Diabetes Mellitus - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

DIABETES MELLITUS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2003 by ICON Group International, Inc. Copyright ©2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Diabetes Mellitus: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83884-4 1. Diabetes Mellitus-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on diabetes mellitus. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON DIABETES MELLITUS ................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Diabetes Mellitus .......................................................................... 8 E-Journals: PubMed Central ....................................................................................................... 69 The National Library of Medicine: PubMed ................................................................................ 74 CHAPTER 2. NUTRITION AND DIABETES MELLITUS ..................................................................... 121 Overview.................................................................................................................................... 121 Finding Nutrition Studies on Diabetes Mellitus....................................................................... 121 Federal Resources on Nutrition ................................................................................................. 125 Additional Web Resources ......................................................................................................... 126 CHAPTER 3. ALTERNATIVE MEDICINE AND DIABETES MELLITUS ............................................... 129 Overview.................................................................................................................................... 129 The Combined Health Information Database............................................................................. 129 National Center for Complementary and Alternative Medicine................................................ 130 Additional Web Resources ......................................................................................................... 136 General References ..................................................................................................................... 141 CHAPTER 4. DISSERTATIONS ON DIABETES MELLITUS ................................................................. 143 Overview.................................................................................................................................... 143 Dissertations on Diabetes Mellitus............................................................................................ 143 Keeping Current ........................................................................................................................ 152 CHAPTER 5. CLINICAL TRIALS AND DIABETES MELLITUS ............................................................ 153 Overview.................................................................................................................................... 153 Recent Trials on Diabetes Mellitus............................................................................................ 153 Keeping Current on Clinical Trials ........................................................................................... 176 CHAPTER 6. PATENTS ON DIABETES MELLITUS ............................................................................ 179 Overview.................................................................................................................................... 179 Patents on Diabetes Mellitus ..................................................................................................... 179 Patent Applications on Diabetes Mellitus ................................................................................. 205 Keeping Current ........................................................................................................................ 236 CHAPTER 7. BOOKS ON DIABETES MELLITUS ............................................................................... 237 Overview.................................................................................................................................... 237 Book Summaries: Federal Agencies............................................................................................ 237 Book Summaries: Online Booksellers......................................................................................... 240 The National Library of Medicine Book Index ........................................................................... 243 Chapters on Diabetes Mellitus................................................................................................... 244 CHAPTER 8. MULTIMEDIA ON DIABETES MELLITUS ..................................................................... 247 Overview.................................................................................................................................... 247 Video Recordings ....................................................................................................................... 247 Audio Recordings....................................................................................................................... 253 Bibliography: Multimedia on Diabetes Mellitus........................................................................ 255 CHAPTER 9. PERIODICALS AND NEWS ON DIABETES MELLITUS .................................................. 257 Overview.................................................................................................................................... 257 News Services and Press Releases.............................................................................................. 257 Newsletters on Diabetes Mellitus .............................................................................................. 259 Newsletter Articles .................................................................................................................... 260 Academic Periodicals covering Diabetes Mellitus ..................................................................... 260 CHAPTER 10. RESEARCHING MEDICATIONS ................................................................................. 263 Overview.................................................................................................................................... 263 U.S. Pharmacopeia..................................................................................................................... 263

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Commercial Databases ............................................................................................................... 265 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 269 Overview.................................................................................................................................... 269 NIH Guidelines.......................................................................................................................... 269 NIH Databases........................................................................................................................... 271 Other Commercial Databases..................................................................................................... 276 APPENDIX B. PATIENT RESOURCES ............................................................................................... 277 Overview.................................................................................................................................... 277 Patient Guideline Sources.......................................................................................................... 277 Finding Associations.................................................................................................................. 294 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 297 Overview.................................................................................................................................... 297 Preparation................................................................................................................................. 297 Finding a Local Medical Library................................................................................................ 297 Medical Libraries in the U.S. and Canada ................................................................................. 297 ONLINE GLOSSARIES................................................................................................................ 303 Online Dictionary Directories ................................................................................................... 305 DIABETES MELLITUS DICTIONARY..................................................................................... 307 INDEX .............................................................................................................................................. 405

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with diabetes mellitus is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about diabetes mellitus, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to diabetes mellitus, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on diabetes mellitus. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to diabetes mellitus, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on diabetes mellitus. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON DIABETES MELLITUS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on diabetes mellitus.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and diabetes mellitus, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “diabetes mellitus” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Association Between Hepatitis C Virus Infection and Type 2 Diabetes Mellitus: What Is the Connection? (editorial) Source: Annals of Internal Medicine. 133(8): 650-652. October 17, 2000. Contact: Available from American College of Physicians. American Society of Internal Medicine. 190 North Independence Mall West, Philadelphia, PA 19106-1572. Website: www.acponline.org. Summary: Chronic hepatitis C virus (HCV) infection and type 2 diabetes mellitus cause devastating long term complications in a significant minority of patients affected with these diseases. This editorial explores the potential link between these two disorders, noting that chronic HCV infection may cause cirrhosis (liver scarring), which, through insulin resistance, predisposes patients to diabetes mellitus. The author reviews a dozen

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studies that look at this connection, then introduces a research study published in the same journal issue as the editorial, which provides strong evidence for the association between HCV infection and type 2 diabetes mellitus. This latter study demonstrates that persons with HCV infection were more than three times more likely to have type 2 diabetes mellitus than those without HCV infection. Alcohol abuse did not seem to link the two disorders in this study. The editorial author addresses some of the potential limitations to this study, and suggests additional research that may further clarify the connection between the two diseases. The editorial concludes that the association between chronic HCV infection and type 2 diabetes mellitus seems genuine. However, numerous questions must still be addressed, most notably those regarding the nature of the link between the disorders. 19 references. •

High Prevalence of Celiac Disease Among Patients with Insulin-Dependent (Type I) Diabetes Mellitus Source: American Journal of Gastroenterology. 92(12): 2210-2212. December 1997. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (800) 638-6423 or (410) 528-8555. Summary: Diagnosis of unrecognized celiac disease is potentially important, due to its association with an increased risk of malignancy and its complications by other conditions such as osteoporosis, infertility, and neurologic disorders (problems that may be averted with gluten restriction). The prevalence of celiac disease in patients with type 1 diabetes (insulin-dependent diabetes mellitus) is uncertain. This article reports on a study of the prevalence of celiac disease in a stratified random sample (n=101) of adults with type 1 diabetes and in an control group matched for age and sex (n=51). Screening was by anti-endomysial antibody, measured by indirect immunofluorescence using sections of human umbilical cord. Celiac disease had not been suspected in any patient at the time of screening. Eight patients tested positive for anti-endomysial antibody; each had a distal duodenal biopsy performed. Five patients had histologic evidence of celiac disease. One patient with negative histology was receiving immunosuppressive therapy for a renal-pancreas transplant. Of the five patients with abnormal histology, two improved on gluten restriction, one was unable to comply, one refused treatment, and one was lost to followup. No control subject tested positive for endomysial antibody. The authors conclude that patients with type 1 diabetes have an increased prevalence of celiac disease. Because most cases are clinically unrecognized, consideration should be given to screening all patients with type 1 diabetes. 1 table. 17 references. (AA-M).

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Risk Factors for Hepatocellular Carcinoma: Synergism of Alcohol with Viral Hepatitis and Diabetes Mellitus Source: Hepatology. 36(5): 1206-1213. November 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Risk factors associated with hepatocellular carcinoma (HCC, liver cancer) are well documented, but the synergisms between these risk factors are not well examined. This article reports on a hospital-based, case-control study that included 115 HCC patients and 230 non-liver cancer control patients. Odds ratios were 15.3 for anti-HCV antigen, 12.6 for hepatitis B surface antigen (HBsAg), 4.5 for heavy alcohol consumption, and 4.3 for diabetes mellitus. Synergistic interactions on the additive model were observed between heavy alcohol consumption and chronic hepatitis virus infection and

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diabetes mellitus. Independent of the effect of HCV, HBV, and diabetes mellitus, heavy alcohol consumption contributes to the majority of HCC cases (32 percent), whereas 22 percent, 16 percent, and 20 percent were explained by HCV, HBV, and diabetes mellitus, respectively. The authors conclude that the significant synergy between heavy alcohol consumption, hepatitis virus infection, and diabetes mellitus may suggest a common pathway for hepatocarcinogenesis (development of liver cancer). 3 tables. 38 references. •

Celiac Sprue and Diabetes Mellitus. (editorial) Source: Journal of Clinical Gastroenterology. 16(1): 4-5. January 1993. Summary: The frequent association of celiac sprue (CS) and insulin-dependent diabetes mellitus (IDDM) that may be the result of interplay between genetic, hormonal, and immunologic factors has obvious therapeutic implications. So contend the authors of this article that explores the association between CS and IDDM. Topics include hormones produced by the small bowel mucosa; the causal relationship between IDDM and CS; and the role of enteroglucagon. The authors hypothesize that a state of chronic hyperglucagonemia associated with low insulin levels may exist in CS patients, predisposing them to develop IDDM. The authors stress that a gluten-free diet may improve the diarrhea in some patients with IDDM where the reason for diarrhea is underlying celiac sprue; the diet may also improve control of DM by normalizing the serum hormonal profile. 32 references.

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Risk Factors for Diabetes Mellitus in Chronic Pancreatitis Source: Gastroenterology. 119(5): 1324-1332. November 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: The influence of disease progression and pancreatic surgery on the appearance of diabetes mellitus in patients with chronic pancreatitis is unknown. This article reports on a prospective cohort study of 500 consecutive patients with chronic pancreatitis (alcoholics, 85 percent); patients were followed over a mean period of 7.0 years (plus or minus 6.8 years) in a medical surgical institution between 1973 and 1996. Analysis of risk factors for diabetes mellitus was performed after the exclusion of 47 patients. Patients who underwent elective pancreatic surgery (n = 231; 51 percent) were compared with patients who never underwent surgery (n = 222; 49 percent). The cumulative rate of diabetes mellitus was 83 percent (plus or minus 4 percent) 25 years after the clinical onset of chronic pancreatitis (insulin requirement, 54 percent). The prevalence of diabetes mellitus did not increase in the surgical group overall but was higher 5 years after distal pancreatectomy (a surgical procedure that removes 50 to 70 percent of the distal pancreas; 57 percent of the patients) than after pancreaticoduodenectomy (36 percent), pancreatic drainage (36 percent), or cystic, biliary, or digestive drainage (24 percent), without difference in the latter ones. Pancreatic drainage did not prevent the onset of diabetes mellitus. Distal pancreatectomy and early onset of pancreatic calcifications were the only independent risk factors for diabetes mellitus. The authors conclude that the risk of diabetes mellitus is not influenced by elective pancreatic surgical procedures other than distal pancreatectomy in patients with chronic pancreatitis. This risk seems to be largely caused by progression of the disease because it increased by more than 3 fold after the onset of pancreatic calcifications. 4 figures. 4 tables. 55 references.

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Disturbances in Anorectal Function in Patients With Diabetes Mellitus and Faecal Incontinence Source: European Journal of Gastroenterology and Hepatology. 8(10): 1007-1012. August 1996. Contact: Available from Rapid Science Publishers. 400 Market Street, Suite 750, Philadelphia, PA 19106. (800) 552-5866 or (215) 574-2210. Summary: This article reports on a study designed to document the anorectal dysfunctions in patients with diabetes and fecal incontinence. Multiport anorectal manometry and electromyography were done in 11 patients with diabetes and fecal incontinence, and in 20 healthy controls. Basal and squeeze pressures were reduced in the patients with diabetes compared with the control subjects. During basal recording, six patients showed regular oscillations in anal electrical activity and pressure. Nine patients also exhibited spontaneous transient anal relaxations, and in six of them, leakage occurred as the anal pressure fell below the rectal pressure. None of the control subjects showed oscillation or spontaneous relaxations. In patients there was a greater tendency for repetitive rectal contractions in response to rectal distension and reduced rectal compliance. During rectal distension, four patients showed no anal relaxation, and in the remainder relaxation occurred at an abnormally high threshold. The authors conclude that the etiology of fecal incontinence in patients with diabetes is multifactorial, and that instability of the internal sphincter probably plays a major role. 2 figures. 1 table. 40 references. (AA-M).

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Costs Associated with the Primary Prevention of Type 2 Diabetes Mellitus in the Diabetes Prevention Program Source: Diabetes Care. 26(1): 36-47. January 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study that describes the costs of the Diabetes Prevention Program (DPP) interventions that are designed to prevent or delay type 2 diabetes. The authors describe the direct medical costs, direct nonmedical costs, and indirect costs of the placebo, metformin, and intensive lifestyle interventions over the 3 year study period of the DPP. Resource use and cost are summarized from the perspective of a large health system and society. Research costs are excluded. The data showed metformin and lifestyle interventions are associated with modest incremental costs compared with the placebo intervention. The evaluation of costs relative to health benefits will determine the value of these interventions to health systems and society. 7 tables. 24 references.

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Gestational Diabetes Mellitus Source: Diabetes Care. 26(2): 385-389. February 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study undertaken to examine anxiety levels of women diagnosed with gestational diabetes mellitus (GDM) and to compare these with glucose-tolerant (GT) women at similar stages of pregnancy. The prospective longitudinal study was conducted on 50 women with GDM and 50 GT women. All women completed the Mental Health Inventory (MHI-5) forms and the Speilberger

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State-Trait Anxiety Inventory (STAI) at the beginning of the third trimester, antepartum, and 6 weeks postpartum. Women with GDM, compared with GT women, had a higher level of anxiety (state rather than trait) at the time of the first assessment. However, before delivery and in the postpartum period, there were no significant differences in anxiety scores between the two groups. Women in both groups were positive about being tested for GDM and wished to be tested during future pregnancies. The authors conclude that there were no sustained increased levels of anxiety for women diagnosed with GDM. Concerns expressed about causing sustained maternal anxiety by testing for GDM could not be substantiated. 3 tables. 20 references. •

Risk of Dementia Among Persons With Diabetes Mellitus: A Population-Based Cohort Study Source: American Journal of Epidemiology. 145(4): 301-308. 1997. Summary: This journal article describes a populations-based, historical cohort study, supported by the National Institute on Aging, which examined the risk of dementia among people with adult onset diabetes mellitus (AODM). The study population consisted of all people with AODM residing in Rochester, Minnesota, on January 1, 1970, plus all people who were diagnosed in Rochester or who moved to Rochester with a diagnosis of AODM between January 1, 1970 and December 31, 1984. All patients were followed from AODM diagnosis until onset of dementia, emigration, death, or January 1, 1985. The diagnosis of a dementing illness was made retrospectively through a review of the patients' complete medical records, using standardized criteria. Of the 1,455 cases of AODM followed for 9,981 person-years, 101 developed dementia, including 77 who met criteria for Alzheimer's disease (AD). The risk of dementia for the Rochester residents with AODM was 1.66 times that for residents without dementia. The authors conclude that this study revealed an increased risk of dementia for people with AODM and refuted the hypothesis that AODM is a protective for AD. 2 figures, 2 tables, 35 references. (AA-M).

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Diabetes Mellitus and the Risk of Dementia: The Rotterdam Study Source: Neurology. 53: 1937-1942. December 1999. Summary: This journal article examines the influence of type 2 diabetes mellitus on the risk of dementia and Alzheimer's disease (AD). Data were obtained from a prospective, population-based study of elderly residents of Rotterdam, Netherlands. The sample consisted of 6,370 participants without dementia who were examined at baseline for the presence of type 2 diabetes. Participants were followed for an average of 2.1 years, and incident dementia was diagnosed using a three-step screening and comprehensive diagnostic workup, or review of medical files for those who could not be reexamined. At baseline, 692 (10.9 percent) of the participants had diabetes. During the follow-up, 126 participants developed dementia, of whom 89 had AD. After adjusting for age and sex, diabetes mellitus nearly doubled the risk of dementia (relative risk 1.9) and AD (relative risk 1.9). Patients treated with insulin were at the highest risk of dementia (relative risk 4.3). The fraction of incident dementia attributable to diabetes was 8.8 percent, suggesting that diabetes may play a role in the pathogenesis of dementia in a substantial proportion of cases. 4 tables, 38 references.

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Federally Funded Research on Diabetes Mellitus The U.S. Government supports a variety of research studies relating to diabetes mellitus. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to diabetes mellitus. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore diabetes mellitus. The following is typical of the type of information found when searching the CRISP database for diabetes mellitus: •

Project Title: A RANDOMIZED TRIAL OF LIAISON PSYCHIATRY IN PRIMARY CARE Principal Investigator & Institution: Katon, Wayne J.; Professor; Psychiatry and Behavioral Scis; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JUL-1987; Project End 31-AUG-2005 Summary: (Applicant Abstract): Rationale - The overall goal is to integrate an organized program of improved care of depression into the management of other chronic diseases in primary care. Diabetes mellitus was selected for study because of its prevalence and its large impact on patients and society. If a Depression Care Program (DCP) improves disability and/or disease outcomes among diabetics, it would help establish the core importance of recognition and management of depression for chronic disease management in primary care. Research goals - (1) We will develop population-based data in a managed care setting concerning the effects of depression on the societal impacts of diabetes and on the quality of diabetes (self)-management. By (self)management we refer to both patients' and providers' roles in ongoing care of a chronic illness. (2) We will evaluate a generalizable and economically feasible Depression Care Program (DCP) for population-based management of depression among patients with diabetes mellitus. These goals will be achieved by two related studies. Aims of Study 1: Study 1 will assess the impact and management of depressive illness among diabetic patients, in an epidemiologic study, which will include patients with and without depression. Study 1 will assess the effects of major depression on societal impacts of diabetes (health care costs and disability) and on the quality of diabetes (self) management. These analyses will control for medical co-morbidity and baseline severity of diabetes. Aims of Study 2: We will evaluate whether a Depression Care program (DCP) for major depression in adult patients with Type 2 diabetes mellitus improves depression outcomes, disability outcomes, and glycemic control (as measured by HemoglobinA1C). Secondary process and outcome measures will include adherence to antidepressant and to diabetic medications, severity of symptoms related to diabetes, self-efficacy in managing diabetes, adherence to diabetes (self) management regimens

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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(diet, exercise, glucose monitoring and medications), and health care utilization and costs. We will assess the cost-effectiveness of the DCP relative to care as usual. Data collection: We will carry out these studies by assessing diabetes and depression status in 4500 diabetic patients. Among Type 2 diabetics with major depression, 290 eligible and willing patients will be randomly assigned to a Depression Care Program or to Usual Care, We will evaluate the effectiveness of the Depression Care Program using selfreport data collected at baseline, 3, 6, 12 and 24 months, and by HbA1C values assessed at baseline, 6, 12 and 24 months. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADHERENCE TO IDDM REGIMEN IN URBAN YOUTH Principal Investigator & Institution: Ellis, Deborah; Psychiatry & Behav Neuroscis; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Studies of medical treatment adherence suggest that substantial percentages of persons do not comply with recommendations given to them for the treatment of acute and chronic health conditions. Insulin dependent diabetes mellitus (IDDM) is a chronic health conditions with a highly complex medical regimen. Substantial data exist that suggest that improving treatment adherence and metabolic control in persons with IDDM can delay the onset of diabetes complications. Unfortunately, those adolescents with IDDM with the poorest diabetes self-management and metabolic control are often the most resistant to hospital-based health care and traditional educational/supportive interventions. They are also faced with multiple barriers to improved adherence, including lack of knowledge about diabetes, family disorganization and conflict, high levels of stress and limited social support and access to community resources. Multisystemic Therapy (MST) is a family and communitybased treatment model which has previously been used with adolescents presenting with serious mental health problems. MST has been shown to be both "effective" and highly transportable to the types of community settings where care is most often provided. Preliminary data suggest that MST is a promising approach for adolescents with IDDM as well. The objective of the present study is to utilize MST to improve the treatment adherence and metabolic control of urban adolescents with IDDM and a glycoslated hemoglobin of 11 percent or above. Additional aims are to determine the stability of MST's effects on treatment adherence and metabolic control over a two year interval, to test hypotheses about mediators of MST treatment effects and to assess the cost-effectiveness of MST when compared to the costs of short-term diabetes complications such as diabetic ketoacidosis (DKA). The experimental design for the present study is a randomized controlled trial with a sample of 100 adolescents, 50 of whom will receive MST in addition to their standard care and 50 of whom will receive only standard care of their IDDM. If successful, MST will provide immediate assistance to a vulnerable population at high risk for diabetes complications and quality of life and may also result in substantial health care savings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALPHA AND BETA CELL FUNCTION IN NORMAL AND DIABETIC MAN Principal Investigator & Institution: Gerich, John E.; Professor of Medicine; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-DEC-1986; Project End 31-DEC-2002

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Summary: (Adapted from Applicant's Abstract): Hypoglycemia is a common and potentially serious problem for diabetic patients regardless of whether they are treated with insulin or oral agents. Conventional risk factors (wrong insulin doses, skipped or delayed meals, exercise) explain only a small percentage of episodes. However, hypoglycemia unawareness and abnormal glucose counterregulation have recently been identified as likely explanations for many cases. The overall goal of this grant is to delineate the mechanisms responsible for hypoglycemia unawareness and for abnormal glucose counterregulation in diabetic patients. The Specific Aims of the grant application are: A) To establish the mechanisms responsible for hypoglycemia unawareness in insulin dependent Type I diabetes. The investigators will; 1) establish the normal threshold for induction of hypoglycemia unawareness by hypoglycemia and test the hypothesis that in diabetic patients the threshold is reduced; 2) test the hypothesis that hypoglycemia unawareness in diabetic individuals involves diminished beta adrenergic sensitivity; 3) test the hypothesis that hypoglycemia per se reduces beta adrenergic sensitivity; 4) test the hypothesis that there are two types of hypoglycemia unawareness - an acute reversible type due to recurrent hypoglycemia and another chronic irreversible type related to duration of diabetes, possibly representing an encephalopathic complication of diabetes. B) To assess the mechanisms responsible for impaired glucose counterregulation in noninsulin dependent diabetes mellitus. The investigator will test the hypotheses that 1) reduced glucagon responses are due to increased plasma free fatty acid levels; 2) that increased catecholamine responses are secondary (e.g. compensatory) to reduced glucagon responses; 3) that increased catecholamine responses are in part the result of poor metabolic control; 4) that subnormal increase in glucose production during hypoglycemia results from impaired glucagon responses; 5) that enhanced suppression of glucose utilization results from the effects of increased catecholamine responses on muscle; and 6) that increased muscle glycogenolysis provides gluconeogenic precursors and promotes the compensatory increase in glucose production observed during hypoglycemia. To achieve these aims the investigator will use a combination of glucose clamp, isotope and limb balance techniques in conjunction with pharmacologic interventions in normal volunteers and in research subjects having either Type I or Type II diabetes. Better understanding of the pathogenesis of hypoglycemia unawareness and abnormal glucose counterregulation should make treatment of diabetes safer and improve the chances of achieving optimal glycemic control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AN ALTERED PEPTIDE LIGAND TO PREVENT TYPE 1 DIABETES Principal Investigator & Institution: Marks, Jennifer B.; Medicine; University of MiamiMedical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2001; Project Start 29-SEP-2001; Project End 31-AUG-2008 Summary: (provided by applicant) Type 1 diabetes mellitus occurs in genetically predisposed individuals as a consequence of the progressive, selective destruction of the pancreatic beta-cells mediated by autoreactive T-cells. Our long-range goals are to understand the natural history of Type 1 diabetes and to participate in the evaluation of potential new approaches to prevent or ameliorate this disease. The objectives of this application are threefold: 1) to complete the ongoing Diabetes Prevention Trial-Type 1 (DPT-1), 2) to be involved in the design and implementation of new intervention strategies and, 3) to propose a novel intervention strategy, to test the effects of an altered peptide ligand (APL), NBI-6024 (Neurocrine Biosciences), in individuals at risk for clinical Type 1 diabetes. The central hypothesis of this proposed study is that

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administration of this APL, containing two natural L-amino acid substitutions from the insulin B-chain (9-23) region, will temper the destructive autoimmune process leading to Type 1 diabetes, preserving beta-cells and their insulin-secreting capacity. The rationale for this study is that, if treatment with this APL is safe and effective at stopping or slowing disease progression in a population at defined risk, it could be tested at an earlier stage of diabetes development, in those with less well-defined risk, and possibly result in large-scale prevention. We will test the central hypothesis of our proposed study and accomplish the objectives as a TriaINet Clinical Center by pursuing the following three Specific Aims: 1. Complete the DPT-1 protocols and achieve their objectives, 2. Establish a network of collaborating investigators to participate in the design and conduct of future studies to evaluate new approaches to prevent or ameliorate Type 1 diabetes, 3. Evaluate the effects of intervention with an APL on progression to clinical diabetes in individuals at risk for Type 1 diabetes. It is our expectation that the DPT-1 protocols will be successfully completed, and that insulin administration will alter the destructive immune response in the beta-cells, and attenuate beta-cell autoimmunity, thereby preventing or delaying the development of Type 1 diabetes. The data collected will also better characterize the natural history of Type 1 diabetes disease development. It is also our expectation, based on our Clinical Center performance in the DPT-1, and on the expertise of our investigators, that our contribution to the Diabetes TriaINet will help to ensure its successful implementation and facilitate its functioning as envisioned in future intervention trials. Additionally, we will test the hypothesis that our innovative intervention plan based on the administration of APL NBI-6024 will prevent or reduce disease progression. If not prevented, a treatment effect that preserves beta-cell function in those who do develop diabetes will provide an important clinical benefit. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANS HYPOGLYCEMIA INDUCED GLUCAGON SECRETION IN DIABETES Principal Investigator & Institution: Havel, Peter J.; Nutrition; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2001; Project Start 26-APR-1997; Project End 31-MAR-2002 Summary: (Adapted from applicant's abstract): The objective of the studies outlined in this proposal is to investigate four fundamental aspects of the physiology and pathophysiology of autonomic regulation of glucagon secretion during hypoglycemia in nondiabetic animals and in animal models of diabetes. Hypoglycemia is a common and serious complication of insulin-treated diabetes mellitus in humans which limits the ability to attain improved glycemic control. The Diabetes Control and Complications Trial found a dramatic decrease of diabetic retinopathy and nephropathy with intensive therapy, but at a cost of a three-fold increase of severe hypoglycemia. Increased secretion of glucagon is a primary factor for recovery from insulin-induced hypoglycemia in nondiabetic humans. Activation of the autonomic nervous system has been demonstrated to make an important contribution to hypoglycemia-induced glucagon secretion in several species including dogs and rats, however, the role of the autonomic nervous system in humans is controversial and experiments of this type in nonhuman primates as models of human physiology have not been previously conducted. In diabetic humans, the glucagon and certain autonomic responses to hypoglycemia are often impaired. The etiology and time of onset of this impairment is poorly understood. Potential factors that may be involved include, but are not limited to, hypoglycemia-associated autonomic failure and autonomic neuropathy. Autonomic

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Diabetes Mellitus

and glucagon responses to hypoglycemia are also known to be impaired in some animal models of diabetes, including diabetic rats, although few mechanistic studies have been conducted to examine the underlying etiology, nor has it been determined if pharmacological interventions can to prevent or decrease the counterregulatory defects. To address these deficits in the understanding of t he regulation of hypoglycemiainduced glucagon secretion: 1) Experiments will be conducted to examine the autonomic contribution to hypoglycemia-induced glucagon secretion in a nonhuman primate (rhesus monkeys) in the absence of diabetes. 2) To define the timing of the onset of impaired autonomic activation and glucagon secretion during hypoglycemia in rhesus monkeys with chemically-induced (streptozotocin) diabetes and the effects of different levels of metabolic control on the deficits. 3) A series of mechanistic studies will conducted in streptozotocin diabetic rats to investigate whether defects in of autonomic activation or reduced A-cell secretory responses to autonomic stimulation could contribute to impaired glucagon secretion and to determine the effects of different treatment regimens, designed to maximize chronic hyperglycemia or induce antecedent hypoglycemia, on autonomic responses and glucagon secretion. 4) Autonomic and glucagon responses to hypoglycemia will be examined in streptozotocin diabetic rats treated with pharmacologic agents that have been shown to ameliorate neural dysfunction in diabetic rats. Collectively, these experiments will lead to greater understanding of the pathophysiology and treatment of impaired hypoglycemic counterregulation in diabetes and the greater use of animal models for this area of investigation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTI-APOPTOTIC ALLOTRANSPLANTATION

GENE

THERAPY:

Principal Investigator & Institution: Giannoukakis, Nick; Children's Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 15213

ISLET Hosp

Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant) Type 1 diabetes mellitus, also termed insulindependent diabetes mellitus (IDDM) is an autoimmune disease that specifically targets the pancreatic beta cells of the islets of Langerhans in a T-lymphocyte-mediated destruction. While insulin replacement therapy corrects the hyperglycemia, it is not a cure, since most IDDM patients eventually succumb to the complications associated with imprecise glucose homeostasis. One approach that can restore tight glycemic control is the replacement of beta cells in the form of islet allografts or xenografts. The latter may not become a clinical reality anytime soon primarily because of concerns for zoonoses. Allografts are ethically acceptable, yet they face both alloimmune rejection as well as autoimmune destruction following transplantation. It appears that three distinct death effector pathways are responsible for beta cell destruction: 1) Fas, 2) tumor necrosis factor alpha and 3) perforin/granzyme B. Similar to autoimmune destruction, it appears that Fas, TNFa and perforin/granzyme B are important death effectors in allograft rejection of islets. Genetic engineering of islets to produce inhibitors of these pathways may facilitate allogeneic islet transplantation and may result in long-term survival. In the non-obese diabetic (NOD) mouse model, engineering islets ex vivo to express a variety of immunoregulatory cytokines and proteins has resulted in significant, but not indefinite, prolongation of allogeneic islet transplant survival. One important reason why long-term or indefinite allograft survival has not been achieved is the nature of the gene delivery vectors, most of which are of viral origin and highly immunogenic or toxic to islet cells. Recent engineering of lentiviruses including human

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immunodeficiency virus (HIV-1), feline immunodeficiency (FIV) and equine infectious anemia viruses (EIAV), has resulted in vectors that are able to infect non-dividing cells, are non-immunogenic in vivo and can stably integrate into the host cell. These desirable characteristics of lentiviral vectors as gene delivery vehicles for islets ex vivo, are in contrast to the highly immunogenic, transient and toxic nature of vectors that have been recently used in islet gene transfer strategies (adenovirus, herpes simplex). While HIVbased lentiviral vectors have been demonstrated to readily infect human islets, the nature of the virus strain is a significant impediment for clinical applications. EIAV, on the other hand, offers the same characteristics as HIV and is not pathogenic in humans. The focus of this proposal is to demonstrate that soluble antagonists of Fas, TNF and granzyme B can protect islets in culture from apoptosis activation and to further develop the EIAV lentiviral system as an efficient gene delivery vector of cDNAs encoding inhibitors of Fas, TNFa and perforin/granzyme B-dependent death effector pathways, alone or in combinations. This may be a desirable approach to facilitate allogeneic islet transplantation as a possible therapy for IDDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIBODIES TO RECOMBINANT AUTOANTIGENS: PREDICTION Principal Investigator & Institution: Eisenbarth, George S.; Executive Director; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 31-JUL-2005 Summary: (provided by applicant): The OPT -1 trial, whose clinical component is sponsored by the National Institutes of Health, is testing the hypothesis that parenteral or oral insulin administration will delay the development of type 1 diabetes amongst cytoplasmic ICA positive relatives of patients with diabetes. The trial represents the largest evaluation of first degree relatives ever undertaken with more than 80,000 relatives screened, and more than 100,000 sera samples analyzed for cytoplasmic ICA, GAO65 and ICA512 (IA-2) autoantibodies and 3,000 analyzed for insulin autoantibodies (micro-lAA assay) under the aegis of this grant. A supplement to this grant has allowed limited one time "staging" of a subset of relatives with "biochemical" autoantibodies but lacking cytoplasmic ICA. Preliminary results indicate: One half of cytoplasmic ICA positive individuals lack all biochemical autoantibodies and have a low probability of being eligible on Staging for the OPT -1 trial. Approximately one fourth of relatives expressing multiple autoantibodies are cytoplasmic ICA negative. Expression of "biochemical" autoantibodies is related to relationship to proband and HLA status. A new micro-insulin autoantibody assay (micro-lAA) has a higher correlation with multiple autoantibody expression compared to the standard anti-insulin assay. A subset of DaB 1 *0602 positive individuals progress to overt diabetes. We believe from the preliminary data that "biochemical" autoantibody determination will be essential for future trials of type 1 A diabetes prevention. Nevertheless specific predictive paradigms cannot yet be precisely specified (too few determinations of micro-IAA (insulin autoantibody), and too little follow up of ICA negative biochemical autoantibody positive relatives). It is now essential to take advantage of the cohorts already assembled and new screenees over the next several years to obtain adequate prospective metabolic and immunologic evaluation. Newer assays (including epitope specific assays and subclass specific assays) combined with the unique OPT clinical study, will be important both for the practical development of "biochemical" autoantibody prediction and understanding of the "natural history" and pathogenesis of type 1A diabetes and response to "insulin" therapy. The current grant seeks support to continue to determine

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Diabetes Mellitus

GAO65 and ICA512 (IA-2) autoantibodies on new samples and to apply new assays, to measure with the recently developed high-throughput insulin autoantibody assay all samples, to prospectively evaluate on an annual basis cytoplasmic ICA negative, biochemical autoantibody positive individuals, to analyze genetic determinants of autoantibody phenotype and metabolic progression, as well as further analyze the wealth of accumulating data. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIGAD MAB POLYMER CONJUGATES FOR DIABETES TREATMENT Principal Investigator & Institution: Kim, Sung W.; Professor; Pharmaceutics/Pharmaceutl Chem; University of Utah 200 S University St Salt Lake City, Ut 84112 Timing: Fiscal Year 2001; Project Start 15-APR-1997; Project End 31-MAR-2003 Summary: (Adapted from the applicant's abstract) Insulin dependent diabetes mellitus (IDDM Type I) is the result of autoimmune destruction of insulin producing beta cells. Disease progression is evidenced by multiple autoantibodies responding in a cascade mechanism, wherein the first antigen induces the activation of the immune system, leading to destruction of beta cells and consequently, exposure of other antigens and autoantibodies. Glutamic acid decarboxylase (GAD) is a primary autoantigen involved in the cascade. One underlying hypothesis of this study is that injected anti-GAD derivatives and conjugates will bind to the GAD antigen, blocking the antigenic determinant and preventing immune recognition by lymphocytes. The applicants' laboratory routinely isolates anti-GAD-IgG and has tested it to prevent IDDM onset in nonobese diabetic (NOD) mice. At 32 weeks of age, a significant decrease in the incidence of diabetes was observed in the anti-GAD treatment group (85 percent) (p