaric oxygen. This finding needs to be reproduced in larger trials before this expensive therapy can be recommended for widespread use. The surgical management of foot ulcers is usually limited to amputation and the debridement of infected and necrotic tissue, but it may have a role to play in directly facilitating wound closure. A small study has described better 6-month healing and recurrence rates when noninfected ulcers were excised and closed surgically than when treated conventionally.

Charcot Neuroarthropathy A Charcot joint is characterized by the simultaneous presence of bone and joint destruction, fragmentation and remodelling. Diabetes is the commonest


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cause of the Charcot foot and most patients have a dense neuropathy, but good circulation. Early animal experiments suggested that walking on an insensitive limb could lead to joint destruction. Excessive and repetitive stress to bones leads to microfractures, which render the bone more brittle and could lead to bone and joint destruction. However, the degree of bone destruction often seen in the absence of major injury has suggested an underlying bone abnormality. Diabetic neuropathy leads to an increase in bone blood flow, which may promote osteoclastic activity and bone resorption. Indeed, a small study has demonstrated increased serum markers of osteoclastic action in patients with acute Charcot that was not accompanied by a concomitant increase in markers of osteoblastic activity. Furthermore, lower limb bone mineral density has been found to be lower in patients with a Charcot foot, when compared to neuropathic controls. A full understanding of the pathological process leading to the often dramatic and progressive destruction seen in this condition has not yet been arrived at, and as it is rare and usually presents late, the opportunities for further studies are limited. In the early acute stages, when bone turnover is high, treatment involves rest and immobilization of the foot (usually with a total contact cast) in an attempt to reduce the metabolic activity within the bone. There is now some evidence that bisphosphonate drugs given during this acute phase may shorten the duration of the acute phase presumably by reducing the bone turnover directly, and hence slowing down the process which weakens the bone and renders it susceptible to further fracture and fragmentation. Whenever unilateral swelling of the foot is present in someone with diabetic neuropathy, Charcot neuroarthropathy must be considered. Plain X-ray is usually adequate to make or exclude the diagnosis, and while the radiological appearances can be similar to those of osteomyelitis, in the absence of a source of infection (such as an overlying ulcer), neuroarthropathy is nearly always the cause.

Conclusion Although the roles of peripheral neuropathy and peripheral vascular disease are now well established as the main aetiological factors in diabetic foot ulceration, there is much work to be done in both the way in which ulcers develop and the interactions of the main risk factors with each other and with all the other risk factors discussed in this chapter. However, this complexity should not deter the clinician, as it is now very clear that simple clinical tests will identify patients at risk of ulceration and amputation, and appropriate, but simple education about footcare can greatly reduce the likelihood of

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developing diabetic foot problems. Foot ulcers can be difficult to heal, but treatment is likely to be successful in the vast majority of cases when pressure is removed, callus and necrotic tissue debrided, infection controlled, and a good circulation is maintained.

Suggested Reading Boulton AJM, Connor H, Cavanagh PR (eds): The Foot in Diabetes, ed 2. Chichester, Wiley, 1994. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW: Assessment and management of foot disease in patients with diabetes. N Engl J Med 1994;331:854–860. Schapper NC, Bakker K (eds): The diabetic foot. Diabet Med 1996;13(suppl 1):1–64. Shaw JE, Boulton AJ: The pathogenesis of diabetic foot problems: An overview. Diabetes 1997;46(suppl 2): 58–61.

Dr J. Shaw, Department of Medicine (M7), Manchester Royal Infirmary, Manchester M13 9WL (UK) Tel. +44 161 276 4452, Fax +44 161 274 4740, E-Mail [email protected]


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Chapter XVI

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Erectile Dysfunction in Diabetes and Its Treatment M. Tagliabue, G.M. Molinatti Dipartimento di Medicina Interna, Universita` degli Studi di Torino, Ospedale Molinette, Torino, Italy

Introduction The existence of sexual disorders in diabetes mellitus has long been recognized. In the pre-insulin era, impotence was considered one of the commonest symptoms of diabetes, being present in both severe and milder forms of the disease. However, only now are sexual function problems receiving their rightful attention, as the medical professional has moved from a mere ‘survivalist’ approach to diabetes and its more invalidating complications towards care for the diabetic individual in all his or her complexity. Today, diabetology is no longer satisfied to keep diabetics in reasonably good health, but also addresses everything that may affect the individual’s quality of life and, from this standpoint, sexuality cannot fail to occupy a role of primary importance. In the diabetic male, it is sexuality in the narrowest sense, namely what is conventionally designated ‘potentia coeundi’, that is compromised and it is precisely in relation to that situation that a comprehensive overview of this condition can provide the diabetic patient with the answer he seeks.

Epidemiology Erectile dysfunction is 3 times more common among diabetics than in the healthy control population. However, the complication is still considered occult since it is often unreported by patients. In the various studies published, the incidence of this dysfunction in diabetics varies from 28 to 59%. The predictive factors are: age, duration of the disease, degree of metabolic com-

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pensation, the presence of microvascular complications (especially retinopathy) and neuropathy, high blood pressure and the drugs taken for that condition, smoking and alcohol abuse. The age factor is particularly important. The very earliest epidemiological studies showed that the incidence of impotence in diabetic males rose from 1.5% in the under-40s to 25% in the 40–60 age group. More recently, others have reported incidences rising from 15% in the under40 group to 55% at 60. The trend revealed by the Wisconsin Epidemiologic Study in particular is highly significant (p=0.0001), rising from 1.1% in the 21–30 age group to 47.1% among insulin-dependent diabetics over 43 years old. Klein himself confirms that significance when he analyses the duration of diabetes: men with a more than 35-year history of the disease are 7.2 times more likely to present this complication than those with only a 10- to 14-year history. However, the link between erectile dysfunction and disease duration is not inevitable, since the erectile disorder occasionally appears before the clinical onset of the diabetes. In addition, diabetic erectile dysfunction is also related to HbA1c levels which indicate the ability to metabolize glucose, the risk of impotence tripling in those worst affected (HbA1c ?9.8%). That increased risk is explained when we consider the treatment needed to control diabetes – restrictive diets and drugs to lower blood sugar and/or insulin – that are most aggressive in the most metabolically compromised patients. Both diabetic retinopathy, especially if severe, and neuropathy, both peripheral and autonomic, are related to a higher incidence of erectile dysfunction which is 5.3 times more likely to occur in such patients. High blood pressure is an additional risk factor especially when treated by certain drugs such as bblockers, methyldopa and particularly diuretics. Finally, excessive drinking and smoking intensify the risk of erectile dysfunction in diabetics. A recent Italian study of 9,868 diabetic patients reported a 35.8% incidence of erectile dysfunction and confirms the reported literature data: incidence increasing with age, duration of diabetes, severity of failure to metabolize glucose, complexity of diabetic therapy, diabetic complications (angiopathy, retinopathy, kidney disease, neuropathy) as well as cardiovascular disease and the use of certain drugs in its treatment and finally habitual smoking. Apart from erectile dysfunction, diabetes can also produce problems with ejaculation, especially retrograde ejaculation as the so-called ‘dry orgasm’ (a dysfunction of the autonomic and somatic nervous system) which occurs in 1–4% of male diabetics, most particularly in those with the longest history of the disease and those who are most metabolically compromised. Ejaculation without orgasm and indeed failure to achieve ejaculation (reflecting a compromised sympathetic nervous system) are also commoner among diabetics than in the general population, accounting for 8% of ejaculatory disorders. By contrast, the incidence of premature ejaculation is almost

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Table 1. Possible causes of erectile dysfunctions in diabetics Psychological causes Poor glycaemic control Vascular alterations (macro-/microangiopathies and venous) Autonomic neuropathy Endothelial alterations (reduced NO secretion) Concomitant pathologies and related drugs

identical in the diabetic and the healthy populations, a finding that confirms the psychosomatic pathogenesis of that disorder. Be that as it may, the organic character of diabetes and its complications should not lead us to forget the influence of psychological factors which may at times be preponderant.

Etiopathogenesis Diabetic erectile dysfunction is often a complex problem given its psychogenic and organic components, the latter linked to the failure to metabolize glucose and the related organic complications, not to mention the pathological conditions known to be caused by the drugs used to treat those complications (table 1). However, many studies have confirmed that erectile dysfunction is primarily organic in origin, since the dysfunction is rarely reversible. In monitoring the nocturnal erections associated with REM sleep, researchers have found fewer REM sleep-erections in diabetic males, a finding which supports the view that impotence in diabetics is more likely to be organic than psychological in origin. Nevertheless, the role of hormonal abnormalities in the physiopathology of organic erectile dysfunction remains controversial. It is therefore vital to examine the fundamental psychological and organic factors involved in the sexual function of diabetics. The Psychological Factor There is substantial evidence to suggest that erectile dysfunction in diabetes is often psychological in origin. The main contributory factors are: awareness of suffering from a chronic condition, relationship problems and the fear of failure during sexual intercourse as a result of that situation. It is not clear whether such psychological factors are greater in the diabetics affected than in the general population of people with erectile dysfunctions, though diabetics with the problem appear more stressed than those unaffected. Accord-

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ing to some authors, diabetic patients are more fearful of developing erectile dysfunctions as a complication of their condition than of going blind, but however great their concern, they are unlikely to discuss it with their doctor. In fact only 50% of erectile dysfunction sufferers report it to their physician. Impaired Glucose Metabolism It is important for the correct management of diabetic erectile dysfunction to repair any severe metabolic disorder the patient may be suffering from. Patients may recover normal erectile function, as soon as insulin injections to correct their impaired glucose metabolism are started. The impaired delivery of oxygen to the tissue, caused by the formation of glycosylated haemoglobin which has a greater affinity for oxygen increases vascular permeability, depositing lipoprotein on the vessel wall and this may be the cause of the vascular damage. Vascular Alterations Vascular disorders cause impotence in 18% of diabetic males. Haemodynamic disturbances in diabetics may be either arterial (macro- and/or microangiopathies) or venous given the direct communication between the two vascular systems. Macroangiopathy causes major arterosclerotic obstructions of the large, medium-sized and small arterial blood vessels which cut off the blood flow to the corpora cavernosa. Many authors claim that the primary cause of impotence in diabetics is of vascular origin and atherosclerosis is, in fact, the earliest lesion on the peripheral arteries of the penis. Histological findings of pathological alterations to the small arteries are also reported to occur before any neurological damage. Later, neurological damage caused by the same atherosclerotic processes appears on the vasa nervorum. Such vascular alterations are the result of proliferating endothelial and intimal cells, fragmentation of the endothelium, calcium deposits, and perivascular fibrosis. Perineural fibrosis may occur without causing any direct damage to the nerve fibres. There is an equally close link between ischaemic heart disease and diabetic erectile dysfunction, both being caused by the ischaemic vasculopathy affecting both areas. Diabetic microangiopathies produce alterations and irregularities in the local microvascular blood flow. Those alterations concern: endothelial cell metabolism and function; the basal membrane of vessel walls, which are thickened; oxygen transportation; the characteristics of blood flow and haemostasis. In the venous system the uncontrolled blood flow and the failure of the arteriovenous anastomoses may also contribute to the erectile dysfunction. Finally, venous occlusions in diabetes may be due to a structural alteration in the fibroelastic components of the trabeculae.


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Neurological and Endothelial Alterations The penile nerve system is both autonomic and somatic and the relaxation of the smooth muscle tissue of the corpus cavernosum results from the interaction of three systems: adrenergic, cholinergic and VIPergic. Other factors like nitric oxide (NO) initially called endothelium-derived relaxing factor (EDRF) and produced by constitutive nitric oxide synthetase (cNOS) which increases the concentration of intracellular cyclic guanosine monophosphate (cGMP) may well be involved in the relaxation of the smooth muscle in the corpus cavernosum. As we know, the earliest studies into NO production by cNOS were carried out on bioptic samples taken from the corpus cavernosum tissue of impotent diabetics who presented reduced acetylcholine vasodilation. The reduced NO production and consequent reduction in intracellular cGMP probably leads to an increase in intracytosolic calcium that is responsible for the contraction in smooth muscle cells. In diabetics there may well also be a reduction in the noradrenaline, VIP and acetylcholine content of the corpus cavernosum and both the cholinergic fibres and their ability to synthesize acetylcholine may be reduced over time, as may the VIPergic pathways. Cholinergic stimulation is certainly known to increase NO production. This would compromise both the neurogenic and the endothelial mechanisms dependent on the relaxation of the cavernosal smooth muscle. Increased levels of endothelin-1, a powerful vasoconstrictor released by the endothelial cells, have also been found in patients with erectile dysfunction, especially those with diabetes. That finding suggests that endothelial dysfunction may contribute to erectile dysfunction and that in the absence of any significant vascular element the increase in plasmatic endothelin-1 may be related to early atherosclerosis. The autocrine role of this peptide, which causes the smooth muscle cells of the corpus cavernosum to proliferate and/or contract, has been confirmed in experimentally induced diabetes mellitus. Somatic and autonomic neuropathy (bladder dysfunction) is often associated with impotence in diabetes and is responsible for 67% of cases, according to recent statistics. The disease causes axonal degeneration of the nerves in the penis (and other parts of the body) together with thickening of the basal membrane. The biochemical abnormalities encountered in diabetic patients can be somewhat improved if their glucose metabolism problem is carefully controlled. Researchers have also found a lack of coordination in the electrical activity of the corpus cavernosum in diabetics with a consequent loss of the diminished or absent activity that is normal in the tumescent or erectile phase. Hormonal Alterations Total basal testosterone levels have been found to be normal or low and researchers have also documented a diminished response in terms of absolute

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testosterone increases after HCG stimulation. Some reports describe a decrease in the free fraction of testosterone and estradiol, which they attribute to a marked increase and/or enhanced binding capacity in SHBG and/or inappropriate gonadotropin secretion. In addition, there also appears to be an alteration in gonadic response to tropine stimulation with a tendential rise in basal LH and a more protracted increase after GnRH stimulation. The evidence on circulating gonadotropin and prolactin is conflicting. Some report an increase in urinary LH among diabetics with primary organic impotence, as well as a reduction in levels of free testosterone. Diabetes and obesity often go together and increased aromatization of testerostene in the adipose tissue produces an increase in oestrogen levels that contributes to erectile failure. In actual fact, there is increasing doubt about the role of steroids and other hormones in the aetiopathology of sexual disorders in the diabetic male and the variations that may be found do not appear to play a particularly important part in the genesis of this complication.

Spermatogenesis The most frequently encountered alteration in spermatogenesis is reduced spermatozoa motility which appears to be closely linked to the metabolic disorders and the presence of autonomic neuropathy. Functional damage to the seminal vesicles is probably a major contributory factor. Studies conducted on rats with streptozotocin-induced diabetes revealed an alteration in the animals’ sexual behaviour and a reduction in the weight of their secondary sex glands, in their production of androgens and in spermatogenesis as a result of altered gonadotropin pulsatility.

Diagnosis Erectile dysfunction is diagnosed in diabetics in much the same way as in their healthy counterparts and diagnosis therefore includes anamnestic assessment, objective examination, laboratory tests and instrumental investigation (table 2). Both the rigidity and the duration of penile erections are affected (reduced arterial blood flow and altered control of the autonomic nervous system over the penile circulation) while, at least initially, the libido remains unaffected. Anamnesis Anamnesis is the first step. In diabetics, erectile dysfunction usually arises insidiously, evolving slowly but inexorably. Physicians should pay particular


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Table 2. Main diagnostic procedures for erectile dysfunction in diabetics Anamnesis (physiology, pathology, pharmacology, sexual) Clinical examination Blood chemical analyses (HbA1c, T, PRL, TSH) Instrumental investigations (penile biothesiometry and cardiovascular tests) Vascular evaluation (office-intracavernosal injection test)

attention to their patient’s smoking and drinking habits and to the presence of any concomitant pathologies (high blood pressure and dyslipidaemias are common) and the drugs they are being treated with, since these often have a negative impact on sexual activity itself. In the case of diabetes mellitus, it is essential to know type, duration and treatment, how far glucose metabolism is compromised and whether or not the patient presents with micro/macroangiopathic and/or neuropathic complications. In order to obtain a full diagnostic picture, the investigation of organic factors must be accompanied by investigation of learning, intrapsychic, dyadic, systemic and sociocultural factors. The sexual anamnesis will cover aspects like the presence or absence of sexual desire, the presence of spontaneous erections on awakening and/or in response to visual stimuli and/or erotic thoughts and/or physical stimulation by a partner, as well as the quality and frequency of sexual intercourse, the presence of any significant changes in recent months and the description of the sexual intercourse itself.

Instrumental Investigations The instrumental investigations indicated include those used to examine the vascular system (ultrasound scans or basal and dynamic Doppler echosonography) which usually involves the intracavernosal injection of prostaglandin (PGE1) and penobrachial plethysmography. Others examine neurological aspects (vibration and heat perception thresholds, autonomic cardiovascular tests, peroneal motor conduction velocity and sural sensitivity tests; possibly also sacral evoked potential tests). Then there are urological tests (cavernosography, cavernosometry, bulbocavernosus reflex). A new minimally invasive test has recently been proposed and has been tested on type 2 diabetics with no vascular disease in whom basal penile tumescence was assessed using the Rigiscan technique and found to be related to autonomic nerve damage.

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An easy-to-use protocol for the diagnosis of level I erectile dysfunctions in diabetics was proposed by the Italian Diabetology Society’s ‘Diabetic Neuropathy’ Study Group in 1996: Anamnestic screening Targeted questionnaire Penile biothesiometry Cardiovascular tests PGE1 drug stimulation Patients =40 years old: 5 lg Patients ?40 years old: 10 lg If the erectile response is absent: repeat after 1 week with 10 or 20 lg PGE1 persistently absent: refer to your andrology unit for further investigation (Rigiscan, Ultrasound, Doppler ultrasonography, invasive vascular tests) If the erectile response is present: oral and/or intracavernosal and/or psychological treatment.

The protocol proposed by Japanese authors is more complex. In it, vascular investigations, Rigiscan and audiovisual sexual stimulation precede intracavernosal drug stimulation. If there is no erectile response, nocturnal penile erectile tumescence is monitored, which, if found, allows us to label our patient as ‘not suffering from any organic disorder’.

Treatment The treatment for erectile dysfunction in diabetics (table 3) is primarily based on rectifying the glucose-metabolizing disorder by diet and/or drug treatment and by persuading the patient to abstain from risk factors like smoking and alcohol abuse. In addition, every possible effort will be made to find substitutes for any drugs with a negative impact on sexual function. Psychological Treatment Psychotherapy can help to minimize anxiety and modify the couple’s sexual habits in a helpful fashion. Even so, ‘psychological problems’ appear to be no more common among diabetics than among the general population. Drug Treatment Treatment with a2-antagonists (yohimbine) or a1-antagonists (doxazosin, terazosin, etc.) can enhance penile vasodilation but cannot alone induce and


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Table 3. Treatment of erectile dysfunction

Psycho- or behavioural therapy Drug treatment Yohimbine a1-antagonists Local nitroderivatives Sildenafil Endourethral alprostadil Intracavernosal injection Papaverine Alprostadil Phentolamine Moxisylyte External mechanical support Vacuum device Revascularization surgery Venous Arterial Penile prosthesis

maintain erection. These drugs are indicated in patients with high blood pressure and certain prostate pathologies. Moderate success has been obtained with topical nitroderivatives that are rapidly absorbed through the skin (nitroglycerin). These act directly by stimulating the release of the adenylase cyclase which relaxes the smooth muscle tissue. Sildenafil, a selective inhibitor of type V cyclic phosphodiesterase in the corpus cavernosus, prevents the breakdown of cGMP and therefore acts on the NO mechanism (NO/cGMP) that plays a dominant part in the relaxation of smooth muscle tissue and hence penile erection. This is a rapidly absorbed drug that is taken 60 min before intercourse and has an effect lasting about 4 h. It does not trigger erection as such but improves its quality by promoting the smooth muscle relaxation initiated by NO release. It is important to remember that Sildenafil is contraindicated in men taking nitrates, given the risk of significant reductions in blood pressure caused by intensification of the vasodilatory effects of such drugs. Caution must also be exercised in a number of other clinical conditions (kidney or liver problems) and/or when the patient is taking other drugs which might interfere with absorption kinetics. In doses of 25–100 mg, Sildenafil has proved effective in 59% of diabetic patients with erectile dysfunction (placebo 15%). It is well tolerated and the

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side effects reported in this population are: headache, dyspepsia and flushing. Other side effects described are temporary and relate to the perception of colours, sensitivity to light and fuzzy vision. Alprostadil (a synthetic preparation of PGE1), also appears as a compound that is incorporated into pellets for intraurethral application (MUSE: Medical Urethral System for Erection). Patients have to be taught how to use the applicator which delivers a microsuppository into the urethra at an average dose of 500–1,000 lg. The side effects are penile pain, stranguria and slight bleeding. MUSE is contraindicated without the use of a condom in intercourse with a partner who is pregnant or liable to conceive. It is not widely used in Italy and may be contraindicated in diabetics with their greater risk of infections. Intracavernosal Injection Intracavernosal pharmacoprosthesis is currently one of the most widely used treatments and enjoys good patient compliance, especially among diabetics who get a satisfactory response in 66% of cases compared to only 23% in nondiabetics with erectile dysfunction. Vasodilatory substances either alone or in combination (papaverine, alprostadil, phentolamine and atropine) are inoculated directly into the corpus cavernosum. The patient has to be trained in the inoculation procedure and doses must be carefully selected in order to avoid prolonged erections or priapism. Erection occurs about 10 min after inoculation of the substance. The incidence of complications depends on the type of drug used. Pain on the inoculation site is rare, but penile fibrosis or priapism may develop over time. The most commonly used drug is alprostadil because of its minimal side effects and the dose varies from 5 to 20 lg. This prostaglandin produces cAMP which acts with cGMP to relax the smooth musculature. Both are metabolized by the type V phosphodiesterase found in both the penile smooth muscle tissue and the eyes. Moxisylyte is a selective a1 drug used in 10- to 20-lg doses. Its minimal side effects include penile pain and prolonged erections. Vasointestinal peptide combined with phentolamine is now in the advanced research stage. Its side effects are flushing and tachycardia and, rarely, penile pain. External Mechanical Support A patient who prefers not to use drugs can employ a so-called ‘vacuum device’. This is a cylinder into which the penis is inserted. The cylinder is pressed against the abdominal wall and a mechanical or electric pump is activated to create a vacuum which draws blood into the corpus cavernosum thereby producing a penile erection. The erection is maintained by a rubber ring around the base of the penis for as long as the ring remains in situ.


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Patient compliance with this system is generally good. However the device should not be used for more than 30 min at a time, since it can create a feeling of chill in the penis. Furthermore, ejaculation is generally impeded and this may make for a less satisfying orgasm. The vacuum device can be used to potentiate the effect of drug treatment. Revascularization Surgery Where erectile dysfunction is caused by vascular disease, both venous and arterial revascularization procedures are a possibility. Penile Prothesis Diabetic patients with irreversible penile dysfunctions are candidates for penile implants, which, however, expose them to the risk of local infections.

Suggested Reading Bancroft J, Gutierrez P: Erectile dysfunction in men with and without diabetes mellitus: A comparative study. Diabet Med 1996;13:84–89. Dunsmuir WD, Holmes SAV: The aetiology and management of erectile, ejaculatory, and fertility problems in men with diabetes mellitus. Diabet Med 1996;13:700–708. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB: Impotence and its medical and psychosocial correlates: Results of the Massachusetts male aging study. J Urol 1994;151:54–61. Klein R, Klein BEK, Lee KE, Moss SE, Cruickshanks KJ: Prevalence of self-reported erectile dysfunction in people with long-term IDDM. Diabetes Care 1996;19:135–141. Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA: Impaired neurogenic and endotheliummediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989;320:1025–1030. Takanami M, Nagao K, Ishii N, Miura K, Shirai M: Is diabetic neuropathy responsible for diabetic impotence? Urol Int 1997;58:181–185.

Prof. G.M. Molinatti, Dipartimento di Medicina Interna, Universita` degli Studi di Torino, Ospedale Molinette, I–10126 Torino (Italy) Tel. +39 (0)11 6635318, Fax +39 (0)11 6634751, E-Mail [email protected]

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Chapter XVII

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Multifactorial Intervention in Type 2 Diabetes mellitus Peter Gæde, Oluf Pedersen Steno Diabetes Centre, Copenhagen, Denmark

Introduction The prevalence of type 2 diabetes mellitus is rapidly increasing. Patients with type 2 diabetes suffer from micro- as well as macrovascular complications, the latter causing the excess mortality seen in these patients compared to the background population. Several risk factors for the outcome of type 2 diabetes have been identified in prospective epidemiological studies. However, until recently the treatment of type 2 diabetes has been empirical rather than evidence based from randomized intervention studies. Although the diagnosis of diabetes is based on blood glucose levels, it is important to realize that patients with type 2 diabetes mellitus share many clinical features with the metabolic syndrome such as dyslipidaemia, hypertension, hyperinsulinaemia and an increased risk of cardiovascular disease. In cardiovascular medicine a multifactorial treatment approach of several risk factors for cardiovascular disease is generally accepted. We suggest a similar approach in the treatment of type 2 diabetes mellitus based on the results from several intervention studies in patients with this disease.

Evidence for the Treatment Effect of Hyperglycaemia The importance of strict glycaemic control for the development and progression of microvascular complications was definitely confirmed in the United Kingdom Prospective Diabetes Study (UKPDS). 3,867 patients with newly diagnosed type 2 diabetes were randomized to intensive therapy with oral hypoglycaemic agents or insulin, or to conventional therapy. Patients were

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followed for a median of 10 years. Mean HbA1c in the intensive group over this period was 7.0% as compared to a mean value of 7.9% in the conventional group. A significant risk reduction of 25% for microvascular events with intensive therapy was found while only a borderline significant effect of 16% (p>0.05) was seen on myocardial infarctions and no effect was seen on mortality. The number of patients needed to treat over a 5-year period to prevent one complication was 39.2. Even though no overall effect on cardiovascular disease was seen in the UKPDS, it is still important to remember that hyperglycaemia is one of the most important predictors for cardiovascular disease in epidemiological studies. There is therefore every reason to believe that intervention against hyperglycaemia also has beneficial effects on this complication in type 2 diabetes mellitus, however the final proof from a randomized intervention study has still to come. Treatment Approach for Hyperglycaemia Treatment goals for different risk factors are shown in table 1. Traditionally, lifestyle modification is the first and basic treatment approach, since this is cheap and without major side effects. Even though pharmacological treatment may be needed, it is important to emphasize the necessity of this basic treatment to patients. Since deterioration of b-cell function is inevitable, regular controls are necessary in order to change treatment whenever needed. Diet An immediate effect on dieting on blood glucose levels is seen in most studies. However, the UKPDS demonstrated that less than half of patients with a normalization of fasting blood glucose after 3 months of dieting alone were able to maintain this effect after 1 year. Therefore, in order to reach the recommended treatment goals, supplemental pharmacological treatment is needed in most cases. Exercise Even 30 min of moderate exercise with an intensity of 50–80% of VO2max 3–4 times a week has beneficial effects both on carbohydrate metabolism and on insulin sensitivity. However, many patients suffer from complications, e.g. cardiovascular complications, arthroses or peripheral neuropathy, which should be taken into account when recommending type of exercise. Oral Hypoglycaemic Agents Different classes of oral hypoglycaemic agents with different mechanism of action exist. Thus, drugs can be combined. It is important to realize that

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Table 1. Treatment goals for behaviour modification, and clinical as well as biochemical variables in type 2 diabetes mellitus Behaviour modification Diet Carbohydrates Proteins Fat

Exercise Smoking

Percent of total energy intake Percent of total energy intake Percent of total energy intake Fat composition Saturated fatty acids Monounsaturated fatty acids Polyunsaturated fatty acids Moderate, 30 min/day No smoking

Clinical Body mass index Systolic blood pressure Diastolic blood pressure

=25 kg/m2 =130 mm Hg =85 mm Hg

Biochemical HbA1c (normal range 5.2–6.4%) Fasting total cholesterol Fasting LDL cholesterol Fasting HDL cholesterol Fasting triglycerides Urinary albumin excretion rate

in the normal range =5.0 mmol/l =2.6 mmol/l ?1.1 mmol/l =1.7 mmol/l =30 mg/24 h

55% 15% 30% 1/3 1/3 1/3

5–10% of patients experience oral hypoglycaemic drug failure per year, in which case insulin treatment must be initiated to maintain satisfactory glycaemic control. In a substudy in the UKPDS, the effect of metformin versus conventional treatment and sulphonylureas or insulin in obese patients was examined. Patients randomized to metformin had lower risks for all-cause mortality, strokes and any diabetes-related endpoint than patients on conventional treatment, sulphonylureas or insulin and metformin was found to cause less weight gain and fewer hypoglycaemic attacks than sulphonylureas or insulin. In another substudy in patients with secondary failure to sulphonylureas, addition of metformin doubled the risk of mortality compared to patients continuing sulphonylureas alone. These results are difficult to interpret because of the study design. However, until results from a randomized study specifically designed to answer the question about the effect of metformin on mortality in secondary failure to sulphonylureas, according to the American Diabetes Association no restrictions in the use of metformin in combination with sulphonylureas is justified.

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Insulin Insulin treatment can be given as monotherapy or as combination therapy with insulin and oral hypoglycaemic agents. From studies comparing several insulin regimens, bedtime NPH insulin in combination with metformin twice daily and self-adjustment of insulin dose based on patients’ own fasting blood glucose measurements seems to be an easy and safe way of obtaining optimal glycaemic control. This combined insulin and metformin treatment regimen is associated with less weight gain than monotherapy with insulin. Whereas hypoglycaemia is frequent in type 1 diabetes mellitus, this is not the case in insulin resistant type 2 diabetes mellitus, even with large insulin doses and HbA1c values near the normal range. It has been discussed whether insulin per se is atherogenous, since hyperinsulinaemia is a risk factor for cardiovascular disease in epidemiological studies, however this effect has not been demonstrated in clinical studies.

Evidence for the Treatment Effect of Hypertension The effect of antihypertensive treatment in type 2 diabetes was examined in a substudy in the UKPDS. 1,148 hypertensive patients were randomized either to tight blood pressure control aiming for a blood pressure =150/85 mm Hg with the use of angiotensin-converting enzyme (ACE) inhibitors or b-blockers or to less tight blood pressure control aiming at a blood pressure =180/105 mm Hg and if possible avoiding the previous mentioned drugs. The mean blood pressure during follow-up was 144/82 mm Hg in the group assigned tight blood pressure control compared to 154/87 mm Hg in the group assigned to less tight control. Significant risk reductions were found for deaths related to diabetes (32%), strokes (44%) and microvascular disease (37%). The effect of blood pressure control was independent of blood glucose control. The number of patients needed to treat over a 5-year period to prevent one diabetesrelated death was 30.0 while it was 12.2 for microvascular disease. Thus based upon the results from intervention trials it seems that blood pressure control is more effective than blood glucose control in type 2 diabetes mellitus. Another important message from this study is that in order to obtain the specified blood pressure goal it is in most cases necessary with two or more different antihypertensive drugs. The results from the Hypertensive Optimal Treatment (HOT) randomized trial also underline the importance of tight blood pressure control. 18,790 patients with hypertension were randomly assigned to three groups with target diastolic blood pressure of p90, p85 and p80 mm Hg. A long-acting calcium antagonist, felodopine, was the primary drug with addition of an ACE inhib-

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itor, b-blocker or diuretic if blood pressure goals were not obtained. In a subgroup analysis in the hypertensive diabetic patients, significant risk reductions in the group assigned to the lowest blood pressure group compared to the highest was found for cardiovascular mortality (67%) and major cardiovascular events while (51%) only a borderline significant reduction was found for allcause mortality (44%). The number needed to treat to prevent one complication is in accordance with the numbers found in the UKPDS (table 2). A positive treatment effect for the elderly hypertensive type 2 diabetic patients was recently demonstrated in a post-hoc analysis from The Systolic Hypertension in Europe Trial. Of the originally enrolled 4,695 patients with systolic hypertension (systolic blood pressure ?160 mm Hg and diastolic blood pressure =95 mm Hg), all patients ?60 years of age, 492 had diabetes. Patients were randomized to treatment with a calcium antagonist, nitrendipine, or placebo. In the group receiving active treatment significant risk reductions were obtained for total mortality (55%), mortality from cardiovascular disease (76%), all cardiovascular events combined (69%), fatal and nonfatal strokes (73%), and all cardiac events combined (63%) compared to the group receiving placebo. The suspicion that calcium channel blockers may be harmful in patients with hypertension and diabetes mellitus could clearly not be confirmed in this study. The question of which kind of antihypertensive drug treatment should be used was also investigated in the Captopril Prevention Project (CAPPP). 10,985 patients with hypertension were randomly assigned the ACE inhibitor captopril or conventional antihypertensive therapy with diuretics or b-blockers. The risk of a major cardiovascular event during an average follow-up of 6.1 years did not differ between treatment groups. An overall reduction in the rate of fatal cardiovascular events was reported in the diabetic subpopulation (n>572), however no data on blood pressure control and actual drug regimens in this subgroup was reported making the results difficult to interpret. Similar, the previously described UKPDS did not find any difference between the treatment effect of ACE inhibitors or b-blockers in the type 2 diabetic patients randomized to tight blood pressure control. Treatment Approach for Hypertension Basic dietary advice recommending weight reduction in obese, a low sodium intake and regular exercise are important in the treatment of hypertension and should be given for 2–3 months before initiating pharmacological therapy. Positive treatment effects have been demonstrated with the use of ACE inhibitors, diuretics, calcium antagonists and b-blockers. This clearly suggests that it is the obtained blood pressure level rather than the type of drug


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Table 2. Number of patients needed to treat for 5 years to prevent one complication in different trials (unless indicated with p value, only significant results from the different studies are shown; numbers are based on extrapolation of results from the original follow-up period to a 5-year period) Trials

Hyperglycaemia UKPDS [UKPDS Group, 1998a] Any diabetes-related endpoint Myocardial infarction (p>0.05) Any microvascular endpoint Hypertension UKPDS [UKPDS Group, 1998b] Any diabetes-related endpoint Diabetes-related death HOT Study (subgroup analysis) [Hansson et al., 1998] Major cardiovascular event Cardiovascular mortality Dyslipidaemia 4S study (subgroup analysis) [Pyo¨ra¨la¨ et al., 1997] Major CHD event CARE [Sacks et al., 1986] Major CHD event (p>0.05) Microalbuminuria Ravid study [Ravid et al., 1993] Progression to nephropathy Aspirin HOT Study [Hansson et al., 1998] Major cardiovascular events Myocardial infarction US Male Physicians’ Health Study [Final report, 1989] Myocardial infarction Multifactorial intervention Steno 2 Study [Gæde et al., 1999] Any microvascular endpoint Progression to nephropathy

Gæde/Pedersen

Number needed to treat

39.2 92.4 71.4

12.2 30.0 16.0 27.0

4.8 12.4

3.4

125.0 153.8 108.2

4.7 5.4

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used that is essential in treating hypertension in type 2 diabetic patients. As mentioned above, most patients will need treatment with two or more antihypertensive drugs in order to obtain a desired treatment response.

Evidence for the Treatment Effect of Dyslipidaemia The term dyslipidaemia covers many patterns of lipid changes from the normal values. The most common pattern in type 2 diabetic patients is elevated serum triglyceride levels and decreased serum HDL cholesterol levels. Evidence for a positive treatment effect of dyslipidaemia in type 2 diabetes mellitus comes from post-hoc analyses of diabetic patients participating in larger secondary intervention studies comprising patients with known cardiovascular disease. Since the risk of a first myocardial infarction in patients with type 2 diabetes is the same as the risk for a re-infarction in a nondiabetic subject, it seems reasonable to extrapolate from the overall results from these studies. The Scandinavian Simvastatin Survival Study (4S) included 4,444 patients with a recent myocardial infarction or angina pectoris and an increased fasting serum-cholesterol level in the range 5.5–8.0 mmol/l. Of these, 202 had diabetes. Patients were randomized to treatment with placebo or simvastatin. The median follow-up time for the diabetic patients was 5.3 years. A significant risk reduction of 55% with lipid-lowering drug therapy was seen for major cardiovascular events, while no effect was seen on total and cardiovascular mortality. The number needed to treat to prevent one major cardiovascular event during a 5-year period was 4.8. The Cholesterol and Recurrent Events (CARE) trial was also a secondary intervention study including 4,159 patients with a fasting serum-cholesterol level =6.2 mmol/l, thus examining the effect of cholesterol-lowering therapy in patients with cardiovascular disease and a fasting serum cholesterol level within the normal range. 586 diabetic patients participated in the study. A borderline significant risk reduction of 25% was found for major cardiovascular events (death from cardiovascular disease or nonfatal myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty). No effect on mortality was found. The Helsinki Heart Study was a primary intervention trial enrolling both nondiabetic and diabetic patients with high fasting serum non-HDL cholesterol levels. The overall result was a significant 34% reduction in the risk for cardiovascular disease with treatment with a fibrate (gemfibrozil), however the 38% risk reduction found in a subanalysis in the type 2 diabetic population was not significant.


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Table 3. Various type of drug therapy of dyslipidaemia

Drug of choice Combination

LDL cholesterol lowering

Triglyceride lowering

Combined dyslipidaemia

Statins Resins

Fibrates Nicotinic acid or statins

Statins Fibrates

It is important to repeat that the evidence for a positive treatment effect of dyslipidaemia is based on post-hoc analyses from secondary intervention studies in mixed populations. No primary intervention trials in type 2 diabetic patients have been published. Treatment Approach for Dyslipidaemia Patients with dyslipidaemia should be examined in order to exclude secondary dyslipidaemia (e.g. renal disease, hypothyroidism), in which case the underlying cause should be treated. Behaviour Modification Diet should be optimized with a reduction in dietary content of saturated fatty acids. Weight loss and increased physical activity will lead to decreased serum triglyceride and increased fasting serum HDL cholesterol levels. Maximal effect of this approach is a reduction in fasting serum LDL cholesterol of 0.4–0.6 mmol/l. Pharmacological Therapy Glucose-lowering therapy reduces both serum levels of triglycerides and to a lesser extent serum LDL cholesterol levels, thus optimizing glycaemic control is prior to treatment with specific dyslipidaemic drugs. The serum LDL cholesterol level for initiation of drug therapy is still debated, but the more risk factors the lower level. In high-risk patients the limit is 2.6 mmol/l. Various types of drug therapy for the different forms of dyslipidaemia are shown in table 3.

Evidence for theTreatment Effect of Microalbuminuria Microalbuminuria (urinary albumin excretion rate in the range 30–300 mg/ 24 h) is an important risk factor for the development of both micro- and macrovascular disease. It is known that both the treatment of hyperglycaemia

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and hypertension can reduce the albumin excretion rate. However, treatment with ACE inhibitors seems to reduce urinary albumin excretion rate independently of the blood pressure-lowering effect of these drugs. 94 patients with type 2 diabetes mellitus and microalbuminuria and a blood pressure =140/90 mm Hg were randomized to treatment with 10 mg enalapril daily or placebo. Over the study period of 5 years, 6 patients in the ACE inhibitor group and 19 in the placebo group developed diabetic nephropathy. This difference could not be attributed to differences in glycaemic control, body mass index, or blood pressure values, which were similar in both groups throughout the study period. Reciprocal plasma creatinine levels as a measure for renal function decreased significantly in the placebo group as a sign of deterioration of kidney function but remained stable in the enalapril group. Treatment Approach for Microalbuminuria Since both the treatment of hyperglycaemia and hypertension decreases urinary albumin excretion rate, these treatment modalities should be optimized. In case of increased albumin excretion rate despite sufficient antihypertensive treatment without an ACE inhibitor, treatment with this drug should be initiated. Treatment with an ACE inhibitor should be started in a low dose and gradually increased, especially in patients with normotension because of the risk for orthostatic hypotension.

Evidence for the Treatment Effect of Aspirin The beneficial effect of low-dose acetylsalicylic acid as secondary prevention of cardiovascular disease is well established in both the diabetic and nondiabetic population. The previously described HOT trial also examined the effect of treatment with acetylsalicylic acid in patients with hypertension. Of the 18,790 patients, half were randomized to 75 mg aspirin daily and the other half to placebo. No specific data for the diabetic subgroup have been published. For the whole study population a significant 15% reduction in the risk for major cardiovascular events was seen, primarily due to a 36% reduction in the risk for myocardial infarction. Fatal bleeds were equally common in the two groups, but nonfatal bleeds (primarily gastrointestinal) were significantly more frequent among patients receiving acetylsalicylic acid than in those receiving placebo. The US Physicians Health Study was a primary prevention trial in which a low-dose aspirin regimen (375 mg every other day) was compared with placebo in 22,071 male physicians. There was an overall significant 44% risk reduction for myocardial infarction in the acetylsalicylic acid-treated group,


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whereas subgroup analysis in the diabetic physicians revealed a relative risk of 0.39 for the diabetic men taking aspirin. Who Should be Treated with Aspirin Primary prevention: Consider aspirin therapy as a primary prevention strategy in type 2 diabetic subjects with at least one of the following criteria: family history of coronary artery disease; cigarette smoking; controlled hypertension; micro- or macroalbuminuria. Secondary prevention: Aspirin should be used as a secondary prevention strategy in all diabetic patients with evidence of large vessel disease. People with aspirin allergy, bleeding tendency, anticoagulant therapy, ongoing or recent gastrointestinal bleeding, and clinically active hepatic disease are not to be treated with aspirin. Therapy should be given as enteric-coated aspirin in doses of 75–325 mg/day.

Evidence for the Effect of Smoking Cessation Smoking may be one of the most important risk factors for cardiovascular disease in type 2 diabetes mellitus. This is based on several epidemiological studies, where smoking is found to be a risk factor for both all-cause mortality, cardiovascular disease and stroke in both the diabetic and nondiabetic population. The Multiple Risk Factor Intervention Trial (MRFIT) randomized 12,866 subjects to a control group or an intervention group with intervention against several risk factors such as diet, smoking and blood pressure. Smoking cessation programmes were used with individual advice by a doctor. A 13% reduction in the number of smokers in the intervention group was seen after 6 years. However, no significant effects on total mortality or mortality from cardiovascular disease was seen in the overall analyses. Despite these negative results from one of the most successful smoking cessation intervention programmes, it is because of the epidemiological evidence recommended that all diabetic patients quit smoking. Smoking Cessation Programmes Trying to convince patients to stop smoking is one of the hardest and most disillusioning tasks for the health worker. Even though several smoking cessation programmes and nicotine replacement therapy exist, the percentage of smokers who quit smoking in these programmes is low. The average rate of success is around 8% after 1 year in unselected smokers. This number can be increased by selecting motivated patients (e.g. patients with myocardial infarctions) but a 1-year stop rate of more than 25% is rarely seen.

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Since most patients who actually quit smoking normally have had two or three unsuccessful smoking cessation periods, it is important to keep on motivating patients to try another programme even though they have already failed once or more.

Evidence for the Treatment Effect of Multifactorial Intervention Several treatment modalities in type 2 diabetes mellitus have been described, some apparently more effective than treatment of hyperglycaemia, thus providing a rationale for multifactorial intervention. The Steno 2 Study compared the effect of intensive multifactorial intervention with standard multifactorial intervention. The study population was 160 type 2 diabetic patients with microalbuminuria. 80 of these patients were randomized to intensive multifactorial intervention comprising behaviour modification (diet, exercise, smoking cessation) and polypharmacological therapy targeting several risk factors (hyperglycaemia, hypertension, dyslipidaemia, albumin excretion rate). Patients were followed for a mean of 3.8 years yielding significant risk reductions for both nephropathy (56%), retinopathy (40%), and neuropathy (62%). Extrapolating these risk reductions, the number of patients needed to treat for a 5-year period to prevent one microvascular complication in this high-risk diabetic population was only 4.7. No differences between groups were seen for major cardiovascular events, however follow-up time may have been too short to detect such a difference because of the small size of the two treatment groups. Treatment Approach for Multifactorial Intervention Multifactorial intervention is a mixture of the treatment modalities already described. It is based on the simultaneous treatment of several risk factors. Frequent and thorough examinations are mandatory, since risk factors may interact and change thus requiring a shift in treatment strategy. This is also the case if there is lack of patient compliance, that may be caused by side effects of the different drugs used. Side Effects Since intensive multifactorial intervention requires the use of polypharmacological therapy, it is crucial to inform patients about the risk of side effects. The physician should consider patients’ age, kidney and liver function and contraindications against the different drugs before starting pharmacological treatment. Drug interactions may present as a major problem. A classic example is the masking of hypoglycaemic symptoms with b-blocker


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treatment, but many drugs also cause increased or decreased response to oral hypoglycaemic agents. Patients treated with anticoagulants should be monitored closely when treatment with statins or fibrates, or b-blockers is initiated. Patient compliance decreases with the number of side effects experienced, however informing patients and starting with low doses may diminish this problem.

Suggested Reading Final report on aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989;321: 1825–1828. Frick MH, Elo O, Haapa K, et al: Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987;317:1237–1245. Gæde P, Vedel P, Parving HH, Pedersen O: Intensified multifactorial intervention in patients with type 2 diabetes and microalbuminuria: The Steno Type 2 randomised study. Lancet 1999;353:617–622. Hansson L, Lindholm LH, Niskanen L, et al: Effect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353:611–616. Hansson L, Zanchetti A, Carruthers SG, et al: Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755–1762. Multiple Risk Factor Intervention Trial Research Group: Multiple Risk Factor Intervention Trial: Risk factor changes and mortality results. JAMA 1982;248:1465–1477. Pyo¨ra¨la¨ K, Pedersen TR, Kjekshus J, Færgeman O, Olsson AG, Thorgeirsson G: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care 1997;20:614–620. Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M: Long-term stabilizing effect of angiotensinconverting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type 2 diabetic patients. Ann Intern Med 1993;118:577–581. Sacks FM, Pfeffer MA, Moye LA, et al: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. Tuomilehto J, Rastenyte D, Birkenha¨ger WH, et al: Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340:677–684. UKPDS Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998a;352:837–853. UKPDS Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998b;317:703–713. Yki-Ja¨rvinen H, Nikkila¨ K, Ryysy L, Tulokas T, Vanamo R, Heikkila¨ M: Comparison of bedtime insulin regimens in NIDDM: Metformin prevents insulin-induced weight gain. Diabetologia 1996; 39(suppl 1):A33.

Dr Oluf Pedersen, Steno Diabetes Centre, Niels Steensens Vej 2, DK–2820 Copenhagen (Denmark) Tel. +45 44 43 90 50, Fax +45 44 43 82 32

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Chapter XVIII

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Managing Diabetes and Pregnancy John L. Kitzmiller Maternal-Fetal Medicine, Good Samaritan Hospital, San Jose, Calif., USA

Introduction and Overview of Perinatal Outcome Pregnancy produces major changes in metabolic fuels and hormones and in this way affects the management of diabetes. Basal hepatic glucose production increases significantly with advancing gestation in lean or obese controls, but increased basal insulin secretion and fetal-placental utilization of glucose result in slightly lower fasting blood glucose levels. Fat deposition is accentuated in early pregnancy, but lipolysis is enhanced later in gestation, and more glycerol and free fatty acids (FFA) are released in the postabsorptive state (distant from meals). The increased FFA may contribute to the insulin resistance on glucose utilization by skeletal muscle during pregnancy. Ketogenesis is also accentuated in the postabsorptive state during pregnancy, probably due to increased provision of substrate FFA and hormonal effects on the maternal liver cells. Despite increased first- and second-phase insulin release after a carbohydrate load in normal pregnancy, in the fed state there is a significant reduction in net insulin-mediated glucose disposal by the third trimester. The result is somewhat higher maternal blood glucose levels in nondiabetic subjects, and marked hyperglycemia in inadequately treated pregnant diabetic women. The contra-insulin effects of gestation are related to hPL, progesterone, cortisol, and prolactin, with the defects at the postreceptor level of muscle and hepatic cells. Due to the insulin resistance and enhanced ketogenesis of pregnancy, ketoacidosis is a great danger during gestation. Markedly increased doses of insulin are usually required to control hyperglycemia after the first trimester. Glucagon is well suppressed by glucose during pregnancy, and secretory responses of glucagon to amino acids are not increased above nonpregnant levels.

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Fig. 1. Model of maternal gestational diabetes, fetal hyperinsulinemia, and infant outcome.

If diabetes is poorly controlled in the first weeks of pregnancy, the risks of spontaneous abortion and congenital malformation of the infant are increased considerably. Later in pregnancy, polyhydramnios is also common in women with poorly controlled diabetes and may lead to preterm delivery. Fetal hypoxia may develop in the third trimester if diabetic control has been inadequate. In such cases careful fetal monitoring must be used to prevent stillbirth. Maternal hyperglycemia and fetal hyperinsulinemia are associated with fetal macrosomia and delayed fetal lung maturation and inadequate production of surfactant apoprotein (fig. 1). Fetal macrosomia or large-for-dates (birth weight ?90th percentile for gestational age) increases the potential for traumatic vaginal

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delivery; primary or repeat cesarean deliveries are more common in these cases. Fetal intrauterine growth retardation may occur in diabetic women with vascular disease. Neonatal risks linked to poor maternal glycemic control include respiratory distress syndrome, hypoglycemia, hyperbilirubinemia, hypocalcemia, and poor feeding. Although these problems are usually limited to the first days of life, excess glucose and b-hydroxybutyrate levels in utero have been related to diminished performance on psychomotor testing during childhood development. However, diabetic women have a ?90% chance of delivering a healthy child if they adhere to a program of careful dietary and glucose management.

Gestational Diabetes A subset of pregnant women (2–8% depending on ethnic group, body habitus, and family history for diabetes) develop impaired glucose tolerance with advancing gestation. Gestational diabetes (GDM) results from sluggish first-phase insulin release in lean pregnant women, in addition to excessive resistance to the action of insulin on glucose utilization, which may predate pregnancy. In overweight women with glucose intolerance, insulin sensitivity decreases with advancing gestation more than in overweight pregnant controls, but circulating insulin levels may be increased, although insulin secretion is actually inadequate in relation to the hyperglycemia. Diagnostic strategies for GDM are outlined in table 1. Once the diagnosis has been made, the patient should be placed on a diabetic diet modified for pregnancy: 25–35 kcal/kg ideal weight, 40–55% carbohydrate, 20% protein, and 25–40% fat, and most patients should be taught to count their carbohydrates. Calories are distributed over 3 meals and 3–4 snacks (table 2) and patients are asked to record their daily food intake. The goal of therapy is not weight reduction but prevention of both fasting and postprandial hyperglycemia. If 1- or 2-hour postprandial self-monitored blood glucose (SMBG) values are consistently greater (respectively) than 7.2 or 5.8 mmol/l (130 or 105 mg/dl), therapy is begun with human insulin (new oral agents with limited placental transfer are under study), and the patient is managed as if insulin-dependent. A large proportion of women with GDM will progress to type 2 diabetes (DM) in the 2–20 years after pregnancy. Risk factors for progression include degree of glucose intolerance during and soon after pregnancy, elevated fasting glucose levels, need for insulin therapy during pregnancy, obesity, and choice of contraception. Follow-up studies indicate that 5–15% of nonobese women with GDM will need treatment in 5–20 years, compared to 35–50% of gestational diabetic women with a body weight greater than 120% of ideal. Studies

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Table 1. Screening and diagnosis of gestational diabetes Risk for GDM should be ascertained at the first prenatal visit Low risk: Universal vs. selective screening remains controversial; most diabetes organizations state that blood glucose testing is not normally required if all of the following characteristics are present: Member of an ethnic group with a low prevalence of GDM No known diabetes in first-degree relatives Age =25 years Weight normal before pregnancy No history of abnormal glucose metabolism or poor pregnancy outcome Average risk: Perform BG testing at 24–28 weeks using one of the following: One-step protocol – 75 g, 2 h OGTT on all women: F =5.3 mmol/l (95 mg/dl) 1 h =10 (180) 2 h =8.6 (155) Two-step protocol – 50 g, 1 h plasma glucose on all women; if test done in fed state, threshold ? 7.2 mmol/l (130 mg/dl); if test done in fasting state, threshold ?7.8 mmol/l (140 mg/dl); then 100 g, 3 h OGTT done in fasting state: F =5.3 mmol/l (95 mg/dl) 1 h =10 (180) 2 h =8.6 (155) 3 h =7.8 (140) If one value abnormal, repeat test in 4 weeks High risk: Perform testing as soon as feasible; if negative, repeat at 24–28 weeks Adapted from Summary and Recommendations, 4th International Workshop-Conference on GDM: Diabetes Care 1998:21(suppl 2):B162.

are underway to determine if type 2 DM can be delayed or prevented in these women by regular exercise, dietary control, or insulin enhancers. Patients with GDM should undergo a 75-gram 2-hour glucose tolerance test at 6–10 weeks after delivery to guide future medical management. Diagnostic criteria for nonpregnant individuals are presented in table 3.

Insulin Management The goal of insulin therapy during pregnancy is to prevent both premeal and postprandial hyperglycemia and to avoid debilitating hypoglycemic reactions. Perinatal outcome data indicate that one should aim for premeal plasma glucose levels below 5.6 mmol/l (100 mg/dl) and postprandial levels below 7.2 mmol/l (130 mg/dl). Somewhat higher blood glucose (BG) targets should be selected for type 1 patients with hypoglycemia unawareness. SMBG at home and in the workplace several times daily with glucose oxidase strips and

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Table 2. Individualized nutrition therapy

Name:

Q Initial plan Q Revised plan Q Actual intake

Diagnosis: —————— Status Q Prepregnant Q Pregnant ——— Weeks Q Postpartum Q Lactating

Height: ————— Prepregnant weight: ——— IBW: ——— % IBW: ——— Present weight: —————– Net weight gain: —————

Supplements Prenatal: ————— Calcium: ————— Iron: ——————– Other: ——————

Insulin a.m. ——— p.m. ———

kcal/kg:

physical activity:

Protein ——— g (

Carbohydrate ——— g (

%)

Calories: —————— Date: ———————–

%)

Fat ——— g (

%)

Meal and snack time

Food exchange group

Total

Milk: Type —————

Fruits

Starches Vegetables Protein: Low fat Medium fat High fat Fats Meal/snack totals: CHO, g Protein, g Fat, g Ratio of U regular insulin: g CHO Registered Dietitian: ————————————


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Table 3. Follow-up of GDM after pregnancy Encourage breast-feeding Occasional postprandial BGs after delivery 75 g 2 h OGTT at 6–12 weeks FBG

Normal Impaired glucose regulation Diabetes

2h

mg/dl

mmol/l

mg/dl

mmol/l

=110 110–125 ?125

6.1 6.1–6.9 7.0

=140 7.8 140–199 7.8–11.1 ?199 11.1

Contraception – barrier, Cu 7 IUD, low-dose sequential BCP. Diet and exercise for those with increased abdominal fat. Annual BG test, especially prepregnancy.

colorimeters with memory capacity is essential to help patients and physicians monitor the course of therapy. Sequential measurement of glycosylated hemoglobin (HbA1c) or fructosamine provides other indicators of long-term control. Most pregnant diabetic patients will benefit from one of the insulin regimens in table 4 to prevent fasting and postprandial hyperglycemia. To help avoid the ‘roller coaster’ effect of low and high BG levels, most patients should be taught to self-adjust their doses of short-acting insulin before meals based on premeal BG levels and anticipated carbohydrate intake. Hypoglycemic episodes are more frequent and sometimes more severe at about 10–14 weeks’ gestation, at a time when there is a slight increase in insulin sensitivity and a temporary drop in insulin requirements. However, the risk of hypoglycemia continues throughout pregnancy. Therefore, patients must use timely between-meal and bedtime snacks and type 1 patients must keep glucagon on hand, and a member of the household should be instructed in the technique of injection. Hypoglycemic reactions have not been associated with fetal death or congenital anomalies, but they pose a risk to maternal cerebral function.

Fetal Development and Growth Major congenital anomalies are those which may severely affect the life of the individual or require major surgery for correction. In the absence of intensified preconception care of diabetes, the incidence of major congenital

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Table 4. Examples of insulin dosage regimens Problem

Solution

Isolated fasting BG ?100 mg/dl

12–20 U NPH at bedtime

Increased FBG+prebreakfast ?130 mg/dl

12–20 U NPH at bedtime

FBGs nl, PPBGs ?130 mg/dl

6 U Reg, 20 U N 30 min prebreakfast

All FBGs and PPBGs elevated

60 kg at 0.7 U/kg>42 U/day 10 U Reg, 18 U N prebreakfast (2/3) 7 U Reg, 7 U N predinner (1/3) (double dosage for obesity) or Reg before each meal, N hs

Predinner BG low, prelunch BG high

14 N prebreakfast, 4U Reg predinner

BG =60 at 3 a.m., FBG ?100 mg/dl

Move NPH to bedtime

Problems c timing of injections and meals, high BG 1 h premeals, low BG 3–4 h postmeals

Use Lispro (H) or Aspart or HumalogÓ at half the dose of Reg, 5 min premeal

Strong dawn phenomenon (increased insulin requirement at 4–8 a.m.)

2–6 U Reg at 4 a.m. by algorithm SC insulin pump c increased basal rate

Variable day-to-day response to insulin injections

Do not inject near exercising muscle in arm or leg Be sure CHO intake is consistent Adjust premeal Reg by premeal BG

anomalies in infants of diabetic mothers (IDM) is 6–12%, compared to 2% in infants of a control population or in infants of diabetic mothers with HbA1c near normal at the beginning of pregnancy. This means that primary care physicians treating diabetic women of reproductive age must evaluate them for the possibility of becoming pregnant and inform them of the risks of unplanned pregnancies related to the level of hyperglycemia. Intensified preconception care of diabetes has been shown to reduce the frequency of major congenital anomalies to that of a the nondiabetic population in a cost-effective manner. Ultrasonography in early pregnancy confirms the dating of gestation and may detect neural tube defects that occur with a higher than normal incidence with maternal BGs ?10 mmol/l (180 mg/dl). Later in pregnancy at 18–22 weeks, targeted perinatal sonography and fetal echocardiography can detect congenital heart defects or other severe anomalies. Subsequent examinations at 28 and 37 weeks measure fetal growth and well-being. En-


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larged fetal abdominal circumference is a marker for fetal hyperinsulinemia and excess fat deposition as a result of maternal-fetal hyperglycemia and excess amino acids and lipids. Prevention of maternal hyperglycemia and excess weight gain with dietary and insulin treatment throughout pregnancy produce near normal levels of branch chain amino acids, FFAs, and triglycerides, and reduce the frequency of fetal macrosomia. The glycemic threshold for fetal macrosomia seems to be postprandial peak values above 7.2 mmol/l (130 mg/dl). On the other hand, average peak postprandial BG levels below 6.1 mmol/l (110 mg/dl) may be associated with insufficient fetal growth and small-for-dates infants, who may also have complications in the neonatal period. Another reason for more serious intrauterine growth restriction is maternal vascular disease, especially diabetic nephropathy with hypertension and reduced glomerular filtration. The poor fetal growth is apparently related to inadequate uteroplacental perfusion. All fetal parameters may be below normal on ultrasonographic measurements (but head sparing is common), and oligohydramnios is frequent. With diabetic nephropathy the goals of maternal treatment are control of hyperglycemia and hypertension (=135/85), adequate rest, and limitation of protein intake to 60–80 g/day. Antihypertensive agents which are safe and effective in pregnancy include methyldopa, diltiazem (reduces proteinuria in diabetic patients more than other calcium channel blockers), clonidine, and prazosin. These medications may need to be added in sequence. Use of b-blockers, such as labetolol, should be limited in mid-pregnancy due to a possible association with fetal growth restriction, and angiotensinconverting enzyme inhibitors should never be used in pregnancy due to potential damage to the fetal kidneys.

Complications of Diabetes in Pregnancy Diabetic gastropathy can severely exacerbate nausea and vomiting in early pregnancy. In addition to the standard obstetrical regimens, patients may benefit from drugs such as cisapride and/or reglan, and some will need hyperalimentation. Background diabetic retinopathy (BDR) can develop or worsen during pregnancy, but it is not a risk to vision, since it usually regresses postpartum. If BDR is present in early pregnancy, progression to proliferative diabetic retinopathy (PDR) occurs in 6–9%. Therefore sequential ophthalmologic examinations are required during pregnancy, and laser photocoagulation treatment of the retina may be necessary. Risk factors for progression to PDR include poor glycemic control, rapid improvement in glycemic control in early preg-

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nancy, and hypertension. Minimization of these risks is an important reason to institute careful preconception control of diabetes. The course of diabetic neuropathy is variable during pregnancy and treatment is often relatively ineffective. Agents commonly used may produce neonatal withdrawal symptoms. The risk of worsening of diabetic nephropathy during pregnancy depends on baseline renal function and the degree of hypertension. Total urinary albumin excretion does not increase much in normal pregnancy, but total urinary protein collections, which obstetricians have used to define preeclampsia, may show a twofold increase in uncomplicated gestation. Diabetic women with microalbuminuria (30–299 mg/24 h) may have worsening of the albuminuria during pregnancy with regression postpartum, and 15–45% will develop the preeclamptic syndrome. Based on pooled data from several studies of pregnant diabetic women with a clinical level of proteinuria (24-hour urinary albumin ?300 mg) at the beginning of pregnancy, if initial renal function is preserved (serum creatinine =1.2 mg/dl or =106 lM; creatinine clearance ?80 ml/min with complete collection), then 15–20% are expected to show moderate decline during gestation, and 6% will have renal failure at followup several years after pregnancy. If initial renal function in pregnancy is impaired (Cr ?1.2 mg/dl or ?106 lM; CrCl =80 ml/min with complete collection), then 35–40% are expected to show further decline during pregnancy, and 45–50% will have renal failure at follow-up. Thus, careful preconception counseling is important for these patients and their family members.

Obstetrical Management (table 5) Decades ago the incidence of apparently sudden intrauterine fetal demise in the third trimester of diabetic pregnancies was at least 5%. Since the risk increased as pregnancies approached term, preterm delivery was instituted but the incidence of neonatal deaths from respiratory distress syndrome (RDS) increased. The risk of fetal demise was associated with poor glycemic control, and the incidence of fetal death exceeded 50% with ketoacidosis. Some instances of fetal demise were associated with preeclampsia, which is a common complication of diabetic pregnancy which can produce fetal hypoxia via decreased uteroplacental perfusion. Advances in perinatal medicine have led to techniques for detecting fetal hypoxia and preventing stillbirth. The infrequency of fetal movement as noted in fetal activity determinations (=4/h) may indicate fetal jeopardy, and semiquantitative ultrasonographic studies of fetal activity patterns such as the biophysical profile have proved useful. The primary mode of fetal assessment


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Table 5. Obstetrical management procedures Procedure

Risk based on glycemic control, vascular disease low risk

high risk

Dating ultrasound

8–12 weeks

8–12 weeks

Prenatal genetic diagnosis

As needed

As needed

Targeted perinatal ultrasound; fetal echocardiography

18–22 weeks

18–22 weeks

Fetal kick counts

28 weeks

28 weeks

Ultrasound for fetal growth

28 and 37 weeks1

Monthly

Antepartum FHR monitoring, backup c biophysical profile

36 weeks, weekly

27 weeks, 1–3/week

Amniocentesis for lung maturity

–

35–38 weeks

Induction of labor

41 weeks2

35–38 weeks

1 2

Not needed in normoglycemic, diet-treated women with GDM. Earlier for obstetrical reasons or for impending fetal macrosomia.

is antepartum fetal heart rate (FHR) monitoring. The presence of FHR accelerations and variability on the nonstress test (NST) and the absence of late decelerations persisting after a uterine contraction almost always suggests that the fetus is well oxygenated and has a low risk of demise within several days, unless episodes of severe hyperglycemia or hypertension occur. In the past, insulin-treated patients were usually admitted to the hospital at 36 weeks’ gestation or earlier for fetal monitoring and careful control of diabetes. However, with reliable SMBG, normotensive women without hyperglycemia have no excess risk of fetal hypoxia and do not require antepartum admission to the hospital except for the usual obstetrical complications. Unless maternal or fetal complications arise, the goal for timing of delivery should be 39–41 weeks, in order to reduce neonatal morbidity from preterm deliveries. On the other hand, the obstetrician may wish to induce labor by 37–38 weeks if there is concern about increasing fetal weight. Before a decision to deliver before 39 weeks is made in a patient who has been hyperglycemic in spite of treatment, fetal pulmonary maturity should be determined by amniocentesis. Standard tests of amniotic fluid for pulmonary maturity indicating a low risk for RDS include the lecithin/sphingomyelin (L/S) ratio ?3.0, presence of phosphatidylglycerol (PG), and reflectance polarization tests. Amniocentesis is not necessary in gravidas who have been normoglycemic in the last months of pregnancy, unless delivery is contemplated before 37 weeks’ gestation.

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Table 6. Protocol for intrapartum insulin Infusion1 Intravenous fluids 1. If BG ?7.2 mmol/l (130 mg/dl), infuse mainline LR at 125 ml/h 2. If BG =7.2 mmol/l (130 mg d/L), infuse mainline LR at TKO and begin D5-LR at 125 ml/hr controlled by infusion pump Insulin infusion 1. Mix 25 U regular human insulin (U 100) in 250 cm3 NaCl 0.9% and piggyback to mainline. Concentration is 1 unit/10 cm3. Adjust intravenous insulin hourly according to algorithm when BG is ?3.9 mmol/l (70 mg/dl) 2. Algorithm BG mmol/l (mg/dl)

Insulin, units/h

Infusion, ml/h

=3.9 (70) 3.9–5.0 (71–90) 5.1–6.1 (91–110) 6.2–7.2 (111–130) 7.3–8.3 (131–150) 8.4–9.4 (151–170) 9.5–10.6 (171–190) ?10.6 (190)

0.0 0 0.5 5 1.0 10 2.0 20 3.0 30 4.0 40 5.0 50 call MD and check urine ketones

1 Protocol also useful for diabetic pregnant women who are npo or treated with b-adrenergic tocolytics or corticosteroids; scale may need to be doubled for latter. Boluses of short-acting insulin will be needed to cover meals.

Once fetal lung maturity is likely, the route of delivery is selected based on the usual obstetric indications. If the fetus seems large (?4,200 g) on clinical and ultrasonographic examination, cesarean section probably should be performed because of the possibility of shoulder dystocia and damage from birth trauma. Otherwise, induction of labor is reasonable, because maternal and peripartum risks are fewer following vaginal delivery. Once labor is under way, continuous FHR monitoring should be performed and maternal BG levels should be kept =7.2 mmol/l (110 mg/dl) with an intravenous insulin infusion (table 6) in order to prevent fetal hypoxia and neonatal hypoglycemia.

Management after Pregnancy Breast-feeding should be strongly encouraged for many reasons, including the possibility that its absence or exposure to cow’s milk in the first months of life may increase the risk of development of type 1 diabetes in the offspring.


251

On resuming eating after delivery, the mother’s insulin doses should be reduced to 30–50% of late pregnancy levels in order to avoid hypoglycemia, and then the doses should be gradually titrated according to SMBG levels. Prevention of hyperglycemia above 10 mmol/l (180 mg/dl) should enhance wound healing and reduce the likelihood of bacterial infections. After discharge from hospital, BG targets should be those which have been demonstrated to reduce the development of complications of diabetes. Barrier contraception may be effective, but if oral contraception is used, the choice of agent should be based on studies which demonstrate lack of effect on lipids and glucose tolerance. Diabetic women should be counseled and induced to maintain good glycemic control marked by a near normal glycohemoglobin level in preparation for a subsequent pregnancy, in order to reduce the chance of early fetal wastage or major congenital malformations.

Suggested Reading Chew EY, Mills JL, Metzger BE, Remaly NA, Jovanovic-Peterson L, Knopp RH, Conley M, Rand L, Simpson JH, Holmes LB, Aarons JH: Metabolic control and progression of retinopathy. The Diabetes and Early Pregnancy Study. Diabetes Care 1995;18:631–637. de Veciana M, Major CA, Morgan M, Asrat T, Toohey JS, Lien JM, Evans AT: Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995;33:1237–1241. Kitzmiller JL, Buchanan TA, Kjos S, Combs CA, Ratner RE: Technical review. Pre-conception care of diabetes, congenital malformations, and spontaneous abortions. Diabetes Care 1996;19:514–541. Kitzmiller JL, Combs CA: Diabetic nephropathy and pregnancy. Obstet Gynecol Clin North Am 1996; 23:173–203. Kitzmiller JL, Elixhauser AE, Carr S, Major CA, de Veciana M, Dang-Kilduff L, Weschler JM: Assessment of costs and benefits of management of gestational diabetes. Diabetes Care 1998;21(suppl 2):B123– B130. Kjos SL, Peters RK, Xiang A, Thomas D, Schaefer U, Buchanan TA: Contraception and the risk of type 2 diabetes mellitus in Latina women with prior gestational diabetes. JAMA 1998;280:533–538. Landon MB, Gabbe SG: Fetal surveillance and timing of delivery in pregnancy complicated by diabetes mellitus. Obstet Gynecol Clin North Am 1996;23:109–123. Reece EA, Coustan DR, Sherwin RS, Tuck S, Bates S, O’Connor T, Tamborlane WV: Does intensive glycemic control in diabetic pregnancies result in normalization of other metabolic fuels? Am J Obstet Gynecol 1991;165:126–130. Silverman BL, Rizzo TA, Cho NH, Metzger BE: Long-term effects of the intrauterine environment. Diabetes Care 1998;21(suppl 2):B142–B149.

John L. Kitzmiller, MD, Maternal-Fetal Medicine, Good Samaritan Hospital, San Jose, CA 95124 (USA) Tel. +1 (408) 559 2258, Fax +1 (408) 559 2658, E-Mail [email protected]

Kitzmiller

252

............................

Author Index

Bek, T. 135 Belfiore, F. 1, 3, 20, 38, 72, 90, 103, 111, 174 Boulton, A.J.M. 199, 208

Iannello, S. 3, 20, 38, 56, 72, 90, 103, 111, 174

Cooper, M.E. 125

Malik, R.A. 199 Mogensen, C.E. 1, 152 Molinatti, G.M. 218

Pedersen, O. 229 Shaw, J.E. 208

Kitzmiller, J.L. 241 Tagliabue, M. 218

Gæde, P. 229

Zuanetti, G. 186

253

............................

Subject Index

Acanthosis nigricans, diabetes association 11, 12 Acarbose effects of treatment 99, 100 efficacy 10 a-glucosidase inhibition 99 side effects 100, 101 a-cell, glucose threshold 21 Acetohexamide, characteristics 31 Acetylcholine, insulin secretion regulation 24 Acupuncture, neuropathy treatment 206 Advanced glycation end-products binding sites 126, 127 diabetic nephropathy role 125–128 inhibitors 127, 128 reactions in formation 125, 126 Alcohol, restriction 66 Allergy, insulin therapy reaction 87 Alprostadil, erectile dysfunction treatment 227 Alstro¨m syndrome, diabetes association 12 Aminoguanidine, advanced glycation end-product inhibition 127 Amitriptyline, neuropathy treatment 206 Amylin diabetes therapy 96 physiological actions 95, 96 Anamnesis, erectile dysfunction diagnosis 223, 224

Angioplasty outcomes in diabetes 190, 191 restenosis prevention 195 Angiotensin-converting enzyme inhibitors diabetic nephropathy management 130 heart failure management in diabetes 196 hypertension management with nephropathy 154, 155, 162–170, 237 myocardial infarction management in diabetes 193, 194 retinopathy prevention 142 Apolipoproteins diabetes mellitus abnormalities overview 178 type 1 diabetes 178, 179 type 2 diabetes 179–181 lipid-lowering intervention in diabetes cardiovascular disease effects 181, 182 dietary modification 182 drug therapy fibrates 182–184 statins 182–184 guidelines for treatment 182, 184 normal metabolism 174–178 Aspartame, safety 68 Aspirin myocardial infarction management in diabetes 192, 193 prevention trials in diabetes 237, 238 Ataxia telangiectasia, diabetes association 12

254

b-blockers heart failure management in diabetes 196 hypertension management in diabetes 162, 163 myocardial infarction management in diabetes 193 Blood flow, insulin resistance role 49, 50 Blood pressure, see Hypertension Body mass index fat distribution and health risks 57, 58 ideal values 57 b-cell, glucose threshold 21 Calcium channel blockers hypertension management in diabetes 54, 162, 163 myocardial infarction management in diabetes 194 Caloric intake, see Diet Capsaicin, neuropathy treatment 206 Carbamazepine, neuropathy treatment 206 Carbohydrate, dietary 59–62 Cardiovascular disease acronyms for diabetes studies 187 aspirin prevention trials in diabetes 237, 238 clinical manifestations in diabetes angioplasty and bypass grafting outcomes 190, 191 heart failure 191 myocardial infarction 188, 189 unstable angina 190 diabetes risks 186 heart failure management in diabetes angiotensin-converting enzyme inhibitors 196 b-blockers 196 lipid-lowering intervention effects in diabetes 181, 182 multifactorial treatment approach 229 myocardial infarction management in diabetes angiotensin-converting enzyme inhibitors 193, 194

Subject Index

aspirin 192, 193 b-blockers 193 calcium channel blockers 194 fibrinolytic agents 192 insulin-glucose infusion 191, 192 platelet inhibitors 193 statins 194 myocardial ischemia treatment in diabetes 194, 195 natural history in diabetes 188 pathophysiology in diabetes 186, 188 prognosis in diabetes 196, 197 restenosis prevention following angioplasty or bypass surgery 195 Cataract, diabetic 135 Charcot neuroarthropathy, see Foot problems, diabetes Cholecystokinin, insulin secretion regulation 24 Cholesterol, dietary 62, 63 Clorpropamide, characteristics 30, 31 Coronary artery bypass grafting outcomes in diabetes 190, 191 restenosis prevention 195 Desipramine, neuropathy treatment 206 Diabetes Control and Complication Trial, outcomes of hyperglycemia control 90, 91 Diabetes type 1, see Type 1 diabetes Diabetes type 2, see Type 2 diabetes Diabetic foot, see Foot problems, diabetes Diabetic gastropathy, gestational diabetes mellitus 248 Diabetic ketoacidosis clinical presentation 104 complications 106 diagnosis 106, 107 hormone roles 103 laboratory data 105, 106 mortality 106 pathophysiology 103, 104 treatment antibiotics 108 bicarbonate 108 insulin 107 potassium 108

255

Diabetic nephropathy control and diabetes progression 236, 237 dietary protein effects 157 ethnic differences 154, 155 genetic predisposition 153 gestational diabetes mellitus 249 hypertension arterial disease 161, 162 glomerular filtration rate fall in type 1 diabetes 158–160 kidney damage role and indicator 153, 154, 156, 157, 160 microalbuminuria 157, 158, 171 pathogenesis 162 sodium retention 161 treatment angiotensin-converting enzyme inhibitor management 154, 155, 162–170, 237 diet 168, 172 guidelines 169–171 microalbuminuria patients 165, 166, 237 normoalbuminuria 164, 165 overt diabetic nephropathy patients 167, 168 United Kingdom Prospective Diabetes Study outcomes 91, 92, 169 incidence 154 metabolic control in prevention 155, 156 pathogenesis advanced glycation end-products and tissue injury 125–127 endothelin 131 extracellular matrix accumulation 131, 132 degradation 133 growth factors 132, 133 hemodynamic factors 129 interactions between hemodynamic and metabolic factors 133 nitric oxide synthase 131 overview 125, 126 polyol pathway metabolism 128 protein kinase C activation 128, 129 renin-angiotensin system 129, 130 transforming growth factor-b 132

Subject Index

Diabetic neuropathy classification 200 clinical features autonomic neuropathies 202 cranial mononeuropathies 201 diabetic amyotrophy 202 isolated and multiple mononeuropathies 201 peripheral sensory neuropathies 202, 203 truncal mononeuropathy 201 definition 199, 200 diagnosis 204, 205 epidemiology 200, 201 foot, see Foot problems, diabetes gestational diabetes mellitus 249 natural history 199 screening 204 treatment drugs 206, 207 stage-specific management 205, 206 Diabetic retinopathy blindness incidence 135 clinical appearance diabetic maculopathy 140, 141 early changes 136 proliferative diabetic retinopathy 137–139 diagnosis fluorescein angiography 145, 146 optical coherence tomography 146 ultrasound 147 epidemiology 141 gestational diabetes mellitus 142, 248, 249 nomenclature 136 prevention 141, 142, 151 psychosocial aspects 150 screening costs 145 interval for screening 145 ocular background examination 143, 144 organization of screening programs 144, 145 rationale 142 visual acuity testing 144

256

treatment retinal photocoagulation exudative diabetic maculopathy 148, 149 indications 146, 147 neovascular glaucoma 149 principle 147 proliferative diabetic retinopathy 147, 148 vitrectomy 149 Diet alcohol 66 caloric requirements 58–60 caloric restriction in obese type 2 diabetes diet components 68, 69 effects 56, 57 carbohydrate 59–62 compliance 70 dyslipidemia treatment 236 exercise prescription 69 fat 62, 63 fiber 64–66 gestational diabetes mellitus management 243 goals of therapy 56 hyperglycemia control benefits 230 protein 63, 64 sodium 66 sweeteners 66–68 Doxazosin, erectile dysfunction treatment 225, 226 Dyslipidemia, see also Apolipoproteins, High-density lipoprotein, Low-density lipoprotein, Very low-density lipoprotein control and diabetes progression 235, 236 treatment diet 236 exercise 236 fibrates 236 statins 236 Edema, insulin therapy reaction 85 Endothelin, diabetic nephropathy role 131 Epinephrine, insulin secretion regulation 24 Erectile dysfunction diagnosis 223–225

Subject Index

epidemiology in diabetes 218–220 etiopathogenesis in diabetes endothelial alterations 222 hormonal alterations 222, 223 impaired glucose metabolism 221 neurological alterations 222 overview 220 psychological factors 220, 221 vascular alterations 221 spermatogenesis alterations in diabetes 223 treatment alprostadil 227 doxazosin 225, 226 external mechanical support 227, 228 intracavernosal injection 227 nitroglycerin 226 penile prosthesis 228 psychotherapy 225 revascularization surgery 228 sildenafil 226, 227 yohimbine 225, 226 Exercise dyslipidemia treatment 236 hyperglycemia control benefits 230 insulin therapy effects 78 prescription with dietary program 69 Fasting plasma glucose diabetes diagnosis 14, 15, 19 reliability 16 Fat, dietary 62, 63, 182 Fiber, dietary 64–66 Fibrates dyslipidemia treatment 236 lipid-lowering intervention 182–184 Fibrocalculous pancreatopathy, diabetes association 12 Foot problems, diabetes Charcot neuroarthropathy 215, 216 neuropathy, see also Diabetic neuropathy autonomic neuropathy 210 somatic neuropathy 209, 210 overview 208 peripheral vascular disease 208, 209

257

Foot problems, diabetes (continued) ulcers behavioral/psychological factors 212 biomechanical aspects 210, 211 cardiovascular factors 212 education of patients 213, 214, 216 ethnic differences 211, 212 glycemic control and prevention 211 infection 214 management 213–215 microcirculation and endothelial dysfunction 212, 213 prevention 213 recurrence 211 retinopathy and nephropathy association 211 wound healing 212 Free fatty acid gestational diabetes mellitus pathogenesis role 241 insulin secretion regulation 22, 28 metabolism in insulin resistance 46–48 Fructosamine, insulin therapy monitoring 84 Fructose, dietary 67

obstetrical management 249–251 post-pregnancy 251, 252 neonatal risks 243 pathogenesis 241 prevalence 12 Glibenclamide, characteristics 31 Gliclazide, characteristics 31 Glipizide, characteristics 31 Gliquidone, characteristics 31, 32 Glucagon, insulin secretion regulation 24, 25 Glucagon-like peptide-1 insulin secretion regulation 24, 28, 36 therapeutic application 36 Glucokinase glucose sensing 21, 22 MODY-2 mutations 10, 11, 22 Glucose insulin secretion regulation 20–22 metabolism in type 2 diabetes 46–48 Glyburide, characteristics 31 Glycated hemoglobin, see HBA1c Glycemic index, foods 61 Glycosuria, monitoring of diabetic control 18

Gabapentin, neuropathy treatment 206 Gastric inhibitory polypeptide, insulin secretion regulation 24 Gestational diabetes mellitus complications gastropathy 248 nephropathy 249 neuropathy 249 overview 12, 13, 242 retinopathy 142, 248, 249 diabetes progression following pregnancy 243, 244 diagnosis 15, 19, 243, 244 fetal effects congenital anomalies 246–248 demise 249 fetal macrosomia 248 intrauterine growth restriction 248 management diet 243 insulin therapy 244, 246, 252

HBA1c insulin therapy monitoring 84 monitoring of metabolic control 18 Heart failure diabetes association and presentation 191 management in diabetes angiotensin-converting enzyme inhibitors 196 b-blockers 196 Hemoglobin, glycated, see HBA1c High-density lipoprotein diabetes mellitus abnormalities overview 178 type 1 diabetes 178, 179 type 2 diabetes 179–181 lipid-lowering intervention in diabetes cardiovascular disease effects 181, 182 dietary modification 182 drug therapy fibrates 182–184 statins 182–184

Subject Index

258

guidelines for treatment 182, 184 normal metabolism 174–178 HMG-CoA reductase inhibitors, lipid-lowering intervention 182–184 Hyperbaric oxygen therapy, foot ulcer treatment 215 Hyperglycemia control and diabetes progression 1, 229–232 treatment diet 230 exercise 230 insulin 231 metformin 230, 231 sulfonylureas 230, 231 type 1 diabetes pathophysiology 6, 7 Hyperosmolar nonketotic syndrome clinical presentation 108 laboratory findings 109 mortality 108 pathophysiology 109 treatment 109, 110 Hypertension comparison between diabetes types 152 control and diabetes progression 232, 233, 235 diabetic nephropathy patients arterial disease 161, 162 glomerular filtration rate fall in type 1 diabetes 158–160 kidney damage role and indicator 153, 154, 156, 157, 160 microalbuminuria 157, 158, 171 pathogenesis 162 sodium retention 161 treatment angiotensin-converting enzyme inhibitor management 154, 155, 162–170 diet 168, 172 guidelines 169–171 microalbuminuria patients 165, 166 normoalbuminuria 164, 165 overt diabetic nephropathy patients 167, 168 United Kingdom Prospective Diabetes Study outcomes 91, 92, 169

Subject Index

treatment angiotensin-converting enzyme inhibitors 162–164 b-blockers 162, 163 calcium channel blockers 162, 163 diuretics 162, 163 glycemic control in treatment 164 Hypoglycemia classification causes of hypoglycemia 113 fasting hypoglycemia factitious hypoglycemia 115 increased glucose utilization 114, 115 reduced glucose production 113, 114 postprandial hypoglycemia, forms 115, 116 clinical manifestations adrenergic symptoms 117 neuroglycopenic symptoms 117, 118 overview 116, 117 definition 111 diagnosis 111, 119–121 glucose counterregulation and hormones 112, 113 infants 111 insulin induction 118, 119 sulfonylurea induction 118, 119 treatment diabetic patients 121, 122 insulinoma and extrapancreatic tumor patients 123 intolerance patients 123, 124 prevention 123, 124 Imipramine, neuropathy treatment 206 Impaired glucose tolerance, conversion to diabetes 15 Insulin dose-response curve 39 metabolic effects, overview 40, 41, 43 secretion process 20 secretion regulation acetylcholine 24 cholecystokinin 24 epinephrine 24 free fatty acids 22, 28 gastric inhibitory polypeptide 24

259

Insulin, secretion regulation (continued) glucagon 24, 25 glucagon-like peptide-1 24, 28, 36 glucose 20–22 leptin 25 neuropeptide Y 24 norepinephrine 24 vasoactive intestinal polypeptide 24 sulfonylurea effects on secretion acute effects 32, 33 chronic effects 33 testing acute insulin response glucose 25 non-glucose stimuli 25, 26 fasting insulin level 25 type 2 diabetes 26, 27 Insulin receptor defects in insulin resistance 44 density 38, 39 fate of ligand complexes 39, 40 isoforms 40 phosphorylation 40, 44 structure 38 Insulin resistance drug therapy metformin 51–53 thiazolidinediones 53, 54 trandolapril 54 verapamil 54 sites of resistance 43 syndrome of immunologic insulin resistance 86, 87 type 1 diabetes 50 type 2 diabetes blood flow role 49, 50 counterregulatory hormones 48 free fatty acid, glucose metabolism 46–48 genetic factors 46 insulin receptor defects 44 leptin role 49 metabolic steps resistant to insulin 45 tumor necrosis factor-a role 48, 49, 55 Insulin therapy altered response conditions 87, 88

Subject Index

complications allergy 87 edema 85 lipoatrophy 85, 86 lipohypertrophy 86 syndrome of immunologic insulin resistance 86, 87 education of patients 88 factors influencing concentration or bioavailability administration routes and injection site 76, 77 antibodies 78 degradation 78 dose and concentration 76 exercise and stress 78 injection depth and massage 77, 78 mixtures of insulin 76 pharmacokinetics 76 storage of preparations 78 gestational diabetes mellitus management 244, 246, 252 hyperglycemia control benefits 231 hypoglycemia induction 118, 119 indications 72, 73 insulin characteristics analogs 74, 75 concentration of preparations 75 duration of action 73, 74 purity 73 types 72, 73 monitoring fructosamine 84 HBA1c 84 self-monitoring blood glucose 84 urine tests 83 regimens continuous subcutaneous insulin infusion 82, 83 multiple daily injection 80–82 single daily injection 79, 80 twice daily injection 80 requirements and dose 78, 79 sulfonylurea combination therapy 94 Insulin-dependent diabetes mellitus, see Type 1 diabetes

260

Insulin-like growth factor I, diabetes therapy 101 Intrauterine growth restriction, diabetes 248 Intravenous glucose tolerance test, diabetes diagnosis 18, 27 Islet transplantation, type 1 diabetes 99 Ketoacidosis, see Diabetic ketoacidosis Leprechaunism syndrome, diabetes association 12 Leptin insulin resistance role 49 insulin secretion regulation 25 Lipoatrophy, insulin therapy reaction 85, 86 Lipodystrophy, diabetes association 12 Lipohypertrophy, insulin therapy reaction 86 Low-density lipoprotein diabetes mellitus abnormalities overview 178 type 1 diabetes 178, 179 type 2 diabetes 179–181 lipid-lowering intervention in diabetes cardiovascular disease effects 181, 182 dietary modification 182 drug therapy fibrates 182–184 statins 182–184 guidelines for treatment 182, 184 normal metabolism 174–178 Macrosomia, fetal 248 Maggot therapy, foot ulcer treatment 215 Maturity-onset diabetes of the young clinical presentation 10, 11 prevalence 10 types and genes familial hyperinsulinemia 11 MODY-1 10 MODY-2 10, 11, 22 MODY-3 11 Metformin dose 53 hyperglycemia control benefits 230, 231 insulin resistance treatment 51–53 pharmacology 51, 52

Subject Index

side effects 52, 53 sulfonylurea combination therapy 94 Microalbuminuria, see Diabetic nephropathy Miglitol, diabetes therapy 99 Multifactorial intervention, diabetes side effects 239, 240 treatment approach and effects 239 Myocardial infarction diabetes association and presentation 188, 189 management in diabetes angiotensin-converting enzyme inhibitors 193, 194 aspirin 192, 193 b-blockers 193 calcium channel blockers 194 fibrinolytic agents 192 insulin-glucose infusion 191, 192 platelet inhibitors 193 statins 194 Myocardial ischemia, treatment in diabetes 194, 195 Nephropathy, see Diabetic nephropathy Neuropathy, see Diabetic neuropathy Neuropeptide Y, insulin secretion regulation 24 Nicotinamide, diabetes therapy 101 Nitric oxide synthase, diabetic nephropathy role 131 Nitroglycerin, erectile dysfunction treatment 226 Noninsulin-dependent diabetes mellitus, see Type 2 diabetes Norepinephrine, insulin secretion regulation 24 Oral glucose tolerance test diabetes diagnosis 14, 15, 26, 27 indications 16 insulin determinations 18 reliability 16 variables affecting results age 17 blood collection site 16 diet 17 glucose dose and concentration 17

261

Oral glucose tolerance test, variables affecting results (continued) glycemia determination method 17 illness 17 physical activity 17 timing of samples 17 whole blood vs plasma or serum 16, 17 Orlistat, obese diabetes treatment 95 Pancreas transplantation, type 1 diabetes 98, 99 PC-1, insulin resistance role 44 Pineal hypertrophy syndrome, diabetes association 12 Platelet inhibitors, myocardial infarction management in diabetes 193 Platelet-derived growth factor, foot ulcer treatment 215 Pramlintide diabetes therapy 96 physiological actions 95, 96 Protein, dietary 63, 64, 157, 168 Protein kinase C, diabetic nephropathy role 128, 129 Rabson-Mendenhall syndrome, diabetes association 12 Renin-angiotensin system, diabetic nephropathy role 129, 130 Repaglinide, insulin secretion effects 35, 36, 94 Retinal photocoagulation exudative diabetic maculopathy 148, 149 indications 146, 147 neovascular glaucoma 149 principle 147 proliferative diabetic retinopathy 147, 148 Retinopathy, see Diabetic retinopathy Rosiglitazone, insulin resistance therapy 54 Saccharin, safety 67, 68 Sildenafil, erectile dysfunction treatment 226, 227 Smoking, cessation effects in diabetes 238, 239 Sodium, dietary restriction 66 Somatostatin, diabetes therapy 95

Subject Index

Statins dyslipidemia treatment 236 lipid-lowering intervention 182–184 myocardial infarction management in diabetes 194 Sulfonylureas, see also specific drugs combination therapy insulin 94 metformin 94 doses 30 efficacy and interactions 32 extrapancreatic effects 34 failure primary 93 secondary 93, 94 first-generation drugs 30, 31 history of development 29, 30 hyperglycemia control benefits 230, 231 hypoglycemia induction 118, 119 indications and contraindications 29 insulin secretion effects acute 32, 33 chronic 33 proinsulin synthesis effects 34 second-generation drugs 31, 32 side effects 35 Sweeteners, diabetic diet 66–68 Thiazolidinediones, insulin resistance therapy 53, 54, 95 Tolazamide, characteristics 30 Tramadol, neuropathy treatment 206 Trandolapril, insulin resistance therapy 54 Transforming growth factor-b, diabetic nephropathy role 132 Tumor necrosis factor-b, insulin resistance role 48, 49, 55 Type 1 diabetes classification and diagnostic groups 3, 4, 13, 14 diagnosis 18, 19 idiopathic disease 6 immune-mediated disease autoimmune pathogenesis 5, 6 clinical presentation 6 cow’s milk role 5

262

genetic predisposition and candidate genes 4, 5 prevalence 4 viral infection role 5 insulin resistance 50 pathophysiology 6, 7 treatment, see also Insulin therapy autoantigen therapy 98 gene therapy 98 immunoregulatory therapy 97 immunosuppression therapy 98 islet transplantation 99 pancreas transplantation 98, 99 Type 2 diabetes, see also Gestational diabetes mellitus, Maturity-onset diabetes of the young classification and diagnostic groups 3, 4, 13, 14 complications 9 diagnosis 19, 26, 27 diet modification, see Diet genetic predisposition 9, 27 glucotoxicity concept 28 hyperglycemia control 9 insulin resistance blood flow role 49, 50 counterregulatory hormones 48 free fatty acid and glucose metabolism 46–48 genetic factors 46 insulin receptor defects 44 leptin role 49 metabolic steps resistant to insulin 45 tumor necrosis factor-a role 48, 49, 55 insulin secretion causes of defect 27, 28

Subject Index

characteristics 26, 27 pathophysiology 9, 10 pharmacotherapy indications 92, 93 Ulcer, see Foot problems, diabetes United Kingdom Prospective Diabetes Study, outcomes of hyperglycemia and blood pressure control 91, 92, 169, 229–231 Unstable angina, diabetes association and presentation 190 Vasoactive intestinal polypeptide, insulin secretion regulation 24 Verapamil, insulin resistance therapy 54 Very low-density lipoprotein diabetes mellitus abnormalities overview 178 type 1 diabetes 178, 179 type 2 diabetes 179–181 lipid-lowering intervention in diabetes cardiovascular disease effects 181, 182 dietary modification 182 drug therapy fibrates 182–184 statins 182–184 guidelines for treatment 182, 184 normal metabolism 174–178 Viagra, see Sildenafil Vitrectomy, retinopathy treatment 149 Waist-to-hip ratio, cardiovascular risk 58 Werner’s syndrome, diabetes association 12 Yohimbine, erectile dysfunction treatment 225, 226

263

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Obesity and Diabetes (Practical Diabetes)

Obesity and Diabetes (Contemporary Diabetes)

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Patient Treatment Adherence: Concepts, Interventions, And Measurement

Diabetes and Exercise (Contemporary Diabetes)

Cannabis Dependence: Its Nature, Consequences and Treatment

Understanding Grief: Its Roots, Dynamics, and Treatment

Gastrointestinal Function in Diabetes Mellitus (Practical Diabetes)

Psychology in Diabetes Care (Practical Diabetes)

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Diabetes in Women: Pathophysiology and Therapy (Contemporary Diabetes)

Type 1 Diabetes - Etiology and Treatment (Contemporary Endocrinology)

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Diabetes and the Brain (Contemporary Diabetes)

Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics: Strabismus - New Concepts in Pathophysiology, Diagnosis, and Treatment

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Psychology in Diabetes Care

Clinical Challenges in Diabetes

New concepts in diabetes and its treatment

New Concepts in Renovating

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Unstable and Brittle Diabetes (Advances in Diabetes)

Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment

Obesity and Diabetes (Practical Diabetes)

Obesity and Diabetes (Contemporary Diabetes)

New Concepts in Cerebral Ischemia

Continence: Current Concepts and Treatment Strategies

Patient Treatment Adherence: Concepts, Interventions, And Measurement

Diabetes and Exercise (Contemporary Diabetes)

Cannabis Dependence: Its Nature, Consequences and Treatment

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Gastrointestinal Function in Diabetes Mellitus (Practical Diabetes)

Psychology in Diabetes Care (Practical Diabetes)

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Diabetes in Women: Pathophysiology and Therapy (Contemporary Diabetes)

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Obesity and Diabetes, 2nd edition (Practical Diabetes)

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Diabetes in America

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