International Journal of Diabetes Mellitus, December 2010

International Journal of Diabetes Mellitus 2 (2010) 139–140

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International Journal of Diabetes Mellitus journal homepage: www.elsevier.com/locate/ijdm

Editorial

Raising the priority accorded to diabetes in global health and development: A promising response. . . On 13 May 2010, the United Nations General Assembly (UNGA) passed a resolution A/RES/64/265 on non-communicable diseases (NCDs). This step is of historic significance in global health and development, as the resolution recognizes the enormous human suffering, premature death and the seriously negative socioeconomic impact caused by NCDs [1]. These diseases, mainly diabetes, cardiovascular diseases, cancers and chronic lung diseases are emerging as a major threat to global development. Their magnitude is rapidly increasing, because of population ageing, unplanned urbanization and globalization of trade and marketing. These preventable problems, largely caused by unhealthy diet, physical inactivity, being overweight and obese, tobacco use and the harmful use of alcohol, are now causing an estimated 36 million deaths every year, including 9 million people dying prematurely before the age of 60 years [2]. Their major impact is on developing populations. Around 90% of deaths before the age of 60 occur in developing countries and economies in transition, in particular among the poorest and the most vulnerable people. NCDs are currently the second leading cause of death for women in low-income countries, and the leading causes of death for women in middle-income countries. Twice as many women die (per 1000 adults) from non-communicable diseases in Africa as in high-income countries [3]. Diabetes and other NCDs, which share the same risk factors, are a development issue because of the loss of household income from unhealthy behavior, from loss of productivity due to disease, disability and premature death, and from the high cost of health care which drives families below the poverty line. Additionally, the level of exposure of people in developing countries to unhealthy diets, physical inactivity, tobacco use and the harmful use of alcohol is higher than in high-income countries where a higher proportion of the population tends to be protected by comprehensive interventions aiming to promote healthier behavior. Also, affordable and accessible primary health care services for early detection, effective treatment and prevention of complications are often inadequate in developing countries [4]. NCDs and their risk factors are also closely related to poverty, and contribute to poverty at the household level. Studies in developing countries demonstrate how health care for a family member with diabetes can consume a considerable proportion of household income, and how treatment of heart disease and other cardiovascular complications greatly increases the likelihood of falling into poverty in developing countries, and due to ‘‘catastrophic” out of pocket expenditure and loss of income from ill-health [4]. NCDs are reported by the World Economic Forum to be a leading macroeconomic risk at a global level [5].

There is also evidence that diabetes and other NCDs are undermining the attainment of the Millennium Development Goals (MDGs). The links between smoking, diabetes and tuberculosis, the rising prevalence of high blood pressure and diabetes, and the increased exposure to NCD risk factors among women of child-bearing age in developing counties have direct consequences in terms of maternal health complications, pregnancy outcomes and child survival [6,7]. As a result, the 63rd World Health Assembly urged Member States, international development partners and WHO, in a resolution on health-related Millennium Development Goals, to recognize the growing burden of NCDs [8]. Demographic and epidemiological transitions, together with unplanned urbanization and globalization, have brought about a deadly interplay between infectious diseases and NCDs like diabetes. Both are major challenges in many developing countries, and both need to be effectively addressed. This interplay must no longer remain nameless and faceless: it represents the health risks and disease profile of the twenty-first century, and it is emerging as a major socioeconomic risk. Addressing this phenomenon, from a health point view requires a more integrated and effective approach to prevention and treatment – one that is based upon strengthening health systems, rather than only peering through the keyhole of one specific disease or another. From the broader development perspective, preventing and minimizing the adverse socioeconomic impact requires the active engagement of all government sectors, the industry and civil society in reducing the level of diabetes risk factors and determinants. Many more gains can be achieved by influencing the policies of non-health sectors like finance, industry, trade, urban development and education than by changes in health policies alone. The challenge can be effectively addressed [9]. There is a sound global vision and a clear road map for global and national action. The vision is represented by the Global Strategy for the Prevention and Control of NCDs, which was endorsed by the World Health Assembly in 2000 [10]. The road map is guided by its six-year Action plan, which was developed with Member States and endorsed by the Assembly in 2008. The Action Plan has six objectives, with clear sets of actions under each objective for countries, the WHO and international partners. The World Health Assembly also endorsed specific global strategies and tools to reduce the exposure to the four key risk factors, such as the WHO Framework Convention on Tobacco Control, the Global Strategy on Diet, Physical Activity and Health, and the Global Strategy to Reduce the Harmful Use of Alcohol. Objective one of the Action Plan for Global Strategy specifically focuses on integrating the prevention of diabetes and other NCDs into the global development agendas and related national

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Editorial / International Journal of Diabetes Mellitus 2 (2010) 139–140

initiatives. To support the implementation of this objective, evidence linking NCDs to socioeconomic development has been examined and discussed in several key events organized over the last two years, in close collaboration with Member States, the United Nations Department of Economic and Social Affairs (UNDESA) and relevant United Nations Regional Commissions. Proposals for addressing the NCDs burden and its developmental challenges were made in Ministerial consultations and the Meeting of the High-level Segment of the UN Economic and Social Council in July 2009. These have made a significant contribution to the consultations of countries that have led to the recent UNGA resolution. The UNGA resolution is a major political event in the struggle against diabetes and other NCDs, and places them at the center of socioeconomic development. The resolution calls for a Highlevel Meeting of the United Nations General Assembly in September 2011 with the participation of Heads of State and Government to address the prevention and control of NCDs. Establishing a global forum on the prevention of diabetes and other NCDs emphasizes the underlying social and environmental drivers of these health problems and their implications for poverty. It is also a clear recognition of the threat that NCDs pose to the economies of countries, leading to increasing inequalities between countries and populations, thereby threatening the achievement of internationally agreed development goals, including the Millennium Development Goals. There is no doubt that the UNGA resolution has already made a major contribution to increasing the awareness of the need for global coordinated action to prevent diabetes and other NCDs, and there is now great hope that the High-level Meeting will focus on galvanizing action at global and national levels, so as to halt and address the health and socio-economic impact of diabetes and other NCDs through multi-sectoral approaches. However, the success of the Meeting will depend on the contribution that countries, the diabetes and NCDs community and other stakeholders will make in supporting the UN discussions over the coming months, and in providing technical guidance on challenges like

integrating the surveillance of NCDs into national information systems, successful mechanisms and approaches for engaging nonhealth sectors in prevention initiatives and in strengthening health systems to deliver more effective care. References [1] United Nations General Assembly. Resolution 64/265. Prevention and control of noncommunicable diseases; 2010. [2] World Health Organization. Global burden of disease 2004 update. <www.who.int/healthinfo/global_burden_disease/2004_report_update>. [3] World Health Organization. Women and health: today’s evidence, tomorrow’s evidence. . [4] World Health Organization. Discussion paper: noncommunicable diseases, poverty and the development agenda (July 2009) ECOSOC high-level segment; 2009. . [5] World Economic Forum. Global risks 2010. A global risk network report; 2010. . [6] Gajalakshmi V, et al. Smoking and mortality from tuberculosis and other diseases in India. Retrospective study of 43,000 adult male deaths and 35,000 controls. Lancet 2003. [7] World Health Organization. Equity, social determinants and public health programmes. WHO; 2010. [8] World Health Organization. Resolution WHA63.15 monitoring of the achievement of the health-related Millennium Development Goals. WHO; 2010. [9] Gaziano TA, Galea G, Reddy KS. Scaling up interventions for chronic disease prevention: the evidence. Lancet 2007;370:1939–46. [10] World Health Organization. Resolution WHA53.17. Prevention and control of noncommunicable diseases. WHO; 2000.

Ala Alwan Assistant Director General, World Health Organization, Geneva, Switzerland E-mail address: [email protected]

International Journal of Diabetes Mellitus 2 (2010) 141–143

Contents lists available at ScienceDirect

International Journal of Diabetes Mellitus journal homepage: www.elsevier.com/locate/ijdm

Original Article

Free radical activity in hypertensive type 2 diabetic patients Suvarna Prasad ⇑, Ajay Kumar Sinha Department of Biochemistry, M. M. Institute of Medical Sciences & Reasearch, Mullana, Ambala, Haryana, India

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Article history: Received 24 July 2010 Accepted 4 October 2010 Keywords: Superoxide dismutase Nitric oxide Malondialdehyde Type 2 diabetes mellitus Hypertension

a b s t r a c t Background: Free radical activity is an important cause of vascular complications in type 1 diabetes mellitus. But data regarding vascular complications in type 2 diabetes mellitus are scant. Objectives: The aim of this study was to examine free radical activity in type 2 diabetic patients with hypertension compared to those without hypertension. Materials and Methods: The serum levels of lipid peroxidation product, MDA malondialdehyde), the free radical scavenger, SOD (superoxide dismutase) and NO (nitric oxide) were studied in 50 type 2 diabetic outpatients. Controls were regarded as those diabetic outpatients who did not have hypertension. Result: Among 50 patients thus studied 19 were hypertensive. The concentration (median (range)) of both SOD (21.31(5.33–26.64) vs. 16.65(6.66–22.64) U/dl; p < 0.05) and NO (18.54 (11.40–37.07) vs. 21.39(15.69–35.65) U/dl; p < 0.05) were reduced in the hypertensive group. Similarly, concentration (median (range) of MDA (359(231–718) vs. 385(256–666) lmoles/dl; p < 0.01 were increased in the hypertensive group. Conclusion: The reduction in serum levels of SOD and NO with a concomitant increase in serum MDA levels is consistent with an increase in free radical activity in hypertensive type 2 diabetics. Ó 2010 International Journal of Diabetes Mellitus. Published by Elsevier Ltd. All rights reserved.

1. Introduction Free radical activity has been implicated in the development of diabetic vascular complications in type 1 diabetes mellitus. It plays an important role in both microvascular and macrovascular complications in diabetes mellitus. However, data regarding vascular complications in type 2 diabetes mellitus are scant. Cardiovascular diseases (CVD) are the major causes of mortality in persons with diabetes, and many factors including hypertension contribute to this high prevalence of CVD. Hypertension is twice as frequent in patients with diabetes compared with patients without the disease. Furthermore, up to 75% of CVD in diabetes may be attributable to hypertension, leading to recommendations for more aggressive treatment for those having hypertension in this disease [1]. Long-term complications of diabetes are supposed to be, at least in part, mediated by increased free radical generation and subsequent oxidative stress. In this study, we have attempted to summarize the experimental evidence in this field, and to emphasize the possible importance of oxidative stress in the development of diabetic vascular complications. Free radicals may be defined as any chemical species that contains unpaired electrons. Unpaired electrons increase the chemical ⇑ Corresponding author. Address: House No. E-54, GH-94, SEC-20, Panchkula, Haryana 134112, India. Tel.: +91 9872174466, +91 9257206509. E-mail address: [email protected] (S. Prasad).

reactivity of an atom or a molecule. Common examples of free radicals include the hydroxyl radical (0H), super oxide anion (02 ), transition metals, such as iron (Fe), copper (Cu), nitric oxide (NO) and peroxynitrite (OONO) [2]. Free radicals and reactive nonradical species derived from radicals exist in biological cells and tissues at very low concentrations [3,4]. Halliwell and Gutteridge [3] have defined antioxidants as substances that are able, at relatively low concentrations, to compete with other oxidizable substrates, and thus, to significantly delay or inhibit the oxidation of these substrates. This definition includes the enzymes SOD, glutathione peroxidase (GPx) and catalase, as well as nonenzymatic compounds such as tocopherol (vitamin E), b-carotene, ascorbic acid (vitamin C), and glutathione, which scavenge the reactive oxygen species. 2. Materials and methods The aim of this study was to investigate whether the serum levels of lipid peroxidation product, malondialdehyde (MDA), serum superoxide dismutase (SOD) and serum nitric oxide (NO) were altered in normotensive type 2 diabetic patients and type 2 diabetic patients who subsequently developed hypertension. We selected 50 type 2 diabetic patients. 19 of these type 2 diabetic patients had subsequently developed hypertension. The criteria for hypertension were a mean arterial pressure of greater than the upper range of accepted normal pressure, and a mean arterial pressure of greater than 110 mm of Hg (normal is 90 mm of Hg) that is considered to be hypertensive.

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S. Prasad, A.K. Sinha / International Journal of Diabetes Mellitus 2 (2010) 141–143

Type 2 diabetic patients were subjected to an evaluation of their hypertensive state by measuring their blood pressure, three times a day for a period of one week, and the average was taken for the evaluation of blood (mean arterial blood pressure = 1/3 of pulse pressure + diastolic pressure). Blood pressure was measured in the supine position, manually in both arms, by a calibrated sphygmomanometer. Subjects underwent a medical history screening, a physical examination and laboratory analysis, which included CBC, serum electrolytes, blood urea, creatinine, fasting blood glucose and HbAc 1, ECG, and echocardiography. Exclusion criteria included tobacco, caffeine use, cardiac and pulmonary disease and evidence of left ventricular hypertrophy. The hypertensive patients were on calcium channel blockers. All medications were stopped 12 h before blood sample collection. In the morning fasting blood sample was taken. Venous blood was collected from the anterior aspect of the forearm with the help of disposable syringes. Serum was separated within 1 h after refrigeration. The straw colored supernatant serum was centrifuged and separated. All three tests were carried out within 2 h, after obtaining venous blood. The method of testing for MDA (malondialdehyde) as a marker of lipid peroxidation product was that of determined through the method of Okhawa et al. (1974) who measured MDA as thiobarbituric acid reactive substances (TBARS) [5]. Superoxide dismutase was assessed by the method of Kakkar et al. [6]. Nitric oxide was assessed through the method of Green et al. [7]. In this method, nitric oxide in serum was estimated indirectly by measuring the amount of nitrates formed from nitric oxide. 3. Observation and results These results are consistent with a significant increase in free radical activity in type 2 diabetic patients with coexistent hypertension. The SOD and NO levels were significantly decreased and MDA levels were significantly increased in those type 2 diabetic patients who had coexistent hypertension (Table 1). 4. Discussion Increased concentrations of oxygen-derived free radicals are implicated in the pathogenesis of vascular complications in diabetes. Superoxide anion appears to block endothelium derived nitric oxide mediated relaxation by inactivating the eNOS. In a hyperglycemic state, the production of superoxide is stimulated, and the en-

zyme superoxide dismutase is inhibited by non-enzymatic glycosylation known as Maillard reaction [8]. Glycation was shown to affect the C-terminal end of the enzyme, reducing its heparin binding affinity. Thus, protection against extra cellular radicals by cell surface attached SOD may be impaired in diabetes leaving the endothelial cell susceptible to damage by super oxide anion. The addition of exogenous SOD restores normal or unmasks even greater acetylcholine induced relaxation in diabetic aorta. Thus, in diabetic conditions, normal levels of antioxidant enzymes may be insufficient or may be functionally impaired, so as to preserve a physiological contractile response [9]. Nitric oxide and superoxide anion readily react to form peroxynitrite (OONO) at nearly diffusion limited rate. During physiologic conditions O2 scavengers and formation of OONO are minimal. During pathologic conditions such as in the presence of increased concentrations of O2 or after O2 scavengers are exhausted, significant concentrations of OONO may be produced. Peroxynitrite directly causes oxidation, peroxidation, and nitration of biologically important molecules (e.g. lipids protein and DNA). It is more cytotoxic than NO in a variety of experimental conditions [10]. An important example of a reaction caused by OONO is the nitration of tyrosine. Tyrosine nitration inhibits tyrosine phosphorylation, alters the dynamics of assembly and disassembly of cytoskeletal proteins, and inhibits tyrosine hydroxylase, thereby inhibiting the cycloskeletal movements of endothelial cells [10]. Nitric oxide has contrasting effects on lipids, particularly on oxidation of LDL lipoproteins in the pathogenesis of atherosclerotic lesions. NO inhibits lipid peroxidation by inhibiting radical chain propagation, reactions via radical reaction with lipid peroxyl and alkoxyl group. As a ligand to iron (and other transition metals), NO modulates the peroxidant effects of iron and thereby limits the formation of hydroxyl radicals and iron dependent electron transfer reactions. NO inhibits all and OONO mediated lipoprotein oxidation in macrophage and endothelial cell systems. However, NO, induced OONO formation can oxidize low density lipoproteins to potentially atherogenic species. In summary, OONO is more cytotoxic than NO in a variety of experimental systems and the balance of NO, O2 , and OONO , scavenging systems determine whether biologically relevant OONO concentrations will occur in tissues. Thus, the endothelium appears to modulate vascular functions by releasing relaxant substances like NO and constrictor substances like superoxide. Superoxide may play a key role in the relationship between cardiovascular diseases and metabolic disorders like diabetes mellitus, and will almost certainly prove to be a focus for future therapies [10].

Table 1 Clinical and Laboratory data of diabetic patients without hypertension as control/diabetic patients with hypertension. Parameters

Controls

Hypertensives

Number Sex (M/F) Age (In years) Wt. (kg) Duration of diabetes (years) Fasting plasma glucose (mg/dl) Glycosylated Haemoglobin (%) Mean arterial pressure (mmHg) MDA (moles/dl) SOD UB/dl NO (U/dl)

31 24/7 54 (35–65) 54 (40–70) 4 (0A–14) 175 ± 67 9.6 ± 1.7 97 ± 2 359 (231–718) p < 0.01, SD ± 55.85 21.31 (5.33–26.64) SD ± 4.64 18.54 (11.40–37.07) SD + 4.34

19 15/4 51 (40–71) 52 (40–71) 3 (0–20) 223± 84 p < 0.001 11 ± 2.8 p < 0.001 116 ± 6 p < 0.05 385 (256–666), SD ± 63.34 16.65 (6.66–22.64) SD ± 4.08 p < 0.05 21.39 (15.69–35.65) SD ± 4.79 p < 0.05,

Median (Range), SOD, superoxide dismutase, NO, nitric oxide; MDA, malondialdehdye. A, newly diagnosed type 2 diabetic patients. B, one unit of enzyme is defined as enzyme concentration required to inhibit the optical density of chromogen production by 50% in 1 min. Table 1 shows the clinical and biochemical details of the study groups. There were no significant differences in the age, weight, sex, and duration of diabetes between the two study groups. Patients with hypertension had higher plasma fasting glucose levels (p < 0.001) and glycosylated hemoglobin levels (p < 0.001) compared to those without hypertension.

S. Prasad, A.K. Sinha / International Journal of Diabetes Mellitus 2 (2010) 141–143

5. Conclusion Much evidence suggests that free radical over generation may be considered the key in the generation of insulin resistance, diabetes and cardiovascular disease. Many new specific causal antioxidants are being developed [10,11], and may become important tools in opposing the increasing epidemic of diabetes a real emergency in our future. It has been demonstrated that insulin resistance is associated in humans with reduced intracellular antioxidant defense [12], and that diabetic subjects prone to complications may have a defective intracellular antioxidant response [13,14] where what we call genetic predisposition to diabetes, as well as liability to its late complications, might be based on a deficient ROS-scavenging ability in b-cells and/or in target tissues such as endothelium. Oxidative stress is involved in various cardiovascular diseases, including atherosclerosis, hypertension and the aging process; therefore, therapeutic strategies to modulate this maladaptive response should become a target for future extensive investigation, and could have a broad application [15]. References [1] Sowers James R, Murray E, Edward DF. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 2001;37:1053–9. [2] Betteridge DJ. What is oxidative stress? Metabolism 2000;49:3–8.

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[3] Tirzitis G, Bartosz G. Determination of antiradical and antioxidant activity: basic principles and new insights. Acta Biochim Pol 2010;57:139–42. [4] Sies H. Strategies of antioxidant defence. Eur J Biochem 2005;215:213–9. [5] Ohkawa H, Ohishi N, Yogi K. Assay of lipid peroxides in animal tissues by thiobarbituric acid reaction. Annal Biochem 1979;95:351–8. [6] Kakkar P, Awasthi S, Vishwanathan PN. Oxidative changes in brain of aniline exposed rats. Arch Environ Contam Toxicol 1992;23:307–9. [7] Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannebaum SR. Analysis of nitrate, nitrite, and [N 15] nitrate in biological fluids. Anal Biochem 1982;126:131–8. [8] Taboshashi K, Saito Y. The role of superoxide anion in relationship between the cardiovascular diseases and the metabolic disorders associated with obesity. Nippon Rinsho 2000;58:1592–7. [9] Szaleczky E, Prechl J, Feher J, Somogyi A. Alterations in enzymatic defence in diabetes mellitus – a rational approach. Postgrad Med J 1999;75:13–7. [10] Ceriello A. New Insights on oxidative stress and diabetic complications may lead to a causal antioxidant therapy. Diabetes Care 2003;26:1589–96. [11] Cuzzocrea S, Riley DP, Caputi AP, Salvemini D. Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol Rev 2001;53:1159. [12] Ceriello A, Morocutti A, Mercuri F, Quagliaro L, Moro M, Damante G, et al. Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy. Diabetes 2000;49:2170–7. [13] Hodgkinson AD, Bartlett T, Oates PJ, Millward BA, Demaine AG. The response of antioxidant genes to hyperglycaemia is abnormal in patients with type 1 diabetes and diabetic nephropathy. Diabetes 2003;52:846–51. [14] Bruce CR, Carey AL, Hawley JA, Febbraio MA. Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA is reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed antioxidant defence mechanism. Diabetes 2003;52:2338–45. [15] Tsutsui Hiroyuki, Kinugawa Shintaro, Matsushima Shouji. Mitochondrial oxidative stress and dysfunction in myocardial remodelling. Cardiovasc Res 2009;81:449–56.

International Journal of Diabetes Mellitus 2 (2010) 144–147

Contents lists available at ScienceDirect

International Journal of Diabetes Mellitus journal homepage: www.elsevier.com/locate/ijdm

Original Article

Association of serum free IGF-1 and IGFBP-1 with insulin sensitivity in impaired glucose tolerance (IGT) Golam Kabir a,b,⇑, Mosaraf Hossain a,b, M. Omar Faruque a, Naimul Hassan a,b, Zahid Hassan a, Quamrun Nahar a, Sultana Marufa Shefin c, Mohammad Alauddin b, Liaquat Ali a a b c

Biomedical Research Group (BMRG), BIRDEM, Dhaka, Bangladesh Department of Biochemistry & Molecular Biology, University of Chittagong, Chittagong-4331, Bangladesh Dept. of Endocrinology and Diabetology, BIRDEM, Dhaka, Bangladesh

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Article history: Received 31 May 2010 Accepted 4 September 2010

Keywords: Free IGF-1 IGFBP-1 BMI IGT

a b s t r a c t Aim and Background: Free IGF-1 and IGFBP-1 are associated with obesity which is one of the major features of insulin resistance. But very few studies exist on free IGF-1 and IGFBP-1 in IGT subjects. The present study was undertaken to investigate the association of free IGF-1 and IGFBP-1 with insulin sensitivity in IGT subjects. Subjects and Methods: Ninety-one subjects with impaired glucose tolerance (IGT) were studied along with age- sex- and BMI-matched sixty-one healthy Controls without family history of diabetes or prediabetes. Insulin, free IGF-1 and IGFBP-1 were measured by standard ELISA method. Insulin secretory capacity (HOMA B) and insulin sensitivity (HOMA S) were calculated using fasting glucose and fasting insulin by HOMA-CIGMA software. Results: Fasting free IGF-1 and IGFBP-1 levels were not significantly different among the study groups. In stepwise multiple regression analysis, when free IGF-1 was considered as a dependent variable with other independent variables, model 1 (b = 0.352, p = 0.03), model 2 (b = 0.355, p = 0.033) and model 5 (b = 0.378, p = 0.026) have shown significant association of fasting glucose with free IGF-1. Similarly when IGFBP-1 was considered as a dependent variable, model 4 (b = 0.865, p = 0.03) and model 5 (b = 0.1.07, p = 0.004) have shown negative association of fasting glucose with IGFBP-1. In this analysis model 5 have also shown negative association of HOMA S with IGFBP-1 (b = 1.015, p = 0.017). Conclusion: IGF1 and IGFBP-1 seems to be negatively associated with fasting glucose in IGT subjects and insulin sensitivity (HOMA S) may also be negatively associated with IGFBP-1 in IGT subjects. Ó 2010 International Journal of Diabetes Mellitus. Published by Elsevier Ltd. All rights reserved.

1. Introduction Insulin, like growth factor-1 (IGF-1), is a multipotent growth factor with important action on normal tissue growth and metabolism. In addition, IGF-1 has been suggested to have beneficial effects on glucose homeostasis, due to its glucose lowering and insulin sensitizing actions. Epidemiological studies suggest that IGF-1 is also involved in the development of common cancer, atherosclerosis and type 2 diabetes [1–4]. In several pathological states, an impairment of IGF-1 action on glucose metabolism has been recorded, along with insulin resistance [5–7]; however, it is not known whether IGF-1 and insulin resistance are always associated and it is not clear whether resistance, when it does occur, affects only glucose uptake and metabolism or protein metabolism as well. Frystyk et al. (1999) have found that circulating fasting free IGF-I is increasingly elevated with increasing obesity, whereas ⇑ Corresponding author at: Department of Biochemistry & Molecular Biology, University of Chittagong, Chittagong-4331, Bangladesh. Tel.: +8801711943681. E-mail address: [email protected] (G. Kabir).

serum total IGF-I is normal. They have proposed that elevated serum free IGF-I may be caused by insulin resistance inducing hyperinsulinemia which suppress IGFBP-1 [8]. Although IGF-1 is structurally related to insulin, unlike insulin, it circulates bound to specific proteins called IGF binding proteins (IGFBPs) with variable affinity [9]. IGFBP-1 levels have been shown to be elevated in type 1 diabetes and in patients with insulin resistance syndromes. Type 2 diabetes tends to have low serum IGFBP-1 levels. Patients with growth hormone deficiency tend to have elevated IGFBP-1 levels [10]. Insulin inhibits the hepatic synthesis and secretion of IGFBP-1 [11,12] and increases the portal concentrations of insulin decrease serum levels of IGFBP-1 in obese subjects [8]. Frystyk et al., 1999 [8] have shown that simple obesity was associated with reduced levels of IGFBP-1 when compared to lean control and obese type 2 diabetes. Free IGF-1 and IGFBP-1 have been well studied in type 1 diabetic subjects and also in type 2 diabetic subjects with higher BMI (BMI > 30). In developing countries like Bangladesh, type 2 diabetic patients mostly possess lower to normal BMI, and no reports of free IGF-1 and IGFBP-1 exist in this physiological

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condition. But this is very important because BMI is a major risk factor for insulin resistance. The variation in serum concentrations of IGF-1 and IGFBP-1 occurs due to racial variation. Moreover Impaired glucose tolerance (IGT), which is also known as the defect of insulin resistance, is not well explored in regard to free IGF-1 and IGFBP-1 issues, which may help to know the early mechanisms of the onset of insulin resistance and the development of diabetes. The present study has been undertaken to explore the association of insulin resistance with free IGF-1 and IGFBP-1 in IGT subjects. 2. Materials and methods This cross-sectional observational study was conducted in Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka. A group of 91 impaired glucose tolerant (IGT) subjects were selected purposively from the Out-Patient Department (OPD) of BIRDEM, along with a group of 61 age-, sex- and BMI-matched healthy subjects without family history of diabetes as Controls from the friend circle of the IGT subjects considering the same socio-economic status. Written consent was taken from all the volunteers; clinical examinations Table 1 Clinical characteristics of the study subjects. Variable

Control (n = 61)

IGT (n = 91)

Age (yrs) BMI (kg/m2) WHR MUAC (mm) Triceps (mm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Fasting glucose (mmol/l) Postprandial glucose (mmol/l)

36 ± 6 25.4 ± 3.8 0.91 ± 0.05 298 ± 27 14.6 ± 5.0 115 ± 9 77 ± 9 5.2 ± 0.5 5.9 ± 1.7

43 ± 9 26.3 ± 4.0 0.92 ± 0.05 303 ± 30 15.3 ± 5.4 122 ± 17 82 ± 9* 5.7 ± 0.6* 9.2 ± 1.3*

Results are expressed as M ± SD. * p < 0.05, significantly different compared to controls when using Student’s ‘t’ test. Table 2 Serum insulinemic, lipid profile, IGF-1 and IGFBP-1 status of the study subjects. Variables

Control (n = 61)

Fasting Insulin (pmol/l) HOMA B HOMA S Triglyceride (mg/dl) Cholesterol (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Free IGF-1 (pg/ml) IGFBP-1 (ng/ml)

were undertaken by a registered physician using a predesigned questionnaire. Anthropometric measurements were taken using standard methods. Subjects were requested to come on a prescheduled morning, after overnight fasting for the fasting blood sample; subjects were then given 75 gm anhydrous glucose dissolved in 250 ml water. Blood was taken at fasting conditions and 2 h after glucose loading. Serum glucose, cholesterol, triglyceride and HDL were determined by the enzymatic colorimetric method, using commercial kits (Randox Laboratories Ltd., UK). The LDL cholesterol in serum was calculated by using the formula: LDLcholesterol = Total cholesterol (TG/5 + HDL-cholesterol). Serum insulin levels were determined by enzyme linked immunosorbent assay (ELISA) method (Linco Research Inc., USA). Serum free IGF-1 and IGFBP-1 concentrations were measured by enzyme linked immunosorbent assay (ELISA) method (Ray Biotech, USA). Insulin secretory capacity (HOMA B) and insulin sensitivity (HOMA S) were calculated from fasting glucose and fasting insulin using HOMA-CIGMA software [13]. 2.1. Statistical analysis Data were expressed as mean ± SD (standard deviation), median (range) and/or percentage (%) as appropriate using SPSS (Statistical Package for Social Science) software for Windows version 10 (SPSS Inc., Chicago, Illinois, USA). The statistical significance of the differences between the values was assessed by Student’s ‘t’ test or Mann–Whitney U test (as appropriate). A two-tailed p value of 2 years, were evaluated for MA; 48 Africans were followed prospectively. Results: Africans had shorter duration of diabetes (median, 8 years vs 11 years), higher HbA1c (10.62(SD 2.52)%, vs 9.02(2.44)%, lower cholesterol (4.45(1.04) vs 5.45(1.16)mmol/l), and fewer (23.5% vs 54.5%) had adolescent diabetes onset (p 0.0030 for each); the prevalence of MA was 39.7% and 24.6% respectively (p = 0.0155). In multiple regression analysis MA was associated with mean HbA1c (p < 0.0001), younger age at diagnosis (p = 0.0060), SBP (p = 0.0012) and African race (p = 0.0287). Prospectively, Africans developing MA (45%) had higher mean HbA1c levels (p = 0.0001), were more likely to have had adolescent onset of DM (33.3% vs 8.0%, p = 0.0310) and lower BMI (p = 0.0340); logistic regression revealed that higher HbA1c and SBP, and lower BMI predicted MA. Nine of 16 African subjects progressed to macroalbuminuria; they were characterised only by extremely poor glycaemic control (mean HbA1c, 13.49(2.00)%). Conclusions: Microalbuminuria, and severe hyperglycaemia, are common in diabetic Africans with short duration TIDM; MA may rapidly progress to macroalbumiuria. African race may be associated with increased susceptibility to diabetic nephropathy. Ó 2010 International Journal of Diabetes Mellitus. Published by Elsevier Ltd. All rights reserved.

1. Introduction Type 1diabetes (T1DM) is relatively rare in sub-Saharan Africans, especially in young children – the peak age of onset is about a decade older than in white Europeans [1–3]. Although data are limited, available information indicates that the prognosis in T1DM is poor in Africa, as a result of both acute and long-term complications [2,4]. Diabetic nephropathy appears to be particularly frequent in diabetic Africans and is a major cause of morbidity and mortality [4–6], perhaps more so than in comparable populations of European extraction; no comparative data have been published. Micro-albuminuria (MA) is a marker of early diabetic renal disease and is a precursor of overt diabetic nephropathy, although it may regress in a substantial proportion of patients [7]. Influences on and risk factors for the development of early diabetic nephropathy or its progression in T1DM include gender, age of onset of diabetes, ⇑ Corresponding author. Present address: Endocrinology Unit, Musgrove Park Hospital, Parkfield Drive, Taunton, TA1 5DA, Somerset, UK. Tel.: + 44 0 1823 344536; fax: + 44 0 1823 344542. E-mail addresses: [email protected], [email protected] (W.J. Kalk), Fredrick. [email protected] (F.J. Raal), [email protected] (B.I. Joffe).

duration of disease, poor glycaemic control, blood pressure, lipids, central obesity and psychosocial and genetic factors [7–20]. The great majority of patients studied have been of European extraction and publications on renal involvement in T1DM from Africa are few and cross-sectional [2,4,22]. Moreover, uncertainty remains about some potential risk factors, notably the roles of blood pressure and dyslipidaemia in the genesis of MA. We have, therefore, investigated the prevalence of early diabetic nephropathy and some associations in a group of African patients with TIDM in urban South Africa, a population in epidemiological transition and characterised by relatively low serum lipid concentrations; an age matched white patient group from the same institution was studied by way of comparison. In a subgroup of Africans, the incidence of and potential risk factors for MA and for progression to macro-albuminuria were evaluated in a prospectively studied cohort. 2. Subjects and methods Patients attending the Diabetes Service at the Johannesburg Academic Hospital, South Africa, between 1994 and 2008, with age at diagnosis of diabetes 640 years, were studied. African

1877-5934/$ - see front matter Ó 2010 International Journal of Diabetes Mellitus. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijdm.2010.10.003

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W.J. Kalk et al. / International Journal of Diabetes Mellitus 2 (2010) 148–153

Table 1 The clinical and laboratory characteristics of all patients with type 1 diabetes and in the African and White subjects separately, excluding those with overt nephropathy. Data are expressed as mean (SD) or median (IQR).

% male Age (years) Age diagnosis Adolescent onset (%) Duration DM BMI Hypertension (%) SBP DBP Smokers (%) (n = 165) HbA1c (%) Cholesterol (mmol/l) LDL-C (mmol/l) (n = 128) HDL-C (mmol/l) (n = 79) Trigycerides(mmol/l) (n = 133) Creatinine (umol/l)

All subjects (n = 202)

African (n = 68)

White (n = 134)

p

60.4 34.7 (10.2) 22.5 (8.1) 44.1 9.0 (5.0,15.3) 24.3 (4.3) 29.2 121.1 (14.1) 76.0 (8.8) 39.0 9.56 (2.57) 5.09 (1.21) 3.03 (1.03) 1.30 (0.42) 1.00 (0.80,1.58) 88.0 (81.0, 98.0)

55.9 34.9 (8.6) 26.2 (7.3) 23.5 8.0 (4.0,11.0) 24.6 (3.9) 33.8 119.3 (14.4) 76.9 (9.5) 31.3 10.62 (2.52) 4.45 (1.04) 2.50 (0.82) 1.31 (0.41) 0.90 (0.70,1.20) 87.0 (79.0,96.0)

62.7 34.6 (11.0) 20.6 (8.0) 54.5 11.0 (6.0,18.0) 24.0 (4.7) 26.9 121.3 (15.3) 75.5 (8.4) 43.1 9.02 (2.44) 5.42 (1.16) 3.34 (1.03) 1.43 (0.42) 1.10 (0.90,1.80) 89.5 (81.8,99.0)

0.459 0.844 6–9 years >9 years

56 (5.2) 204 (18.9) 288 (26.7) 160 (14.9) 369 (34.3)

(25.4) (27.3) (23.7) (12.6) (11)

Type of complications

n (%)

No complications Microvascular complications Retinopathy Neuropathy Nephropathy Retinopathy, neuropathy Retinopathy, nephropathy Neuropathy, nephropathy Retinopathy, neuropathy and nephropathy Microvascular and macrovascular complications Total

48 (4.5) 841 (78.0) 15 (1.4%) 19 (1.8%) 273 (25.3%) 14 (1.3%) 87 (8.1%) 221 (20.5%) 212 (19.6%) 188 (17.5%) 1077 (100%)

1.40 ± 0.54 mmol/L and mean TG was1.74 ± 0.85 mmol/l. Non-achievement of the ADA guideline for LDL-C, total cholesterol, triglycerides, and HDL-C were 54.3%, 36.8%, 42%, and 32%, respectively (Table 3). In the aspect of the Metabolic Syndrome, the overall prevalence of dyslipidaemia was 93.7%, hypertension was 92.7%, and obesity (BMI >23 kg/m2) was 81.5%. 3.1. Type of vascular complications among type 2 DM patients

Table 3 Characteristics of clinical variables of type 2 DM patients. Variables

n (%)

Mean (±SD)

HbA1c (%) Optimal 8%

252 (23.4) 258 (24) 567 (52.6)

8.72 (±2.34)

Fasting plasma glucose (mmol/l) Optimal 7.8 mmol/l

498 (46.3) 163 (15.1) 416 (38.6)

7.89 (±3.72)

Most of the patients, 841 (78%) had microvascular complications alone, 188 (17.5%) had a combination of microvascular and macrovascular complications, and of these, 137 (12.8%) had coronary heart disease, only 51 (4.7%) had cerebrovascular disease and a minority 48 (4.5%) had no complications (Table 4). Diabetic nephropathy was the most common complication, accounting for 91.0%, followed by neuropathy 54.4%, retinopathy 39.3%, and macrovascular complications (17.5%).

10.03 (±4.38)

3.2. Univariate analysis of risk factors affecting the development of complications

PPG (mmol/l) Control 120–139 mmHg 140–159 mmHg P160 mmHg Diastolic blood pressure (mmHg) 100 mmHg

634 (58.9) 443 (41.1)

332 (30.8) 289 (26.8) 296 (27.5) 160 (14.9) 753 (69.9) 33 (3.1) 213 (19.8) 78 (7.2)

LDL cholesterol (mmol/l) ADA Normal 4.1 mmol/l

493 (45.7) 285 (26.5) 186 (17.3) 113 (10.5)

Total cholesterol (mmol/l) ADA Target 1.3 mmol/l (>50 mg/dl) Non-target (female) 61.3 mmol/l (650 mg/dl)

384 (35.7) 92 (8.5) 348 (32.3) 253 (23.5)

135.98 (±19.78)

80.62 (±9.83)

Table 5 shows the simple logistic regression of risk factors affecting the development of vascular complications. There were significant associations between the complications and age, BMI, WC, PPG, triglyceride, duration of diabetes and systolic blood pressure. 3.3. Final model of multivariate analysis on complications Using a backward stepwise logistic regression, all factors found to be significant at P-value