Diabetes - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References 0597838461, 9780597838460, 9780585494487

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

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: 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: 0-597-83846-1 1. Diabetes-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. 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 .................................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Diabetes....................................................................................... 13 E-Journals: PubMed Central ....................................................................................................... 52 The National Library of Medicine: PubMed ................................................................................ 73 CHAPTER 2. NUTRITION AND DIABETES ....................................................................................... 121 Overview.................................................................................................................................... 121 Finding Nutrition Studies on Diabetes ..................................................................................... 121 Federal Resources on Nutrition ................................................................................................. 128 Additional Web Resources ......................................................................................................... 128 CHAPTER 3. ALTERNATIVE MEDICINE AND DIABETES ................................................................ 135 Overview.................................................................................................................................... 135 National Center for Complementary and Alternative Medicine................................................ 135 Additional Web Resources ......................................................................................................... 152 General References ..................................................................................................................... 173 CHAPTER 4. DISSERTATIONS ON DIABETES .................................................................................. 175 Overview.................................................................................................................................... 175 Dissertations on Diabetes .......................................................................................................... 175 Keeping Current ........................................................................................................................ 196 CHAPTER 5. CLINICAL TRIALS AND DIABETES ............................................................................. 197 Overview.................................................................................................................................... 197 Recent Trials on Diabetes .......................................................................................................... 197 Keeping Current on Clinical Trials ........................................................................................... 222 CHAPTER 6. PATENTS ON DIABETES ............................................................................................. 225 Overview.................................................................................................................................... 225 Patents on Diabetes.................................................................................................................... 225 Patent Applications on Diabetes................................................................................................ 247 Keeping Current ........................................................................................................................ 264 CHAPTER 7. BOOKS ON DIABETES ................................................................................................. 265 Overview.................................................................................................................................... 265 Book Summaries: Federal Agencies............................................................................................ 265 Book Summaries: Online Booksellers......................................................................................... 316 The National Library of Medicine Book Index ........................................................................... 322 Chapters on Diabetes.................................................................................................................. 324 Directories.................................................................................................................................. 343 CHAPTER 8. MULTIMEDIA ON DIABETES ...................................................................................... 347 Overview.................................................................................................................................... 347 Video Recordings ....................................................................................................................... 347 Audio Recordings....................................................................................................................... 382 Bibliography: Multimedia on Diabetes ...................................................................................... 386 CHAPTER 9. PERIODICALS AND NEWS ON DIABETES ................................................................... 389 Overview.................................................................................................................................... 389 News Services and Press Releases.............................................................................................. 389 Newsletters on Diabetes............................................................................................................. 394 Newsletter Articles .................................................................................................................... 395 Academic Periodicals covering Diabetes .................................................................................... 406 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 409 Overview.................................................................................................................................... 409 NIH Guidelines.......................................................................................................................... 409

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Contents NIH Databases........................................................................................................................... 411 Other Commercial Databases..................................................................................................... 422 The Genome Project and Diabetes.............................................................................................. 423 APPENDIX B. PATIENT RESOURCES ............................................................................................... 429 Overview.................................................................................................................................... 429 Patient Guideline Sources.......................................................................................................... 429 Associations and Diabetes.......................................................................................................... 532 Finding Associations.................................................................................................................. 536 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 539 Overview.................................................................................................................................... 539 Preparation................................................................................................................................. 539 Finding a Local Medical Library................................................................................................ 539 Medical Libraries in the U.S. and Canada ................................................................................. 539

ONLINE GLOSSARIES................................................................................................................ 545 Online Dictionary Directories ................................................................................................... 550 DIABETES DICTIONARY........................................................................................................... 551 INDEX .............................................................................................................................................. 674

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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 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, 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, 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. 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, 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. 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 Overview In this chapter, we will show you how to locate peer-reviewed references and studies on diabetes.

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, 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” (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: •

Is Diabetes Associated With Cognitive Impairment and Cognitive Decline Among Older Women? Source: Archives of Internal Medicine. 160: 174-180. 2000. Summary: This journal article describes a study of the association between diabetes and cognitive decline among older women. The sample consisted of 9,679 communitydwelling white women, aged 65 years and older, from four research centers in the United States. Physician-diagnosed diabetes and other aspects of health history were assessed by interview. Cognitive function was assessed with the Digit Symbol test, the Trails B test, and a modified version of the Mini-Mental State Examination (m-MMSE) at baseline and 3 to 6 years later. Women with diabetes (n=682) had lower baseline scores than those without diabetes on all three tests of cognitive function, and experienced an accelerated cognitive decline on the Digit Symbol test and m-MMSE. Diabetes also was

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associated with increased odds of major cognitive decline (defined as the worst 10th percentile change) on the Digit Symbol and Trails B tests after controlling for age, education, stroke, depression, visual impairment, heart disease, hypertension, physical activity, estrogen use, and smoking. Women who had diabetes for more than 15 years had a 57 to 114 percent greater risk of major cognitive decline than those without diabetes. 1 figure, 3 tables, 46 references. (AA-M). •

Diabetes and Dementia in Long-Term Care Source: JAGS. 47(4): 423-429. April 1999. Summary: This study examined the presence or absence of dementia and the prevalence rates for different dementias in patients with and without adult onset diabetes (AODM). A group of 476 long-term care residents (mean age 74.8 years) participated. Demographic data and the presence of dementia and diabetes were determined from chart data; and hypertension, myocardial infarction, congestive heart failure, and hypercholesterolemia were determined through chart diagnoses. NINDS-ADRDA criteria were used for diagnoses of probable or possible AD. Results show 21 percent (99) of the residents had AODM; patients with probable and possible Alzheimer's disease (AD) were 0 and 6.1 percent, respectively; and 47.4 percent of the patients with vascular dementia had AODM. Age, sex, and race influenced both the risk of having a dementia as well as the type of dementia. When these variables were adjusted for multiple logistic regression analysis, results show AODM was still a robust predictive factor because of its significant negative association with AD. Patients with unspecified dementias or no dementia showed rates of AODM (about 20 percent) that were roughly comparable with and intermediate between vascular dementia and AD. The study shows AD diagnosed clinically and AODM did not co-occur, whereas AODM was associated with vascular dementia diagnosed clinically. Conversely, in non-AD, nonvascular dementias diagnosed clinically, the rates of AODM were equivalent to those in nondemented patients. 4 tables, 32 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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Risk of Dementia Among Persons With Diabetes Mellitus: A Population-Based Cohort Study Source: American Journal of Epidemiology. 145(4): 301-308. 1997.

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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). •

Feet First: Diabetes Care Source: AJN. American Journal of Nursing. 99(2): 26-34. February 1999. Summary: This journal article provides nurses with information on the care of foot problems among people who have diabetes. Foot problems are the most common cause of hospitalization for people who have diabetes. People who have diabetes have many complications that can cause chronic skin ulcers. The main etiologic mechanisms involved in the formation of diabetic ulcers are ischemia, neuropathy, and infection. Ischemia occurs when inadequate perfusion leads to cellular death. Neuropathy occurs when a disturbance in metabolism caused by hyperglycemia results in reduced blood flow and subsequent nerve damage. Infections occur as the neuropathy and vascular disease associated with diabetes create opportunities for microbial invasion. Infections on the skin surface usually result from aerobic Gram-positive cocci, nail infections may be caused by fungi, and deeper infections may involve aerobic Gram-negative bacilli and anaerobic organisms. Superficial foot ulcers usually do not threaten the limb, but deep ulcers with polymicrobial infections extending into the subcutaneous tissue are limb threatening. Mechanisms of injury include mechanical stress and shearing. Charcot foot, a form of diabetic osteoarthropathy, is usually limited to people who have moderate to severe neuropathy and is believed to be triggered by an incidental trauma. A foot ulceration risk profile includes both external and internal factors. Tests for assessing risk for ulcer development include the Semmes Weinstein monofilament esthesiometer and neuropathy classification. Wound management involves classifying the ulcer, relieving pressure on the ulcerated foot with total contact casting, removing necrotic tissue and exudate, cleansing and dressing the wound with the appropriate products, and providing followup care. Other treatment methods include taking the drug pentoxifylline and undergoing arterial reconstruction surgery. Patient education is an important part of foot ulcer prevention. 2 tables and 8 references.

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Charcot Foot in Diabetes: Six Key Points Source: American Family Physician. 57(11): 2705-2710. June 1998. Contact: American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237 or (913) 906-6000. E-mail: [email protected]. Website: www.aafp.org.

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Summary: This journal article provides health professionals with information on the diagnosis and management of Charcot foot in people who have diabetes. Although the exact pathogenesis is unknown, underlying sensory neuropathy is nearly universal. Arteriovenous shunting due to autonomic neuropathy is also thought to have a role in the condition. Repeated unrecognized microtrauma or an identifiable injury may be the inciting factors for Charcot foot, which commonly goes unrecognized, particularly in the acute phase, until severe complications occur. Early recognition and diagnosis, immediate immobilization, and a lifelong program of preventive care can minimize the morbidity associated with this potentially devastating complication of diabetic neuropathy. If unrecognized or improperly managed, Charcot foot can have disastrous consequences, including amputation. The acute Charcot foot is usually painless and may mimic cellulitis or deep venous thrombosis. Although the initial radiography may be normal, making diagnosis difficult, immediate detection and immobilization of the foot are essential to the management of Charcot foot. A lifelong program of patient education, protective footwear, and routine foot care is required to prevent complications such as foot ulceration. Reconstructive surgery is reserved for patients who have recurrent ulceration despite compliance with a prescribed treatment regimen. 7 figures and 6 references. (AA-M). •

Colorectal Cancer Screening in North Carolina: Associations With Diabetes Mellitus and Demographic and Health Characteristics Source: Preventive Medicine. 32(2):163-167, February 2001. Summary: Researchers investigated factors associated with colorectal cancer screening behavior, including the presence of diabetes mellitus. The study involved data from the North Carolina Behavioral Risk Factor Surveillance System of 1993, 1995, and 1997. Researchers included only people over age 49 years, whom they stratified according to gender, race, age, education level, income, self-rated health, health care coverage, and self-report of diagnosed diabetes. They evaluated respondents' self-reported screening rates within the guidelines for fecal occult blood testing (FOBT) and sigmoidoscopy/proctoscopy (sig/proct). Results indicated that overall, 28.6, 27.2, and 19.7 percent, respectively, had received either FOBT or sig/proct within guidelines. Respondents' screening rates varied by certain demographic variables (e.g., gender, race, income, and health insurance) but not by diabetes mellitus status. However, the presence of diabetes mellitus changed some relationships between screening and some demographic/health characteristics. The researchers conclude that people with diabetes mellitus in North Carolina are as likely to get colorectal cancer screening, but some groups with diabetes mellitus (ethnic minorities, persons of low socioeconomic status) may be at high risk for not getting screened. Educational efforts to increase screening should target these groups. 2 tables, 16 references.

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Screening Mammogram Utilization in Women With Diabetes Source: Diabetes Care. 24(12):2049-2053, December 2001. Summary: Researchers examined utilization of screening mammography by women with diabetes. The purpose of the case control study was to test the hypothesis that women with diabetes have fewer screening mammograms than women who are not diabetic. The cases consisted of 424 women with diabetes, age 50 to 75 years, who received their primary care from general internists at a large multispecialty group practice in Rochester, Minnesota. The cases were identified from a database of patients diagnosed with diabetes created and maintained by the Mayo Clinic at Rochester. The controls consisted of 845 females without diabetes, matched to the cases by age,

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provider, and date of primary care visit. Researchers reviewed records of the cases and controls to determine the percentage who had had a screening mammogram 1 year before or 30 days after an index date, defined as the most recent care visit after August 1997 and before January 2000. The mean age of the cases and controls was 64 years. Women with diabetes were more likely to be insured through Medicaid or Medicare than the controls, 60.4 versus 52.0 percent, respectively. Cases were also more likely to be non-Caucasian than the controls, 4.9 versus 1.9 percent. Fewer women with diabetes had a mammogram than women without diabetes, the percentage being 78.1 versus 84.9 percent. Logistic regression analysis applied to the data indicated that the decrease in mammography utilization by the cases was statistically significant. After adjusting for medical insurance status and race, case women with diabetes still had a lower rate of mammography use. Researchers conclude that women with diabetes were significantly less likely to participate in screening mammography than women without diabetes. Special attention should be given to encouraging use of screening mammography in women with diabetes. 2 tables, 23 references. •

Low National Breast and Cervical Cancer-screening Rates in American Indian and Alaska Native Women With Diabetes Source: Journal of the American Board of Family Practice. 13(4):239-245, July-August 2000. Summary: Researchers determined national breast and cervical cancer screening rates for American Indian and Alaska Native women with diabetes, using data from the Indian Health Service (IHS) patient care data system. The IHS conducts an annual audit on patients with diabetes, including cancer screening. Researchers extracted cancer screening rates from the 1995 diabetes audit for the 12 IHS areas. These rates were compared with rates for women without diabetes of the same age, 50 to 69 years, by chart review, at four HIS hospitals in the Aberdeen IHS area. Screening rates in the 12 areas varied for women with diabetes who had received (1) a mammogram ever, 35 to 78 percent; (2) a clinical breast examination (CBE) in the last year, 28 to 70 percent; and (3) a Papanicolaou (Pap) smear in the last year, 26 to 69 percent. The Aberdeen IHS area women with diabetes had 51 percent more clinic visits per year than women without diabetes, but the groups had similar screening rates. Breast cancer screening rates were highest in the Alaska, Albuquerque, and Portland IHS areas, and lowest in the Tucson, Navajo, Phoenix, and Nashville HIS areas. Pap smear and CBE rates were similar for all areas except Tucson. Pap smear rates were highest in the Alaska, Albuquerque, and Portland HIS areas and lowest in the Aberdeen, Phoenix, Nashville, and Oklahoma IHS areas. The researchers conclude that cancer screening rates for American Indian and Alaska Native women vary by region. In the Aberdeen IHS area, women with diabetes had more visits (missed opportunities) than women without diabetes, but similar screening rates. 4 figures, 1 table, 13 references.

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Use of Alternative Therapies by Diabetes Educators Source: Diabetes Educator. 25(6): 945-946, 948-950, 954, 956. November-December 1999. Summary: This journal article describes a study of the extent to which diabetes educators use or recommend alternative therapies in their routine care. A second purpose was to determine if any correlations exist between educators' demographic characteristics and use of alternative therapies. A total of 2,850 questionnaires were sent to members of the American Association of Diabetes Educators in the western half of the United States; 829 questionnaires (34 percent) were returned. Sixty-three percent of the respondents reported using or recommending alternative therapies. Physical activity

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and lifestyle diets were among the most frequently used or recommended therapies; other commonly used or recommended therapies include self-help groups, laughter and humor, relaxation therapy, prayer, imagery or visualization, meditation, massage, and music therapy. Gender, age, ethnicity, professional specialty, and years in diabetes education were significantly correlated with the use of certain alternative therapies. The article has 3 tables and 20 references. •

Maternally Inherited Diabetes and Deafness: A Multicenter Study Source: Annals of Internal Medicine. 134(9 Part 1): 721-728. May 1, 2001. Contact: Available from American College of Physicians-American Society of Internal Medicine. 190 North Independence Mall West, Philadelphia, PA 19106-1572. Summary: Maternally inherited diabetes and deafness (MIDD), which is seen in 0.5 percent to 2.8 percent of patients with type 2 diabetes mellitus, is related to a point mutation at position 3243 of mitochondrial (mt) DNA. The clinical description of MIDD is incomplete. This article reports on a study of the clinical presentation and complications of diabetes in patients with MIDD, undertaken to identify clinical characteristics that may help select patients with diabetes for mtDNA mutation screening. The study included 54 patients with type 2 diabetes mellitus and the mtDNA 3243 mutation, from 16 French departments of internal medicine, diabetes, and metabolic diseases. On average, patients with MIDD were young at diabetes onset and presented with a normal or low body mass index. None were obese; 73 percent of subjects had a maternal family history of diabetes. Diabetes was non insulin dependent at onset in 87 percent of patients; however, 46 percent of patients had non insulin dependent disease at onset but progressed to insulin therapy after a mean duration of approximately 10 years. Neurosensory hearing loss was present in almost all patients. Of the patients who received an ophthalmologic examination, 86 percent had macular pattern dystrophy (a specific retinal lesion). Myopathy (muscle weakness and wasting) was found in 43 percent of patients, 15 percent had cardiomyopathy (wasting and weakness of the heart muscles), and 18 percent (9 of 51 patients) had neuropsychiatric symptoms. The prevalence of diabetic retinopathy (eye disease) was 8 percent among patients who received an ophthalmologic examination, lower than expected after a mean 12 year duration of diabetes; prevalence of kidney disease was 28 percent. This suggests that a specific renal involvement was the result of mitochondrial disease. The authors conclude that MIDD has a specific clinical profile that may help identify patients with diabetes who should undergo mtDNA testing. 2 figures. 1 table. 46 references.

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Cochlear Dysfunction in Type 2 Diabetes: A Complication Independent of Neuropathy and Acute Hyperglycemia Source: Metabolism. 48(11): 1346-1350. November 1999. Contact: Available from W.B. Saunders Company. Metabolism, Periodicals Department, P.O. Box 628239, Orlando, FL 32862-8239. (800) 654-2452. Summary: This article reports on a study which investigated the effects of type 2 diabetes mellitus on evoked otoacoustic emissions (eOAEs) elicited by clicks in subjects with normal hearing; the involvement of the central (CNS) and peripheral nervous system and acute hyperglycemia were also investigated. In Study I, 110 patients with type 2 diabetes and 106 controls were investigated by eOAEs; central and peripheral neuropathy were evaluated respectively by auditory brainstem responses (ABR) and according to San Antonio Consensus Conference criteria. In Study II, 10 healthy men and 10 men with type 2 diabetes, all with normal eOAEs, underwent a 5 hour

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hyperglycemic clamp study (eOAEs were performed before and during the hyperglycemic clamp). In Study I, eOAEs were impaired in 51.8 percent of the subjects with diabetes, compared to 4.7 percent of the controls. People with diabetes and impaired eOAEs, in comparison to those with normal eOAEs, were older, had diabetes longer, achieved poorer metabolic control, and had more peripheral neuropathy. In Study II, there were no significant changes in eOAE intensities compared with basal values during the entire hyperglycemic clamp in either diabetic or control subjects. The eOAE dysfunction does not associate with either an injury to the auditory nervous pathway or diabetic microvasculopathy. The apparent interference of peripheral neuropathy in eOAEs loses significance when corrected for the duration of diabetes. 1 figure. 5 tables. 30 references. •

Hearing Loss in Diabetes Source: Journal of Laryngology and Otology. 107(3): 179-182. 1993. Summary: This article reports on a study in which 44 people with insulin-dependent diabetes (IDDM) were compared with 38 age-and sex-matched controls to determine the relationship between diabetes and sensorineural hearing loss. All had pure tone and speech audiometry performed, with any person with diabetes showing sensorineural deafness undergoing stapedial reflex decay tests. In 14 people with diabetes, stapedial reflex tests showed no tone decay in any patient, but seven showed evidence of recruitment. Analysis of variance showed the people with diabetes to be significantly more deaf than the control population. The hearing loss affected high frequencies in both sexes, but also low frequencies in the males. Speech discrimination scores showed no difference. Duration of diabetes, insulin dosage, and family history of diabetes were not found to have a significant effect on threshold. 1 figure. 2 tables. 33 references. (AAM).

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Brittle Diabetes: An Update Source: Clinical Diabetes. 10(6): 83-86. November-December 1992. Summary: This article reminds physicians of some of the problems inherent in treating patients with brittle diabetes, defined broadly to include any diabetes patient with wide swings in blood glucose concentration. After a section emphasizing the importance and difficulty of the proper diagnosis of brittle diabetes, the authors focus on seven common causes of brittle diabetes: communication disorders, malingering, factitious disease, gastroparesis, insulin resistance, counterregulatory hormone insufficiency, and drug addiction. The authors note that communication disorders, the most common cause of brittle diabetes in adults, limit the ability of the patient to receive, process, or perform instructions about diabetes care that are given by the physician. The authors discuss the types of communication disorders, clues to diagnosing the role of a communication disorder in brittle diabetes, and treatment strategies.

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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.

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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 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. •

Diabetes and the Gastrointestinal Tract Source: Clinical Diabetes. 18(4): 148-151. Fall 2000. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article considers the interplay between diabetes mellitus and the gastrointestinal (GI) tract. The authors note that GI disorders are common among all people and as many as 75 percent of patients visiting diabetes clinics will report significant GI symptoms. Common complaints in this population may include dysphagia (difficulty swallowing), early satiety (fullness after eating), reflux (return of gastric acid from the stomach up the esophagus, resulting in heartburn), constipation, abdominal pain, nausea, vomiting, and diarrhea. Many patients go undiagnosed and under-treated because the GI tract has not been traditionally associated with diabetes and its complications. As with other complications of diabetes, the duration of the disorder and poor glycemic control seem to be associated with more severe GI problems. Patients with a history of retinopathy (eye disease), nephropathy (kidney disease), or neuropathy (nervous system disease) should be presumed to have GI abnormalities until proven otherwise. The authors review the problems that may be encountered in each part of the GI tract, including the esophagus and stomach (gastroparesis, ulcer disease, candida infections), the small intestine, the colon (including diabetes related diarrhea), the pancreas, and the liver. Symptoms can be complex and varied, because of the impact of diabetes on each part of the GI tract. The workup starts with a thorough patient history and appropriate laboratory, radiographic, and GI testing. In addition to drug therapy, glycemic control, and diet therapy play an important role in managing GI disorders in people with diabetes. Accompanying the article is a patient education sheet that includes an eight item questionnaire for screening patients for GI problems associated with their diabetes.

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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

Studies 11

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. •

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 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.

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Gallstones and Diabetes: A Case-Control Study in a Free-Living Population Sample Source: Hepatology. 25(4): 787-790. April 1997. Summary: This article reports on a case-control study to determine the prevalence of diabetes mellitus in a group of subjects with gallstones or who have undergone cholecystectomy (cases). The authors compared these subjects with a control group of subjects without gallstones, selected during an epidemiological study. The subjects were matched for sex, age, and body mass index; there were 336 cases and 336 controls, aged 30 to 69 years. All subjects with fasting glycemic levels of less than 140 mg per dL and without a documented history of diabetes were submitted to a simplified oral glucose

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tolerance test (OGTT) and then classified according to the National Diabetes Data Group criteria. The prevalence of diabetes in the subjects affected by gallstone disease was significantly higher than that in controls (11.6 percent versus 4.8 percent). Diabetes was more frequent in subjects with gallstone disease than in the control group, even according to sex (18.3 percent versus 9.9 percent for men; 9.3 percent versus 2.6 percent for women). The authors conclude that an altered glucose metabolism may increase the risk of developing cholelithiasis in certain subjects. 3 tables. 36 references. (AA-M). •

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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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

Studies 13

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).

Federally Funded Research on Diabetes The U.S. Government supports a variety of research studies relating to diabetes. 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. 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. The following is typical of the type of information found when searching the CRISP database for diabetes: •

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

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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to, hypoglycemia-associated autonomic failure and autonomic neuropathy. Autonomic 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: ATHEROSCLEROSIS, DIABETES AND LPL Principal Investigator & Institution: Semenkovich, Clay F.; Professor; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2002 Summary: Adapted from applicant's abstract): Atherosclerosis is common in humans with diabetes. The underlying mechanisms are not completely clear. Common genetic conditions such as heterozygous LPL deficiency could potentiall be involved. However, the exact role of LPL and atherosclerosis, especially in diabetic patients is uncertain. The long term objective of the application is to understand the mechanisms of premature atherosclerosis in diabetic patients The applicants have generated a mouse with heterozygous LPL deficiency. These heterozygous mice have been crossed with low density lipoprotein receptor knockout mice to generate double knockout mice. The investigators have demonstrated the feasibility of diet-induced atherosclerosis in these models, as well as the production of experimental diabetes. The studies proposed will test the hypothesis that genetic heterozygous LPL deficiency promotes atherosclerosis in diabetes. The application has the following Specific Aims: To determine the effects of the LPL deficient heterozygous state alone and in combination with the LDL receptor deficient phenotype on atherosclerosis in mice with streptozotocin-induced diabetes used as a model for Type-I diabetes. To define how the LPL deficient heterozygous state interacts with streptozotocin-induced diabetes to affect vascular wall gene expression and lipoprotein biology. To determine the effects of the LPL heterozygous deficient state alone and in combination with the LDL receptor knockout phenotype on atherosclerosis in mic with dietary-induced diabetes used as a model for Type-II diabetes. To define how the LPL heterozygous deficient state interacts with this model of diabetes to affect vascular wall gene expression and lipoprotein biology.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AUTONOMIC FUNCTION IN INSULIN RESISTANCE AND DIABETES Principal Investigator & Institution: Carnethon, Mercedes R.; Preventive Medicine; Northwestern University Office of Sponsored Programs Chicago, Il 60611 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): This proposal describes a 3-year mentored training program during which the candidate will substantially enhance her knowledge in cardiovascular and endocrine function, acquire additional skills in the clinical assessment of cardiovascular autonomic function, and increase her experience designing and conducting a population-based study. While the candidate has formal training in cardiovascular disease epidemiology, she has no training or experience in the above referenced areas that are critical for success in her area of research. Dr. Philip Greenland, a clinician and epidemiologist who Chairs the Department of Preventive Medicine (DPM), will oversee the scientific and career development aspects of the candidate as described in this proposal as the primary mentor. In addition, Dr. Alan Kadish in the Division of Cardiology, will oversee the candidate's training in cardiovascular electrophysiology and in the assessment of autonomic tone, and Dr. Kiang Liu, a biostatistician/epidemiologist will mentor the candidate in the design and recruitment aspects of the proposed population-based study. Research in this proposal will focus on the temporal association between the autonomic nervous system (ANS) and the development of diabetes and cardiovascular complications from diabetes. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in persons with diabetes, and the ANS has been proposed as a mechanism to explain the association between diabetes and CVD. ANS dysfunction was previously thought to be a late-onset complication of diabetes that was the result of hyperglycemia-associated degradation of the microvasculature. However, evidence that the ANS plays a role in the regulation of glucose and fat metabolism, even in the absence of frank diabetes, makes it plausible that ANS dysfunction occurs early in the temporal sequence for disease. This study proposes to extend beyond previous epidemiological research that has identified the presence of ANS dysfunction in early diabetes, by assessing the type and extent of impairment using tools that have traditionally been used only at the clinical level. The PI hypothesizes that ANS function, as estimated by autonomic innervations, resting autonomic tone, and the autonomic response to physical and pharmacological provocation, predisposes persons to the development of diabetes and diabetes complications, including CVD, when impaired. Specific aims are to: 1) investigate the temporal sequence between ANS dysfunction and the development of diabetes in two established epidemiology studies using available measurements; 2) learn to implement and compare a comprehensive battery of ANS function tests; and, 3) recruit a population sample to compare the cross-sectional relationship between this battery of ANS function tests among healthy persons, persons who are insulin resistant but not diabetic, and persons who are diabetic. Data from these investigations will be used to modify hypotheses and develop a future prospective examination focused on the type and temporal sequence of autonomic impairment in persons with varying levels of insulin resistance, glucose uptake and metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CARDIOVASCULAR RISKS IN ADOLESCENTS WITH DIABETES Principal Investigator & Institution: Faulkner, Melissa S.; None; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2001; Project Start 20-SEP-2000; Project End 31-MAY-2005 Summary: Cardiovascular disease (CV) is a leading cause of morbidity and mortality in the United States. An increase of two to four times in the risk of heart disease is reported in persons with diabetes, regardless of whether they have type 1 or type 2 diabetes. In spite of the magnitude of this problem, few investigators have explored the effects of diabetes diagnosed during youth on the development of cardiovascular disease. The limited research that is available does suggest that cardiovascular risks, such as lipids and lipoproteins, are elevated for youth with type 1 diabetes compared with nondiabetic counterparts. Additionally, a decrease in heart rate variability has been documented for adolescents with type 1 diabetes, although no data were found regarding adolescents with type 2 diabetes. Greater numbers of adolescents are being diagnosed with type 2 diabetes, particularly in minority populations, secondary to sedentary lifestyle behaviors, obesity, and increased dietary fat consumption. The intent of this proposal is to describe differences in adolescents with type 1 and type 2 diabetes pertaining to cardiovascular risks, personal factors, and behavioral factors. In addition, we will examine relationships among these three sets of variables and determine how sociodemographic components influence each set of variables. A descriptive correlational design with a sample of 100 adolescents with type 1 diabetes and 100 adolescents with type 2 diabetes will be used to investigate cardiovascular risks, as well as predisposing factors such as exercise beliefs, level of physical activity, dietary practices, self-competence, and body mass index. Sociodemographic variables such as race, gender, socioeconomic status, family structure and history will be included. Determining variations in cardiovascular risks and predisposing factors for youth with type 1 versus type 2 diabetes is essential prior to designing interventions that promote positive health outcomes, ultimately control escalating costs for diabetes care, and minimize adverse effects on health status and well being. This investigation is particularly relevant given the limited research on cardiovascular risks in adolescents with type 2 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CENTRAL OBESITY AND ALBUMIN EXCRETION IN TYPE 1 DIABETES Principal Investigator & Institution: Sibley, Shalamar D.; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2006 Summary: (adapted from the application) In subjects with diabetes, microalbuminuria predicts end-stage renal disease (ESRD) and cardiovascular disease (CVD). Despite gains, many patients still progress to ESRD and diabetic nephropathy (DN) is the leading cause of ESRD. CVD is the leading cause of death and risk begins to accelerate with microalbuminuria. Central obesity syndrome, which appears to be present in some subjects with type 1 diabetes and many subjects with type 2, increases risk of CVD and elevated albumin excretion rate (AER). This proposal will define the roles of intraabdominal fat (IAF) and the renin-angiotensin system (RAS) in the development of elevated AER and dyslipidemia in subjects with diabetes through an observational cross-sectional study of a subpopulation (three Minnesota cohorts and the Seattle cohort) of the Epidemiology Interventions and Complications Study and an

Studies 17

independently-recruited interventional weight loss study of overweight subjects with type 1 diabetes. Additionally, population studies will examine frequencies of the G-6A angiotensinogen variants in subjects with and without hypertension (HTN) and elevated AER. The specific aims of the project are: (1) to characterize the RAS and its relationship to elevated AER, gender, and IAF (as measured by abdominal CT) in subjects with type 1 diabetes; (2) to define the relationship between IAF, central obesityrelated dyslipidemia, RAS, and AER in subjects with type 1 diabetes; (3) to determine the frequency of the G-6A haplotype subdivisions in subjects with type 1 diabetes and determine the associations of those haplotypes with HTN and AER; and (4) to compare frequencies of the G-6A AGT genotype in the highest and lowest quartiles of diastolic blood pressures among subjects in the top quartile of weight gain on intensive therapy during the Diabetes Control and Complications Trial. These studies will define mechanisms underlying the relationship between central obesity and the earliest stages of DN, providing insights applicable to some subjects with type 2 diabetes and HTN. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CENTRAL OOBESITY SYNDROME IN A SUBSET OF TYPE 1 DIABETES Principal Investigator & Institution: Brunzell, John D.; Prpfessor of Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 01-SEP-1976; Project End 31-MAR-2007 Summary: (provided by applicant): Project 2 started as an ancillary study of lipoprotein metabolism to the NIH sponsored clinical trial of intensive diabetes therapy in type 1 diabetics to prevent microvascular disease called the Diabetes Control and Complication Trial (DCCT). The Epidemiology of Diabetes Intervention and Complications (EDIC) is a ten year non-interventional follow-up of DCCT to evaluate the natural history of macrovascular and nephropathy complications in type 1 diabetes. In DCCT, we found that atherogenic small dense LDL were increased with hyperglycemia, microalbuminuria and were increased in that subset of subjects who gained excess weight as a complication of intensive diabetes therapy during DCCT. Those who gained weight with intensive diabetes therapy were centrally obese, insulin resistant, hypertensive, dyslipidemic and had type 2 diabetic parents. This suggests they had inherited the metabolic-central obesity syndrome in addition to type 1 diabetes. This new proposal will use the phenotypes of 1) excessive weight gain with intensive diabetes therapy and 2) the presence of small dense LDL particles as markers of the central obesity-insulin resistance metabolic syndrome that occurred in this subset of type 1 subjects during intensive diabetes therapy. These markers of the central obesity syndrome will be used to predict the occurrence of cardiovascular events and the development or progression of microalbuminuria during the course of EDIC. Candidate genes for development of the central obesity syndrome and for the interaction of excess weight gain with the development of hypertension will be examined. Intraabdominal fat by CT scan and postheparin plasma hepatic lipase will be measured to further develop the phenotype associated with the excessive weight gain with intensive therapy and with development of nephropathy in the Seattle cohort and three Minnesota cohorts of EDIC. The development of the central obesity syndrome with intensive diabetes therapy in type 1 diabetic patients may predispose them to increased risk of cardiovascular disease and nephropathy. If so, modifications of clinical therapy will need to be made in this subset of individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHICAGO CHILDHOOD DIABETES REGISTRY Principal Investigator & Institution: Lipton, Rebecca B.; Associate Professor; Pediatrics; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2003; Project Start 30-SEP-1992; Project End 31-MAY-2008 Summary: (provided by applicant): Recent increases in childhood diabetes present an urgent public health challenge: to mount effective primary and secondary prevention efforts as soon as possible. We must therefore understand the mechanisms underlying the current epidemic, particularly the interaction of genetics with the changing epidemiology of behavioral risk factors. We propose to investigate the determinants of childhood diabetes risk in affected probands and their family members. This is a competing continuation application for the population-based Chicago Childhood Diabetes Registry. This database represents the largest number of non-Hispanic black children with diabetes worldwide, and the largest patient database for Latino children in the continental US. Ongoing ascertainment of incident cases will provide basic epidemiologic data and will anchor a further effort, in families of affected children, to describe the spectrum of youth-onset glucose intolerance in terms of inheritance and the expression of disease susceptibility alleles within families. We will specifically address these hypotheses: 1. That diabetes in youth is caused by a spectrum of etiologic processes, from the insulinopenia of autoimmune type 1 to obesity-related, insulinresistant type 2 diabetes. A subset of children demonstrate a mixed etiology, with autoimmune beta-cell destruction aggravated by the presence of insulin resistance due to genetic susceptibility, obesity and/or physical inactivity. 2. That secular changes in the epidemiology of childhood diabetes are directly related to changes in the prevalence of both type 1 and type 2 risk factors, including obesity, physical inactivity, and perinatal exposures. 3. That familial aggregation of specific traits affects the risk of chronic complications in young people with diabetes, over and above that of glycemic control. Ultimately, this approach will permit a truly population-based molecular epidemiologic study of early-onset diabetes in families from a range of ethnic groups. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPUTERIZED MOTIVATIONAL INTERVIEWING IN DIABETES Principal Investigator & Institution: Welch, Garry W.; Baystate Medical Center 759 Chestnut St Springfield, Ma 01199 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The management of type 2 diabetes is demanding and complex from the patient's perspective and requires considerable lifestyle and health behavior change. The diabetes educator has a primary role in the provision of behavior change support. However, few educators receive training in communication skills and behavior change counseling. Moreover, there is a paucity of practical, teachable behavioral methods that can be used in busy clinic settings. Motivational Interviewing (MI) is a theory-based approach to behavior change counseling in diabetes. Rollnick et al.'s MI model posits that patient self care motivation is related to two distinct dimensions that must be measured and explored by the educator: patient perceptions of the importance of behavior change and patient self-efficacy that behavior change can be achieved. MI has recently been shown to be effective in brief interventions that target patient motivation in diabetes and other chronic illnesses. Further, computerized assessment tools and structured interview protocols have both been shown to be effective mechanisms for delivering behavior change interventions in busy clinic settings. We have developed a computerized MI-based assessment tool and a

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structured MI-based interview protocol to help diabetes educators deliver an MI intervention to poorly controlled patients with type 2 diabetes. In the proposed randomized, controlled trial there will be 3 active conditions: 1) incorporates both our computerized MI assessment tool and MI interview protocol; 2) uses the computerized assessment alone; 3) uses the interview protocol alone. We expect all active interventions to be superior to our attention control condition in reducing our primary outcome (HbAlc) over the 12-month intervention period, and the combined condition to be superior to either intervention delivered alone. Secondary endpoints will be diabetes quality of life and treatment satisfaction. N=296 adult type 2 patients will be randomized to one of the 4 study conditions and be followed-up at 6 and 12-months. Educator training in MI will involve an intensive one-month training period and monitoring and training during the interventions using standardized procedures and assessments. A contribution of our research will be our careful attention to issues of adherence to the treatment conditions by the study educators. Importantly, we will specifically examine the role of theoretical mediators in a series of hierarchical regression analyses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONSORTIUM LINKAGE STUDIES OF TYPE 2 DIABETES Principal Investigator & Institution: Cox, Nancy J.; Associate Professor; Medicine; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: The transmission of complex phenotypes such as type 2 diabetes is likely to reflect the actions and interactions of multiple genetic and environmental factors. Linkage studies designed to localize genes for type 2 diabetes have yield few regions with highly significant evidence for linkage and fewer still that have been replicated in additional studies. While these results are disappointing, they can hardly be considered surprising. The failure of the current generation of studies to demonstrate conclusive and reproducible localization of the genes contributing to type 2 diabetes likely results from the combined effects of inadequate sample sizes, incorrect or incomplete models for genetic analysis, and the genuine complexity of the genetic component to disease susceptibility. While it is widely recognized that increasing the size of the sample included in linkage studies will provide the power to detect and localize susceptibility loci with modesty or moderate effects, collection of family data is the most expensive and time-consuming aspect of linkage studies. In an effort to maximize the utility of data that already have been collected to map genes for type 2 diabetes, we have formed The International Type 2 Diabetes Linkage Analysis Consortium to combine existing data sets for linkage analysis. The specific aims are: (1) to conduct linkage analyses over all human autosomes and the X chromosome within and across the racial/ethnic groups represented in the combined Consortium data to identify regions most likely to contain type 2 diabetes susceptibility loci; and (2) to conduct additional genotyping in Consortium data in regions of interest identified in analyses of Consortium data and for mutations in diabetes susceptibility loci identified by us or others during the course of this study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONTROL OF NO BY EXERCISE & INSULIN IN DIABETIC HEART Principal Investigator & Institution: Hintze, Thomas H.; Professor; Physiology; New York Medical College Valhalla, Ny 10595

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Diabetes

Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Diabetes is one of the leading causes of cardiovascular death and disability in the United States and despite the treatment with insulin, patients with diabetes still have severe coronary vascular disease and altered cardiac metabolism. The goal of our studies is to better understand the mechanism responsible for diabetic cardiac disease especially the consequences of reduced production of NO on cardiac metabolism. Our approach will combine physiologic studies quantifying NO production and changes in cardiac metabolism over an extended period of time (5 weeks) after alloxan induced diabetes in chronically instrumented conscious dogs with in vitro studies of tissues from those dogs to determine microvessel NO production, ecNOS gene expression and the control of cardiac metabolism by NO. We will examine the potential consequences of alterations in NOS gene expression in the reduced NO production which we have already documented. A major focus of our studies both in vivo and in vitro will be the potential role of NO in the control of cardiac oxygen consumption and myocardial substrate utilization. We hypothesize that the loss of NO production during the development of diabetes contributes to the metabolic consequences of this disease. Since we have previously shown that exercise can upregulate NO production and mild regular exercise is beneficial in patients with diabetes we will test the hypothesis that regular exercise training will at least partially restore NO dependent control of tissue metabolism by increasing ecNOS. Furthermore, we will test the hypothesis that administration of Simvastatin (since "statins" increase the message half life for ecNOS and since our preliminary data suggest that NO production in vivo and in vitro is increased by statins) to correct the decrease in ecNOS enzyme, restores the cardiac metabolic dysfunction associated with diabetes. Thus, our aims will provide for an integrated approach to study: 1) the mechanism of the reduction in NO production we have found in diabetes, 2) the potential that this results in a cardiac metabolic defect, and, 3) the treatment of the cardiovascular complications of diabetes with exercise or Simvastatin corrects the cardiac metabolic defect. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEFINING DIABETES IN YOUTH Principal Investigator & Institution: Hamman, Richard F.; Professor and Chairman; Preventive Med and Biometrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): There is very limited information about the epidemiology of Type 2 diabetes mellitus in youth, though it is believed that the prevalence is increasing rapidly. Risk factors similar to those in adults with Type 2 are thought to be important, (e.g., obesity, insulin resistance, diet, physical activity, positive family history), however, there are no reliable epidemiological studies of these risk factors in youth with type 2 diabetes using appropriate controls. In addition, risk factors such as low birth weight lack of breast-feeding, maternal diabetes during pregnancy and family dysfunction and depressive symptoms have received little epidemiological study in populations other than American Indians. This application addresses the lack of such studies. The Defining Diabetes in Youth (DDY) project will focus on type 2 diabetes in youth aged 10-19, drawing upon the CDC funded SEARCH diabetes registry project in Colorado and South Carolina. The SEARCH project will ascertain all cases of diabetes in youth, collect immunologic, clinical, and metabolic information, and classify cases as Type 1 or 2 diabetes. DDY will only have to recruit appropriate controls aged 10-19 from three ethnic backgrounds including African Americans (AA), Hispanics

Studies 21

(H), and non-Hispanic whites (NHW) to test specific etiologic hypotheses in the cases classified by SEARCH as Type 2 diabetes. It will also explore cardiovascular risk factor differences in youth with Type 2 diabetes and controls, and will evaluate insulin resistance and secretion differences among controls by level of obesity and other factors. The primary design is a case-control study, through which risk factors for diabetes, selected complications and CVD risk factors will be evaluated. The current application is an approved SEARCH ancillary study. Collaborating investigators bring expertise in multiple areas relevant to diabetes in youth, and experience in large epidemiological studies of diabetes (both type 1 and 2) in minority populations. Given the low prevalence of Type 2 in Youth, DDY is an efficient design, since case ascertainment and typing will be conducted by SEARCH, and only control recruitment, addition of new measures, and analysis are requested. The biostatistical analysis, data management and central laboratory will be the same as used in SEARCH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES AND ENDOCRINOLOGY RESEARCH CENTER Principal Investigator & Institution: Accili, Domenico; Professor of Medicine; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 31-JAN-2008 Summary: (provided by applicant): We seek to establish a Diabetes and Endocrinology Research Center at Columbia University. The DERC will promote interactions among research groups in diabetes, immunology, transplantation and obesity at the Naomi Berrie Diabetes Center, The New York Obesity Research Center, and the historically strong groups in arteriosclerosis/lipid research at Columbia University. We envision that these interactions will extend to groups currently pursuing basic research in structural biology, genomics, complications, cell biology and clinical investigators in the areas of body composition, energy expenditure, genetic epidemiology of type 2 diabetes in adolescents, islet transplantation and prevention of diabetes complications. The DERC will strengthen existing NIH training grants in Endocrinology, Metabolism, Pediatrics, Arterioeclerosis, Immunology, Genetics and Obesity by broadening the pool of mentors and laboratories for the trainees' benefit. To meet these goals, the DERC will provide core services in six areas of research: Hormone/metabolite, Protein expression, Immunology/cell banking, Genomics, Analytical determinations of body composition and tissue metabolites, and Mouse phenotyping. Additionally, the DERC will provide opportunity and encouragement for established scientists in other research areas at Columbia University to enter the diabetes field, and will make available initial funding for young investigators through a pilot/feasibility grant program modeled after the existing Naomi Berrie Fellowship Award. The DERC will broaden the research base through program enrichment activities aimed at increasing the awareness of diabetes research in the scientific/academic community of Columbia University and New York City and through more extensive interactions with other academic institutions in the greater New York area. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIABETES COMPUTER HEALTH PERFORMANCE ASSESSMENT Principal Investigator & Institution: Clark, D Joseph.; Videodiscovery, Inc. 1700 Westlake Ave, N, Ste 600 Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2003

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Summary: (Scanned from the Applicant's Abstract): Multimedia computer-based technologies are reshaping the practice of diabetes patient education. We propose to develop a computer-based performance assessment to be targeted for children with diabetes (age 10-17) that will provide a comprehensive measure of patient diabetes health knowledge and skills. The assessment will take the form of rich multimedia dramatized simulations in which a series of decisions and observations must be made. The events will be administered using the Computer Performance Based Assessment system developed by Videodiscovery, Inc. The technology uses distributed Linux based server appliances that provide high bandwidth access to streaming video and text within an institution's network. All logical branching, questions, scoring, and student record keeping are stored in the database on the server. Teachers or medical professionals can review student responses and view a summary performance profile for skill and knowledge objectives. In Phase II, the Diabetes Computer Health Performance Assessment will be field tested in a randomized clinical trial and, after final revisions, will be sold directly to diabetes centers, diabetes educators, or persons with diabetes as a online subscription service or stand-alone CD-ROM. PROPOSED COMMERCIAL APPLICATION: The Computerized Diabetes Health Performance Assessment system will be sold directly to diabetes centers, diabetes educators, or persons with diabetes as an intemet subscription or as stand?alone CD?ROMs. The assessment could be used by state and federal agencies to determine the effectiveness of diabetes health education promotion initiatives. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES ENDOCRINOLOGY RESEARCH CENTER Principal Investigator & Institution: Hsueh, Willa A.; Professor of Medicine and Chief; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 31-JAN-2008 Summary: (provided by applicant) UCLA and UCSD and their affiliated campuses at Cedars-Sinai and Salk, respectfully, have integrated, highly productive and well-funded programs in diabetes and its complications and in endocrinology. Because of growing interaction and collaboration between Los Angeles-based and San Diego-based investigators, the Southern California Diabetes Endocrinology Consortium (SCDEC) was conceived as a means to formalyze, enhance, and continue to fertilize these relationships. By joining forces and aligning common interests, basic and clinical scientists at both Centers have recognized the enormous potential to strengthen and expand their research opportunities and resources. Thus, the SCDEC DERC represents a critical foundation to consolidate diabetes and endocrinology investigation at two premier academic centers. The objectives of the SCDEC DERC are to: 1) Unite investigators from relevant disciplines in a manner that will enhance and extend the effectiveness of their research in diabetes/endocrinology and the complications of diabetes, 2) Foster collaborations between diabetes/endocrinology researchers at UCLA and UCSD so the whole is greater than the sum of its parts, 3) Enhance, support and develop Cores to facilitate diabetes/endocrinology research at UCLA and UCSD, and 4) Develop new areas of research and foster young investigators focused in diabetes and its complications through pilot and feasibility grants. Herein, the SCDEC DERC presents six exceptionally strong Research Bases comprised of 93 talented investigators supported by six Research Cores. The Research Bases include 1. Nuclear (n=10), 2. Signaling (16), 3. Metabolism (21), 4. Macrovascular (23), 5. Microvascular (14), and 6. Beta Cell (10). The Cores are: A. Transgenic and Knockout Mouse, B. Mouse

Studies 23

Phenotyping, C. Transcriptional Genomics, d. Human Genetics, and E. Biochemistry and Molecular Assay. These Cores are designed to specifically meet the greatest needs of DERC investigators. They represent high quality, state-of-the-art and novel technology, which if provided to the SCDEC DERC will bring diabetes and endocrinology research in Southern California to a new level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES EVALUATION IN WASHINGTON (DEW-IT) CLINICAL CEN* Principal Investigator & Institution: Hagopian, William A.; Principal Scientist; Pacific Northwest Research Institute 720 Broadway Seattle, Wa 98122 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 31-DEC-2007 Summary: (provided by applicant): The etiology of Type 1 (autoimmune) diabetes involves both genetic and environmental influences of roughly equal magnitude. Large cooperative arrangements pooling many patient samples have aided in identification of several of the causative genetic polymorphisms. Identification of environmental factors has been more difficult, but should also benefit from a cooperative approach. The Diabetes Evaluation in Washington (DEW-IT) study is a 32,000 subject populationbased screening program, which will identify more than 6,000 young children at elevated genetic risk of future diabetes. Combining subject groups with similarly sized population-based screening studies in the US and elsewhere should make it possible to achieve sufficient sample sizes and statistical power to identify common environmental triggers. We propose to follow subjects at high genetic risk (DEW-IT family and DEW-IT general cohorts) through three putative disease stages: a) seroconversion to single antibody positivity to one of GAD, ICA512/IA2, and insulin, b) progression from one to multiple defined autoantibodies, and c) development of low beta cell function (fasting C-peptide) or clinical diabetes. First degree relatives will be followed sequentially through all stages, but stages b) and c) will be augmented by antibody-positive genetically-at-risk children from the general DEW-IT cohort, prior to intense environmental sampling. Frequent patient sampling will include serum, PBMC, throat swabs, hair, urine and stool. We will also survey children on food intake, vaccinations, allergies, illnesses and other stressors. Environmental sampling will also include selected foodstuffs identified in patient diaries. Genotyping will include HLA DR-DQ and 10 other known diabetes risk loci, as well as 10 other loci designed to detect polymorphisms at beta cell genes known to mitigate toxic exposures. Trios, including both parents, will be collected for TDT analyses. Measured environmental exposures include enteroviruses, dietary mycotoxins, environmental toxins selected by the CDC, and exposures proposed by other sites. Disease progression will be analyzed with respect to gene effects, environmental effects, and gone x environment effects. Disease staging, sample collection and analyses, and statistical approach will follow the consensus approach developed by the consortium. The overall goal is to identify environmental factors initiating and/or propagating the pathogenesis of childhood autoimmune diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIABETES GENOME ANATOMY PROJECT (DGAP) Principal Investigator & Institution: Kahn, C Ronald.; Director; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007

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Summary: (provided by applicant): The Diabetes Genome Anatomy Project (DGAP) represents a new initiative in unraveling the interface between insulin action; insulin resistance and the genetics of type II diabetes. The project was developed in conjunction with NIDDK and in response to the report of the Diabetes Research Working Group, and is presented in the form of a Bioengineering, Bioimaging, and Bioinformatics Research Partnership (BRP), representing the efforts of investigators from five institutions. There are six projects and four cores that form a highly interactive matrix and also serve as a scaffold on which to build future projects or interactions with related projects and grants. The overall goal of the project is to identify the sets of the genes and gene products involved in insulin action and the predisposition to type 2 diabetes, as well as the secondary changes in gene expression that occur in response to the metabolic abnormalities present in diabetes. There are five major and one pilot project involving human and rodent tissues that will allow us to: (1) Create a database of the genes expressed in insulin-responsive tissues, as well as accessible tissues such as lymphocytes, that are regulated by insulin, insulin resistance and diabetes. (2) Assess levels and patterns of gene expression in each tissue before and after insulin stimulation in normal and genetically-modified rodents; normal, insulin resistant and diabetic humans, and in cultured and freshly isolated cell models. (3) Correlate the level and patterns of expression at the mRNA and/or protein level with the genetic and metabolic phenotype of the animal or cell. (4) Generate genomic sequence from a panel of humans with type 2 diabetes focusing on the genes most highly regulated by insulin and diabetes to determine the range of sequence and expression variation in these genes and the proteins they encode, which might affect the risk of diabetes or insulin resistance. The resultant information will be used to create a highly annotated and interactive public database, standardized protocols for gene expression and proteomic analysis, and ultimately diabetes-specific and insulin action-specific DNA chips for investigators in the field. In this manner, we propose to define the normal anatomy of gene expression (i.e. basal levels of expression and response to insulin), the morbid anatomy of gene expression (i.e., the impact of diabetes on expression patters and the insulin response) and the extent to which genetic variability might contribute to the alterations in expression or to diabetes itself. This will aid all investigators in the quest to unravel the complexity of insulin action and its alterations in diabetes, and ultimately help develop more effective and specific modes for classification, metabolic staging and therapy of the disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES ETIOLOGY/COMPLICATION

IN

PUERTO

RICAN

CHILDREN:

Principal Investigator & Institution: Frazer, Teresa E.; Ponce School of Medicine G.P.O. Box 7004 Ponce, Pr 00731 Timing: Fiscal Year 2001; Project Start 30-SEP-1986; Project End 31-MAY-2005 Description (provided by applicant): Puerto Ricans bear a great burden from diabetes. The incidence of insulin deficient diabetes (IDDM) is the highest reported in the US for both the island and mainland populations. The prevalence rate of insulin resistant diabetes (NIDDM) is 2-fold higher than rates of non Hispanic Caucasians; 1 of 4 Puerto Ricans over the age 40 has NIDDM. Like the etiology of diabetes, the etiology of diabetic susceptibility is unknown. Under the WHO DiaMond genetic project, we have shown that HLA Class II DR and DQ genes are clearly susceptibility markers to childhood IDDM in Puerto Ricans. However, these alleles occur with similar frequencies in all reported ethnically mixed Western hemisphere populations and do not account for

Studies 25

the increased incidence of diabetes in PR. We now propose that genetic and cultural factors interact in Puerto Ricans to induce either a novel type of diabetes, and/or onset at an earlier age, leading to excessive disease rates. To test these hypotheses, we will expand the IDDM registry to include a sub-registry of non-insulin requiring childhood cases of diabetes to ascertain the following epidemiology of the disease: age of onset, sex distribution, seasonal and geographical variation of the disease. Utilizing our network of diabetes registration, we will begin immunological studies of newly diagnosed diabetics, both IDDM, NIDDM and controls to determine the autoimmune nature of PR diabetes. To ascertain if there are genetic similarities between insulin and non-insulin dependent children, we will type the HLA region of patients with childhood onset NIDDM and compare it with our data base of IDDM and controls. Additionally, as part of our participation in WHO DiaComp project, we will continue to monitor complication rates of IDDM patients and to confirm patient-reported complications of the first phases of this project. These studies will better enable us to characterize childhood diabetes in Puerto Ricans. Because of the therapeutic differences in treatment of insulin deficient and insulin resistant diabetes, these data will help to determine if present standards of childhood diabetic care should be modified for the Puerto Rican population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES PREVENTION PROGRAM Principal Investigator & Institution: Orchard, Trevor J.; Professor; Epidemiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 15-AUG-1994; Project End 31-JAN-2008 Summary: (provided by applicant): The Diabetes Prevention Program is a multicenter controlled clinical trial examining the efficacy of an intensive life-style intervention or metformin to prevent or delay the development of diabetes in a population selected to be at high risk due to the presence of impaired glucose tolerance (IGT). Development of diabetes, defined by 1997 ADA criteria, is the primary outcome while cardiovascular disease and its risk factors are important secondary outcomes. The DPP began recruitment in mid-1996. At the time of this application, total study exposure is a mean of approximately 3 years (range 2 to 5) with a total of approximately 10,000 patient years in the 3,234 volunteers in the 3-arm study. On the basis of a statistically significant and clinically compelling decrease in the development of diabetes in the life-style intervention and metformin-treated groups (58% and 31% reductions, respectively) compared with the placebo treated group, the DPP Data Monitoring Board and NIDDK ended the masked treatment phase of the study in May, 2001, one year earlier than originally planned. This application is designed to take further advantage of the scientifically and clinically valuable cohort of DPP volunteers and the large volume of data collected during the study. The highly compliant DPP cohort, including 45% minorities, is the largest IGT population ever studied. Moreover, the subcohort that has developed diabetes (n approximately 700) has been followed from near the exact time of diabetes onset. Clinically important research questions remain in the wake of the DPP. The carefully collected, centrally measured and graded data in this cohort should help to answer, definitively, a number of important questions regarding the clinical course of IGT and early onset type 2 diabetes. Specific aims include: 1. Examine the long-term effects and durability of prior DPP intervention on the major DPP outcomes including diabetes, clinical cardiovascular disease, atherosclerosis, CVD risk factors, quality of life and cost-benefit; 2. Determine the clinical course of new onset type 2 diabetes and IGT, in particular regarding microvascular and neurologic complications; 3. Determine the

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incidence of cardiovascular disease (CVD), CVD risk factors and atherosclerosis in new onset type 2 diabetes and IGT; and 4. Examine topics 1-3 in minority populations, men vs. women, and in older subjects in the DPP. The current application is for 5 years of funding, although the some of the goals of the projects described will require a 10-year study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES PREVENTION PROGRAM LONG-TERM FOLLOW-UP STUDY Principal Investigator & Institution: Pi-Sunyer, F. Xavier.; Director; St. Luke's-Roosevelt Inst for Hlth Scis Health Sciences New York, Ny 10019 Timing: Fiscal Year 2003; Project Start 15-AUG-1994; Project End 31-JAN-2008 Summary: (provided by applicant): The Diabetes Prevention Program is a multicenter controlled clinical trial examining the efficacy of an intensive life-style intervention or metformin to prevent or delay the development of diabetes in a population selected to be at high risk due to the presence of impaired glucose tolerance (IGT). Development of diabetes, defined by 1997 ADA criteria, is the primary outcome while cardiovascular disease and its risk factors are important secondary outcomes. The DPP began recruitment in mid-1996. At the time of this application, total study exposure is a mean of approximately 3 years (range 2 to 5) with a total of approximately 10,000 patient years in the 3,234 volunteers in the 3-arm study. On the basis of a statistically significant and clinically compelling decrease in the development of diabetes in the life-style intervention and metformin-treated groups (58% and 31% reductions, respectively) compared with the placebo treated group, the DPP Data Monitoring Board and NIDDK ended the masked treatment phase of the study in May, 2001, one year earlier than originally planned. This application is designed to take further advantage of the scientifically and clinically valuable cohort of DPP volunteers and the large volume of data collected during the study. The highly compliant DPP cohort, including 45% minorities, is the largest IGT population ever studied. Moreover, the subcohort that has developed diabetes (n approximately 700) has been followed from near the exact time of diabetes onset. Clinically important research questions remain in the wake of the DPP. The carefully collected, centrally measured and graded data in this cohort should help to answer, definitively, a number of important questions regarding the clinical course of IGT and early onset type 2 diabetes. Specific aims include: 1. Examine the long-term effects and durability of prior DPP intervention on the major DPP outcomes including diabetes, clinical cardiovascular disease, atherosclerosis, CVD risk factors, quality of life and cost-benefit; 2. Determine the clinical course of new onset type 2 diabetes and IGT, in particular regarding microvascular and neurologic complications; 3. Determine the incidence of cardiovascular disease (CVD), CVD risk factors and atherosclerosis in new onset type 2 diabetes and IGT; and 4. Examine topics 1-3 in minority populations, men vs. women, and in older subjects in the DPP. The current application is for 5 years of funding, although the some of the goals of the projects described will require a 10-year study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIABETES RESEARCH AND TRAINING CENTER Principal Investigator & Institution: Granner, Daryl K.; Professor of Medicine & Biochemistry; Molecular Physiol & Biophysics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917

Studies 27

Timing: Fiscal Year 2002; Project Start 13-FEB-1996; Project End 31-MAR-2007 Summary: (provided by applicant): The Diabetes Research and Training Center (DRTC) at Vanderbilt is one of a network of Core Centers established by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) to conduct research and training in diabetes mellitus and related endocrine and metabolic disorders consistent with the National Diabetes Mellitus Research and Education Act, the report of the National Commission on Diabetes, and the Administrative Guidelines for DRTCs, as promulgated by the NIDDK. The Vanderbilt DRTC is a multi-disciplinary program with 111 participating faculty and staff members distributed among 13 departments in 2 schools and 3 colleges of the University. The Biomedical Research Component consists of a research base of 81 investigators in the following interest areas: Etiology, Gene Regulation/Function, Beta Cell Function/Channel Biology, Complications, Nutrition/Obesity, Metabolic Regulation, Signal Transduction These investigators are supported by seven Biomedical Research core facilities including Hormone Assay, Amino Acid Assay, Cell Imaging, Transgenic Mouse/ES Cell, Animal Resources, DNA Microarray and DNA Sequencing. Research formerly supported by a Model Demonstration Unit-Education/Evaluation component of the DRTC is now supported by an independently acquired research base in the Prevention/Control and Clinical Component. A major focus of this research is the disparity in diabetes care in underserved populations. This research, by 7 investigators, is supported by a Clinical Outcomes and Behavioral Sciences core. Four faculty members from Meharry Medical College also participate in this aspect of the DRTC through a Meharry Behavioral Health Disparities Core subcontract. A Pilot and Feasibility Studies Program provides up to two years of support in an effort to help new investigators initiate their research programs in diabetes or a related area. Established investigators who wish to enter the field of diabetes are also eligible. The Center coordinates three NIH/NIDDK-sponsored training programs that provide education and laboratory training in diabetes /endocrinology to medical students and graduate students and postdoctoral training for MDs and PhDs. An Enrichment Program provides continuing education through a Diabetes Research Day, a seminar series and symposia. The Administrative Component provides both scientific and administrative leadership for the total program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES RESEARCH AND TRAINING CENTER Principal Investigator & Institution: Bluestone, Jeffrey A.; Professor and Director; Diabetes Center; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The University of California at San Francisco Diabetes Center, an organized research unit at UCSF, has functioned for more than a half-century as a basic and clinical research enterprise at the forefront of diabetes research. Historically, the program has had an ongoing enrichment program, Pilot & Feasibility studies, strong basic science and clinical research interface. The goal of the Center is to support a highly interactive team involved either directly or indirectly in Type 1 and Type 2 diabetes research to advance the study and treatment of the disease. In this application, the UCSF Diabetes Center proposes to establish a Diabetes Research and Training Center (DRTC) that will support Core Laboratories, an Enrichment Program and Pilot and Feasibility studies. The Center will encompass a broad range of intellectual and research expertise from over 12 departments and organized research units and three UCSF campuses focused on basic research with an eye towards clinical

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application. The center will combine immunology, metabolic research, cell biology and genetics in the field of diabetes to develop unique approaches to understand and treat this devastating disease. Investigators of the DRTC are organized in the following programmatic areas: Cell Biology of Islets, Developmental Biology, Islet Transplantation and Immunology, Autoimmunity, Receptors and Signaling, and Obesity & Metabolism and Obesity, Complications of Diabetes. Seven Core facilities are designed to facilitate interdisciplinary investigations of these scientists ( Enrichment Core, Islet Production Facility Core, Microscopy & Cellular Imaging Core, Genomics & Bioinformatics Core, Mouse Genetics Core, Mouse Metabolism, and Human Metabolism Cores). A Pilot and Feasibility Grant Program serves to foster new initiatives in diabetes research primarily of junior faculty and those senior faculty from outside the diabetes focus area. An intensive academic enrichment program which organizes seminars and various symposia is designed to keep Center investigators abreast of the latest discoveries and to maintain the research program at this center at the forefront of biomedical science. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES SELF-MANAGEMENT OUTCOMES: A META-ANALYSIS Principal Investigator & Institution: Upchurch, Sandra; Nursing Systems and Technology; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2000; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: Diabetes, a chronic multi-faceted disease, results in serious microvascular and macrovascular complications. Recent studies documented that normal or nearnormal blood glucose levels delayed progressions of diabetes related complications. The key to reducing complications is good glycemic control Diabetes self-management education has shown to improve glycemic control. The objective of the proposed study is to conduct a meta-analysis of published and unpublished research on Type 2 diabetes to evaluate health outcomes of diabetes self-management education. Primary outcomes of interest include glycosylated hemoglobin, fasting blood glucose, body weight, blood pressure, serum lipids, foot lesions, and psychosocial outcomes (e.g., quality of life and depression). Specific aims of the study are to: 1. Describe diabetes, self management education and health outcomes as reported in the literature since 1990. 2. Examine relative contributions of content areas in the national standards of diabetes selfmanagement education (e.g., foot care, dietary principles, etc.) to positive health outcomes for persons with Type 2 diabetes. 3. Compare effects of diabetes selfmanagement education on health outcomes in different ethnic groups. 4. Explore changes in medical treatment, such as medications, reported in studies that result from diabetes self- management education. 5. Explore cost savings of diabetes selfmanagement. 6. Identify gaps in the in the research on the effects of components of diabetes education on health outcomes. Meta-analytic procedures will be used to synthesize both published and unpublished research reports. Computer searchers, surveys of professional schools, contact with research centers and other diabetes researchers, and ancestry search procedures will be used to located relevant studies. Coding instruments will be checked for inter-rater/intra- rater reliability and content validity. Studies selected for inclusion will involve a sample of diabetes subjects who have participated in diabetes self-management education; and at least one measure of a health outcome as the result of the self-management intervention. Studies meeting inclusion criteria will be analyzed and data will be extracted and recorded on a Code Sheet. A code Book will provide guidance for decisions during the coding process. Descriptive analysis will be completed to identify the characteristics of the diabetes selfmanagement education. An effect size will be computed for each primary studies. A

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mean effect size will then be calculated independently for each outcome across the sample of studies. Results of the meta-analysis will be used by the Principal Investigator to design a diabetes self-management education intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES, INFLAMMATION AND VASCULAR DISEASE Principal Investigator & Institution: Smyth, Susan S.; Assistant Professor; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Diabetes mellitus is a major risk factor for cardiovascular morbidity and mortality. Diabetic macrovascular disease is characterized by accelerated atherosclerosis, a propensity for acute thrombotic events, and a higher risk of clinical restenosis following percutaneous coronary intervention due to increased development of intimal hyperplasia after vascular injury. However, the pathogenesis of diabetic macrovascular disease is incompletely understood. Diabetes has many features of both a chronic inflammatory and pro-thrombotic state. Platelet-leukocyte interactions may play an important role in both thrombotic and inflammatory states and may serve as a crucial link between these systems and the development of vascular disease. This grant application is designed to test the hypothesis that platelets contribute to enhanced intimal hyperplasia in diabetes via P-selectin-mediated recruitment of both mature leukocytes and progenitor cells to sites of vascular damage. Furthermore, we propose that platelet mediated recruitment of exogenous angioblasts from normoglycemic donors could be used to enhance re-endothelialization at sites of injury and reduce the development of intimal hyperplasia in diabetic mice. The specific aims are: (1) To determine the role of platelet-leukocyte interactions in the development of intimal hyperplasia in mice with type I diabetes. (2) To determine the role of platelet recruitment of circulating progenitor cell in the development of intimal hyperplasia in mice with type I diabetes. (3) To determine the role of P-selectin in the development of intimal hyperplasia after vascular injury in mice with type I diabetes. (4) To determine whether administration of exogenous angioblasts will reduce the development of intimal hyperplasia in mice with type I diabetes. (5) To establish an in vitro assay to measure the effects of diabetes on platelet-progenitor cell interactions. Our findings should advance understanding of how diabetes alters the response to arterial injury and may direct therapeutic strategies that could be used to prevent restenosis in diabetic patients. Moreover, our results may have broad implications for the treatment and prevent of accelerated atherosclerosis and thrombosis in diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DOES TREATMENT AFFECT COGNITION IN TYPE 1 DIABETES? Principal Investigator & Institution: Jacobson, Alan M.; Senior Vice President; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2006 Summary: (provided by applicant): The neuropsychological effects of type 1 diabetes, its treatment and its metabolic consequences remain controversial. Because intensive diabetes therapy (IDT) greatly increases the risk of severe hypoglycemia, it is widely believed -- though unproven -- that cognitive skills may be compromised in patients treated with IDT. Other research suggests that persistent hyperglycemia may affect the integrity of the central nervous system and thereby compromise cognitive ability. To

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resolve these issues, we are proposing to study a well-characterized, carefully followed group of patients with type 1 diabetes who were treated with either conventional therapy, or with IDT as participants in the Diabetes Control and Complications Trial (DCCT), and were evaluated in terms of medical and neuropsychological outcomes. These individuals (n = 1409) are currently being followed for an additional 12 years, as part of the Epidemiology of Diabetes Intervention and Complications (EDIC) study. By the end of that study, the cohort will have been followed for 18 years on average and will be approximately 46 years old with an average duration of diabetes of 24 years. Biomedical measures and assessments of complications, including retinopathy, neuropathy, and cardiovascular risk factors and outcomes are regularly and routinely assessed in the cohort and will be available for our analyses, as will genetic markers thought to be associated with cognitive functioning e.g., angiotensin converting enzyme (ACE) and apolipoprotein E (APOE) genotypes. We will reassess cognitive ability at the end of the EDIC, using the original DCCT neuropsychoiogical test battery, augmented by measures that will allow us to characterize patients on several aspects of cognitive functioning previously found to be affected by metabolic abnormalities of diabetes. Our research aims to address three primary hypotheses: 1) The group treated with intensive diabetes therapy (IDT) during the DCCT will show less of a decline on six domains of cognitive function relative to DCCT entry compared to those in the conventional therapy group. 2) Individuals with better prior glycemic control, as indexed by a lower mean HbAlc over the duration of the DCCT and the EDIC, will manifest less cognitive decline relative to DCCT entry, particularly on domains of psychomotor efficiency (processing speed) and simple motor speed. 3) Individuals with fewer episodes of severe hypoglycemia over the duration of the DCCT and EDIC will show less of a cognitive decline relative to DCCT entry, particularly on measures of abstract reasoning, block design, object assembly and symbol digit learning. In addition, we will examine the effects of key demographic and biomedical variables such as age of diabetes onset, gender and current age, history of hypertension, lipid levels and cardiovascular status (assessed by carotid intimal-medial thickening and calcification of coronary arteries) on cognitive functioning. The proposed study is in unique position to provide important evidence about the effects of diabetes and its treatment on central nervous system functioning and will extend our understanding of the interplay of biomedical factors and cognition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVALUATION OF DIABETES SELF-MANAGEMENT CONSULTANT CARE Principal Investigator & Institution: Anderson, Robert M.; Professor, Senior Research Scientist; Medical Education; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 20-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Evaluation of Diabetes Self-Management Consultant CareThe overall objective of this study is to develop, implement and evaluate the effectiveness of a collaborative care intervention to improve blood glucose control and diabetes-related quality of life for subjects with type 2 diabetes being cared for in two different health care systems. The effectiveness of their diabetes Self Management Consultant (SMC) Collaborative Care intervention will be evaluated by comparing it with a randomized usual care control group for subjects with type 2 diabetes.Specific Aims 1. Develop a diabetes Self-Management Consultant (SMC) intervention designed to improve blood glucose control and diabetes-related quality of

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life for adults with type 2 diabetes. 2. Recruit SMCs, Primary Care Physicians (PCP)s, and subjects for the study. 3. Pilot test the feasibility of all major elements of the SMC intervention including data collection and self-management consultant protocols and activities with a small number of subjects. 4. Implement the intervention in both the Detroit Department of Health and the University of Michigan Department of Family Medicine. 5. Conduct a randomized clinical trial to evaluate the relative effectiveness of the SMC intervention compared to usual care in improving blood glucose control and diabetes-related quality of life. 6. Identify variables (e.g., program site, demographic, psychosocial, resource, and health) that predict which subjects benefit from participating in the SMC intervention. 7. Estimate the cost-effectiveness of the SMC intervention, relative to the cost of usual care, in the short-term, from the perspective of the health care insurer. 8. Estimate the expected effect the SMC intervention has on endstage subject outcomes (both microvascular and macrovascular complications) and longterm costs through the use of Monte Carlo simulation models. 9. Disseminate the results, materials, and protocols developed for this study, nationally, and provide training and technical assistance to health care professionals who wish to use the SMC intervention (or parts of it) in local settings.HypothesisThe SMC intervention will be more effective than usual care in improving blood glucose control and diabetes-related quality of life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FAMILY, AUTONOMY AND SELF-CARE IN ADOLESCENTS WITH IDDM Principal Investigator & Institution: Dashiff, Carol J.; None; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-MAY-2000; Project End 31-JAN-2004 Summary: Effective intervention programs must be based on salient variables that improve diabetes control. Although literature supports that family relational processes influence diabetes control in adolescence and suggests that autonomy development is a major process associated with self-care, little attention has focused on autonomy as a primary capability that ungirds self- care and diabetes control as adolescence progresses. The long- term objective of this research is the facilitation of autonomy development in adolescents with IDDM to enhance self-care and diabetes control as adolescent's progress through early and middle adolescence. Specific aims are (1) to describe the developmental progression of family relational processes, autonomy, selfcare and diabetes control in adolescents with IDDM and (2) to evaluate a model of influences of adolescent autonomy development and family relational processes on selfcare and diabetes control, in which autonomy development has a central mediating role. A combined cross-sectional and longitudinal cohort-sequential design will be used and 274 adolescents between the ages of 11 and 15 years and their families will be enrolled and followed prospectively for 2 years until ages 13 through 17. The focus will be on the parent- adolescent subsystem and data will be obtained during a home visit through self-report questionnaires and a revealed difference family interaction task. The task will involve discussion of adolescent and diabetes specific family issues by parent(s) and adolescent. Measures of adolescent autonomy (emotional, cognitive and behavioral), family relational processes (cohesion, hostile conflict, parental separation anxiety, autonomous-relatedness, and inhibition of autonomy), self care (universal, illness-related and division of diabetes responsibility), and diabetes control will be employed. Diabetes control will be by glycosylated hemoglobin levels at two intervals four months apart. Cross sectional data will be analyzed using regression/correlational procedures. Longitudinal data will be analyzed by hierarchical linear models (HLM)

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with random coefficients. Model fit will be evaluated by several methods, including goodness of fit and diagnostic plots of individual subject slopes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FAMILY-CENTERED DIABETES PROJECT Principal Investigator & Institution: Herman, Carla J.; Internal Medicine; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 01-AUG-1993; Project End 31-DEC-2006 Summary: Diabetes is a major health problem among Native American (NA) communities nationally and in New Mexico. Diabetes prevention efforts should concentrate on modifiable risk factors. Young NA women are important recipients of diabetes prevention activities because of their pivotal role in the family environment as they purchase and prepare food, and care for their children and families. They are also important recipients of diabetes prevention because of their own high risk of diabetes. Therefore, the long-range goal of this study is to reduce modifiable diabetes risk factors in NA women and their families through a culturally specific intervention. The specific aim of this study is to determine whether a healthful lifestyle intervention program, "Sharing Wisdom", delivered to young NA women without diabetes will reduce diabetes risk factors. A randomized trial design will be used with two experimental groups: intervention group, and comparison group who will receive a delayed intervention. Measures will be completed at the General Clinical Research Center (GCRC) with assistance from the research team at baseline, post intervention, and 6 and 12 months post intervention. Process evaluation will be conducted by a separate team. The target population is NA women ages 18-40 who attend the Indian Health Service (IHS) clinics or an urban Indian clinic. The following hypotheses will be tested: i) Intervention participants will attend the Sharing Wisdom program with a greater than or equal to 80 percent retention rate for the intervention and will evaluate the program positively. ii) Intervention participants will have improvement on diabetes risk factors (primary outcomes) when compared to the comparison group post intervention: decreased percent fat from kcal in the diet, increased vegetable consumption measured using the Block Food Frequency Questionnaire, and increased percent of participants who do moderate or strenuous physical activity for 30 minutes greater than 3 times a week using the Modifiable Activity Questionnaire of Kriska. iii) Intervention participants will improve on clinical measures (secondary outcomes) compared to the comparison group post intervention: improved physical fitness measured by predicted VO2 peak, decreased body fat measured by skinfold thickness, decreased body weight, and decreased insulin resistance using the HOMA model. iv) Improvement in outcome measures will be maintained by intervention participants when compared to the comparison group at 6 and 12 months post intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETICS OF BONE AND VASCULAR CALCIUM IN TYPE 2 DIABETES Principal Investigator & Institution: Carr, John J.; Div of Radiologic Sciences; Wake Forest University 2240 Reynolda Rd Winston-Salem, Nc 27106 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): The broad long-term objectives are to improve health and reduce deaths in people from osteoporosis, CVD and type 2 diabetes. The specific aims are focused on the genetic and environmental factors that contribute to

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vascular calcification (VC) and bone mineralization (BM) in type 2 diabetic families. The health relatedness is that cardiovascular disease (CVD) is the number one cause of death in the U.S. and the risk of CVD is significantly increased in individuals with type 2 diabetes. Osteoporosis is present in 10 million citizens with another 18 million estimated to have low bone mass. This is an ancillary proposal to the "Genetic Epidemiology of Subclinical CVD in Type 2 Diabetes" (HL67348) also know as the "Diabetes Heart Study" or DHS. DHS uses a family study design and quantitative measurement of CVD phenotypes to locate and identify genes contributing to subclinical atherosclerosis in sibling pairs concordant for type 2 diabetes. The impact of lifestyle and environment on gene expression for subclinical disease as measured by BM and VC will be determined. In this proposal, measures of bone mineralization and aortic VC will be added to our existing array of CVD phenotypes, which include vascular calcium (VC) of the coronary and carotid arteries. We will use the additional quantitative measures of BM (QCT, DXA, QUS & Biomarkers) to understand the genetic relation between BM, VC, CVD, osteoporosis and type 2 diabetes. The Specific Aims are: 1) Measure and describe BM & VC in a high-risk population for CVD, families with sibling pairs concordant for type 2 diabetes and unaffected family members. 2) Measure the strength of association between vascular calcium and bone mineralization - further characterize the association by presence or absence of type 2 diabetes, ethnicity, and gender. 3) Estimate the familial aggregation and heritability of BM & VC in the Diabetes Heart Study families.4) Investigate if candidate gene polymorphisms, previously identified for BM & VC, are associated with the primary phenotypes measured in DHS. 5) Identify specific chromosomal regions containing quantitative trait loci (QTLs), which influence BM &VC, using the genome-wide screen. 6) Perform fine mapping, conduct association and haplotype analyses, and identify novel candidate genes for chromosomal regions with strong evidence for linkage to the primary phenotypes, BM, VC and CVD. An established and active multidisciplinary team of investigators using advanced methods of phenotype quantification, molecular genetics, and genetic epidemiology will conduct this research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS OF DIABETIC RETINOPATHY Principal Investigator & Institution: Hanis, Craig L.; Professor; Human Genetics Center; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: (Applicant's Abstract) Diabetic retinopathy substantially contributes to the morbidity of type 2 diabetes mellitus and is a strong predictor of subsequent, often early, mortality in those with diabetes. Susceptibility to type 2 diabetes has long been known to have a substantial genetic component. Not only does diabetes aggregate in families, but so do its complications. Preliminary results demonstrate an 8.3 fold increased risk for retinopathy in diabetic siblings of a diabetic with no retinopathy. It is likely that diabetes susceptibility alleles impact the clinical courses of the disease and development of retinopathy. It is also plausible that other genes influence susceptibility to retinopathy, but exert their influence only after the development of diabetes. To determine the contribution of genetic factors to diabetic retinopathy, 1,000 Mexican Americans with type 2 diabetes distributed in 750 sibling pairs will undergo detailed eye examinations on 2 occasions (2.5 years apart). Examinations will include stereoscopic fundus photography and scoring according to standard protocols. Except for the retinal examinations, these individuals have been and are being characterized in ongoing studies in Starr County, Texas. These characterization includes genotypes at

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markers spanning the entire genome at an average distance of 8 to 10 centi-Morgans. All marker data will be available prior to the completion of the first round of retinal examinations. Documentation of the presence and severity of diabetic retinopathy in this sibling pair genotype resource and an additional confirmatory set of 200 individuals with diabetes will permit: 1) Determining the sibling pair concordance for retinopathy, 2) Localizing retinopathy susceptibility loci based on two-point and multi- point sibling pair linkage analysis, and 3) Identification of variation by DNA sequence scanning of genes in linked regions impacting on the presence and development of retinopathy. The end result will be improved understanding of mechanisms and exploitable pathways for moving retinopathy treatment from palliative to preventive. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS OF OBESITY AND DIABETES Principal Investigator & Institution: Attie, Alan D.; Professor; Biochemistry; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2006 Summary: (Scanned from the Applicant's Description): The majority of persons with non-insulin-dependent diabetes mellitus (NIDDM) are obese. Nevertheless, although most obese people have insulin resistance, the great majority never develop NIDDM. There are essentially no biochemical clues that allow us to predict which obese individuals will develop diabetes, much less why they develop diabetes. In addition, there is limited mechanistic information to help us understand why obesity is so intimately related to diabetes. The objective of this project is to identify genes that link obesity and diabetes in mice. We have mapped two gene loci that determine whether or not an obese mouse will develop Type 2 diabetes. We have also mapped two loci that strongly affect body weight in a population of obese hyperphagic mice. The aims of this project are to: 1) Create interval-specific congenic strains for each mapped locus. 2) Refine the obesity and diabetes phenotypes. 3) Use a positional candidate strategy to identify the genes responsible for the mapped traits. Identification of obesity and diabetes susceptibility genes will provide clues to novel pathways and biochemical mechanisms underlying complex disease problems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IL-2 IN AUTOIMMUNE DIABETES Principal Investigator & Institution: Flavell, Richard A.; Professor and Chairman; Immunobiology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Type 1 insulin-dependent diabetes mellitus is caused by an autoimmune attack on the islets of Langerhans. The susceptibility to this disease is determined both genetically and by environmental events. The elucidation of the underlying mechanisms of this disease has been greatly facilitated by the mapping of genes conferring susceptibility or resistance to diabetes in humans. Further, the availability of animal models, including the non-obese diabetic (NOD) mouse has made it possible to perform fine mapping of the corresponding mouse genes. Idd3 is a critical diabetes-susceptibility gene, which has profound effects on development of disease. NOD mice carrying an Idd3 gene from the diabetes-resistant B6 mouse show a substantially reduced incidence of insulitis and diabetes as well as greatly retarded kinetics of disease development. The Idd3 locus has been mapped to a 780 kb region of chromosome 3. The most likely candidate gene in this region is the IL-2 gene. This gene

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shows several structural differences between alleles that are derived from resistant or susceptible strains of mice. However, definitive evidence for or against a role of IL-2 has not yet been obtained, since it has not been possible until recently to target genes in the NOD genetic background. In this study we will establish gene knock-in technology on the NOD genetic background by using NOD/129 F1 ES (embryonic stem) cells, which we have recently found to be very effective in all the steps of gene targeting. Specifically, to establish or refute a role of IL-2 in T1 DM, we will use gene targeting to replace the IL-2 gene of the NOD mouse with the IL-2 gene of the diabetes-resistant B6 mouse. We hypothesize that the NOD allele of IL-2 confers susceptibility to diabetes in one of two ways. First, IL-2 is required for antigen induced cell death (AICD) and we propose that AICD in NOD mice is deficient as a result of a defective IL-2 gene. Our second hypothesis proposes that suppressor (also called regulatory) T-cells, which are IL-2 dependent, are defective in the NOD mouse as a result of an IL-2 deficiency in this strain. We will utilize our IL-2 knock-in mice to test these two mutually nonexclusive hypotheses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPROVING DIABETES BY PRIMARY CARE TRANSLATION (IMPACT) Principal Investigator & Institution: Peterson, Kevin A.; Family Practice & Cmty Health; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): A group-randomized and controlled trial is proposed in 24 primary care clinics located in St. Paul, Minnesota and the surrounding communities to evaluate a highly developed multifaceted diabetes-specific intervention, The broad goal of the study is to successfully translate empirical knowledge regarding diabetes treatment and management into sustainable clinical practice. The focus is on the primary care environment, where the majority of patients with diabetes seek ongoing health care. The clinical trial evaluates the effectiveness of the TRANSLATE intervention multifaceted diabetes intervention program promoting better comprehensive diabetes management. The intervention begins by evaluating the organizational structures of primary care offices and identifying existing barriers in these small complex systems. A set of nine well-developed intervention components selected from among some of the most successful strategies in the literature for altering clinical outcomes are then introduced to correct existing deficiencies at each clinic. The TRANSLATE components function as an interdependent system, providing substantial support to both the provider and patient. Key features include the targeting of high-risk patients, a patient reminder system for routine visits, both passive and patient-specific physician reminders, a disease-specific networked reporting system, and physician education. Implementation is facilitated by a local diabetes intervention team assisted by a site coordinator and a local physician champion. Notably, the model does not centralize care, but rather promotes dissemination of care delivery improvements by promoting infrastructure changes at the primary care clinic where most care is delivered. Quality improvement methods are employed to optimize implementation in each unique clinic setting. Upper level administrative personnel are integrated into the regular review of implementation measures and resource use. The study evaluates average A1c and systolic blood pressure values for over 6,400 diabetes patients in control and intervention clinics. In addition, the study implements widely used diabetes performance measures to evaluate the quality of health care delivery. Finally, short and long term cost of the intervention is evaluated from the perspective of the health system.

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The intervention was developed by a strong collaborative group of primary care physicians, endocrinologists, managed care organizations, and health care purchasers, and has been pilot tested in nine clinics where substantial improvement in average A1c levels and in disease process measures have been demonstrated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN PROTEIN TRANSLATION IN DIABETIC NEPHROPATHY Principal Investigator & Institution: Kasinath, Balakuntalam S.; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: Our objective is to investigate the role of protein translation in matrix accumulation, a major contributor to loss of renal function in type 2 diabetes. The rationale is based on our observation that the insulin receptor (IR) and its specific signal transduction pathways are activated in the renal cortex of db/db mice in early stages of type 2 diabetes at a time when the mice are hyperinsulinemic. At this time, increased matrix protein accumulation is associated with decrease in matrix protein laminin mRNA. Furthermore, in renal cells in vitro, insulin increases matrix laminin synthesis by augmenting its translation and activating the same signaling pathways as seen in the renal cortex of db/db mice. Insulin activates eukaryotic initiation factor 4E (elF4E) and elongation factor, eEF2 that critically regulate protein translation. Central hypothesis: In type 2 diabetes, hyperinsulinemia stimulates specific signaling pathways leading to activation of factors controlling protein translation, resulting in accumulation of matrix in the kidney. We will study db/db mice in pre-diabetic, early, and established phases of diabetes, with appropriate controls. Specific Aim I: In vivo studies To identify IR signal transduction pathways involved in activation of elF4E, eEF2 and augmented matrix translation in renal cortex of mice with type 2 diabetes. We will assess phosphorylation of elF4E, its binding protein 4E-BP1, and eEF2. Polyribosomal analysis will directly examine translation initiation of matrix protein laminin. Activation of IR and insulin-stimulated kinases that regulate protein translation, i.e., PI 3-kinase, Akt, p70s6k, Erk-1/-2 type MAP kinase and PKC will be studied to establish the role of these signals in activating translation. Specific Aim II: In vitro studies To identify IR signaling kinases required for augmenting matrix translation employing proximal tubular epithelial (PTE) and mesangial cells. Role of individual kinases will be assessed by employing specific inhibitors, antisense oligos and dominant negative mutants in renal cells, in a milieu simulating type 2 diabetes. Specific Aim III: In vivo studies To evaluate the role of PTE cell-IR in activation of signaling pathways leading to augmented matrix translation in renal cortex of mice with type 2 diabetes by targeted IR gene deletion. PTE cell-specific IR deletion will be accomplished using Cre/LoxP system. We will generate a transgenic mouse on db/db background, in which Cre recombinase is driven by a PTE-cell specific kidney androgen regulated protein (KAP) promoter. IR (lox/+) mice will be obtained from Dr. C. Ronald Kahn. Hybrids of the IR (lox/+) and KAP-Cre mice will be used to generate kidney IR knockout mice. Functional (GFR, proteinuria), histologic (matrix proteins), IR signaling and protein translation events in these mice will be compared with those in wild type db/db mice. This strategy permits a definitive assessment of role of PTE celMR in pathogenesis of nephropathy in type 2 diabetes. Novel mechanistic data on renal disease in type 2 diabetes is expected, and may lead to unique therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ISCHEMIA/REPERFUSION INJURY IN DIABETIC HEART Principal Investigator & Institution: Mcdonagh, Paul F.; Professor; Surgery; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2001; Project Start 01-AUG-1997; Project End 31-JUL-2003 Summary: Diabetes is now considered a prime risk actor for cardiovascular disease, particularly ischemic heart disease. The risks for myocardial infarction, reinfarction, ischemic heart failure, stroke and the associated mortalities are all significantly increased in diabetes. The pathobiology underlying the excessive and severe ischemic heart disease in diabetes is unclear. Myocardial ischemia-reperfusion (I'R)injury involves both early and late phases. In the early phase, the initial deposition of leukocytes amplifies cardiac injury via an acute inflammatory response. The initial step in acute inflammation is leukocyte, particularly PMN, deposition in the coronary microcirculation. It is not clear how PMNs initially accumulate in the microcirculation, but recent studies suggest that this step is amplified in the diabetic heart following ischemia. Once accumulated, the PMNs activate and produce oxygen free radicals, causing further damage to the vasculature and myocytes. Following ischemia, if PMN deposition is excessive in the diabetic coronary microcirculation an(LIor if diabetic PMNs are hyper-responsive to cytokines released from ischemic tissue, then the severity of leukocytemediated reperfusion injury may be excessive as well. In this project, we will test the hypothesis that diabetes causes alterations in both the blood and the coronary blood vessels. These alterations set the stage for an excessive leukocytemediated reperfusion injury in the diabetic heart. If so, then pharmacologically blocking early PMN-mediated inflammation will reduce reperfusion injury and improve the recovery of myocardial contractile function. We will first investigate specific mechanisms, suspected to cause the excessive blood-coronary microvessel interactions observed in diabetes. We will then compare leukocyte adhesion protein characteristics and the "reactivity" of PMNs to stimulation in Type I and Type II diabetic animals and in patients with Type II diabetes. We will determine if platelets and plasma complement, modulate leukocyte function and leukocyte reactivity in diabetes. The therapeutic potential of limiting leukocyte-mediated inflammation in diabetes will be evaluated. Those pharmacologic agents and antibodies that prove to attenuate the early PMN-mediated response will be tested for efficacy to improve the recovery of myocardial contractile function in the diabetic. The lessons learned from these studies will aid in developing improved therapies to reduce the excessive ischemic heart disease observed in diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MANAGING TYPE 2 DIABETES: A WEB SITE FOR PHYSICIANS Principal Investigator & Institution: Triant, Randi S.; New England Research Institutes, Inc. 9 Galen St Watertown, Ma 02472 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-OCT-2003 Summary: Diabetes is a major cause of morbidity and mortality in the US, with prevalence increasing steadily over the past four decades. Over 10 million Americans are affected, with a prevalence of 7.8% among adults over age 20 years and 18.8% among those over age 60 (Harris, 1998). More than one in ten health care dollars and one in four Medicare dollars are spent on people with diabetes (DRWG, 1999). Despite the rise in diabetes, training primary care practitioners on diabetes management remains inadequate. This product will be designed to help practitioners evaluate and manage diabetes patients who are misdiagnosed, under- treated or have poor compliance. Our

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proposed Web site program on type 2 diabetes goes beyond text-book teaching by emphasizing multi- disciplinary, hands-on, problem-based learning. Specific goals include: Developing content base din collaboration with our consultant on scientific literature on type 2 diabetes. Designing and formatting the Web-based program for CME accreditation. Developing a script and storyboard for one section of the program. Producing one Web-based section of the program to reflect quality of the full program. Evaluating feasibility of the program and initiating CME accreditation. Finalizing a production schedule, evaluation plan, and budget for Phase II. PROPOSED COMMERCIAL APPLICATIONS: This Web site will be marketed as a CME course to the 82,000 general practitioners in hospital, managed care, and private practice. In addition, it will be marketed to the 128,000 internal Medicine physicians and 64,000 Family Practice Physicians in the US. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS BY WHICH GDM LEADS TO DIABETES IN OFFSPRING Principal Investigator & Institution: Simmons, Rebecca A.; Associate Professor of Pediatrics; Pediatrics; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) In the human, diabetic pregnancy induces marked abnormalities in glucose homeostasis and insulin secretion in the fetus that results in aberrant fetal growth. Studies have suggested that there are long-term consequences for the offspring of diabetic mothers. We have developed a model of gestational diabetes (GDM) in the rat to determine whether an altered metabolic intrauterine milieu is directly linked to the development of diabetes later in life. Uteroplacental insufficiency is induced in the pregnant rat on day 19 of gestation. Offspring are growth retarded at birth, however they catch-up by 5- 7 weeks of age. At 8 weeks of age they are bred to normal males. During pregnancy these animals develop hyperglycemia, hyperinsulinemia, and hyperlipidemia accompanied by impaired glucose tolerance and insulin resistance. Offspring, (F2's) are heavier at birth and remain heavy throughout life. F2's are insulin resistant very early in life and glucose homeostasis is progressively impaired. F2 rats go on to develop diabetes as adults. Although F2 animals display marked insulin resistance, the failure of the Beta-cell to compensate for defects in insulin action is the essential factor coincident with onset of diabetes. This failure of the Betacell to compensate may be due to a lack of compensatory increase in insulin secretion, an increased rate of cell death, a reduction in the rate of Beta-cell proliferation, or a combination of these events. The mechanism(s) underlying this lack of Beta-cell compensation and eventual decrease in Beta-cell mass in F2 animals are the focus of this proposal. We hypothesize that mitochondrial DNA damage from hyperglycemia via the production of reactive oxygen species (ROS) results in further escalation of genetic damage in the mitochondria, specifically in mutations. A self- reinforcing cycle of progressive deterioration in mitochondrial function leads to a corresponding decline in Beta-cell function. Finally, a threshold in mitochondrial dysfunction and ROS production is reached and Beta-cell death occurs. The onset of diabetes ensues when a critical level of abnormal Beta-cell insulin secretion combined with Beta-cell loss is reached. We will test the hypothesis that GDM does in fact cause mitochondrial dysfunction, oxidative stress, and deletions in mtDNA in the Beta-cell of the offspring, and whether these effects act synergistically to lead to the development of the Beta-cell failure and type II diabetes. To link the damage to the mitochondria caused by

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hyperglycemia to the Beta-cell phenotype observed in type II diabetes we will induce Beta-cell failure in vitro by transferring damaged mitochondria from F2 animals into Beta-cells from unaffected. non-F2 animals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF ENDOTHELIAL DYSFUNCTION IN DIABETICS Principal Investigator & Institution: Beckman, Joshua A.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 13-AUG-1999; Project End 31-JUL-2004 Summary: Vascular disease is the principal cause of death and disability among the 12 million patients in the United States with diabetes mellitus. Macrovascular complications, including myocardial infarction, stroke, and amputation are the leading cause of morbidity and mortality among this cohort of patients. Reduced bioavailability of endothelium-derived nitric oxide has been implicated in atherogenesis and may be a fundamental factor in the development of vascular disease in diabetes. Increased degradation of nitric oxide by reactive oxygen radicals and inhibition of nitric oxide synthase via activation of protein kinase C are each potential mechanisms to account for decreased nitric oxide. The sponsor's laboratory has demonstrated impaired endothelium-dependent vasodilation in patients with diabetes mellitus and in healthy, nondiabetic subjects with experimental hyperglycemia. Further experiments showed that vitamin C improved endothelium-dependent vasodilation implicating a culpable role for superoxide. The soluble, glutathione-dependent antioxidant pathway, responsible for detoxification of polar peroxides, is also adversely affected by hyperglycemia and may represent a specific physiologic mechanism causing, in part, the impaired endothelial function demonstrated in diabetes mellitus. This proposal will examine the effect of ebselen, a glutathione peroxidase mimetic on endothelial function in subjects with diabetes mellitus (type I and type II) and healthy, age-matched controls to determine if polar peroxides play an important role in endothelial dysfunction in diabetes. Hyperglycemia causes the up-regulation of protein kinase C isoform beta2 (PKC beta2) which may phosphorylate nitric oxide synthase, reducing its activity. This proposal will also examine the role of LY333531, a PKC beta2 inhibitor, on endotheliumdependent vasodilation in forearm resistance and conduit vessels in subjects with type I and type II diabetes mellitus and age-matched health controls. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MORBIDITY IN SCHIZOPHRENIA--A FOCUS ON DIABETES Principal Investigator & Institution: Dixon, Lisa B.; Professor; Psychiatry; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Persons with schizophrenic disorders have significantly higher mortality rates than persons in the general population. It is likely that modifiable patient behaviors and health care delivery system characteristics contribute to this phenomenon. Identification of such modifiable patient and health care system factors may be critical to improving the health status and longevity of persons with schizophrenia. Due to the complexity of this issue, we selected a "tracer" condition strategy, focusing on a single medical disease, diabetes, as a prototypical serious, chronic medical problem from which lessons may generalize to other disorders. Diabetes is a highly prevalent chronic medical disorder which requires active self-care and which may serve as a prototype disorder to understand problems that persons with

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schizophrenia and other severe mental illnesses have in obtaining and making use of adequate medical care. Using the health beliefs model as a conceptual framework, this study will compare 100 persons with schizophrenia who have diabetes to 100 persons with major depression and to 100 persons without serious and persistent mental illness who suffer from diabetes on: 1) diabetes-specific health behaviors (e.g., compliance), health outcomes (control of blood sugar), and quality of diabetes care received; 2) potential mediating variables, hypothesized to differ between schizophrenics and nonschizophrenics, including diabetes health beliefs and illness knowledge. Additional analyses will compare the schizophrenia sample to published norms on diabetes-specific measures. We will also examine whether system characteristics (e.g., integration of physical care and psychiatric care) and clinical characteristics (e.g., social skills and symptoms) account for poorer outcomes among persons with schizophrenia and major depression. Patients with schizophrenia and major depression will be drawn from a variety of mental health centers in the Baltimore area. A matched sample will be drawn from a University of Maryland Family Practice Clinic. Patients will receive a single assessment and chart review. This proposal thus focuses on diabetes and schizophrenia, although our underlying assumption is that our findings will contribute to our understanding of management and outcomes of other medical illnesses in persons with schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PALM-TOP DIETARY MANAGER FOR CHILDREN WITH DIABETES Principal Investigator & Institution: Sirotinin, Sergey V.; Dbaza, Inc. 5001 Baum Blvd, Ste 770 Pittsburgh, Pa 15213 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-DEC-2003 Summary: (Scanned from the Applicant's Abstract): We are seeking SBIR Phase II support in order to produce and test the effectiveness of a technically refined, and commercially viable dietary self-management software suite for youngsters with Type I diabetes, a prevalent chronic disorder of childhood. The software suite called "Meals and Things" (MAT) consists of two modules: (a) a meal planning and recording software module that operates on a hand-held device; and (b) a supporting customizable management module that operates on a desktop PC (or commercial server). The final products will incorporate findings from a recent market test of the Phase I prototype. MAT seeks to help youths to adhere to their meal plans in order to facilitate better regulation of blood glucose and improve long-term medical outcomes. The final product will be examined with respect to: (a) its effectiveness to improve dietary selfmanagement; (b) its impact on blood glucose regulation (HbA1 levels); and (c) user's satisfaction. MAT will be tested in randomized trials with 50 recently diagnosed 8-13 year old children, using a pre-post-test design. The software suite will be targeted to youths with IDDM, parents, diabetes educators, and health care professionals. PROPOSED COMMERCIAL APPLICATIONS: The "Meal and Things" will serve as a valuable dietary self-management tool appropriate to school-age youths with Type I diabetes, their parents, diabetes educators, and health care professionals. The program, together with the Interactive CD-ROM "Kids and Diabetes" (also being developed by dbaza) will address components of diabetes self-care in a comprehensive fashion, with educational, conceptual, and visual continuity. It will appeal to health care providers, since it will reduce costs by providing more effective diabetes dietary education with no increase in staff; and to parents and youths, because it facilitates adherence to the medically recommended meal plan which then should impact positively on overall diabetes self-management and glycemic control.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: 'PARENT-CHILD CO-REGULATION OF PEDIATRIC DIABETES' Principal Investigator & Institution: Gonder-Frederick, Linda A.; Associate Professor; Psychiatric Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Successful diabetes management relies on a process of self-regulation in which treatment behavior is guided by feedback about changing blood glucose (BG) levels and decision-making. The processes involved in selfregulation have been studied extensively in adults with Type 1 Diabetes Mellitus (T1DM), leading to the development of sophisticated research tools that have significantly advanced our understanding and ability to predict clinical outcome. Additionally, this research has led to the development of a highly effective, empirically based, psychobehavioral intervention, Blood Glucose Awareness Training (BGAT), developed by our research team, that improves self-regulation and clinical outcome in adults with T1DM. Unfortunately, the processes involved in the self-regulation of pediatric diabetes have received virtually no empirical attention. The purpose of the proposed project is to correct this scientific neglect by adapting the conceptual and methodological tools used in adult studies to 1) investigate the process of diabetes regulation by school-aged children (6-11 yrs) with T1DM and their parents and 2) develop and test an intervention to enhance the skills critical to this process. This is an important population to target for this line of inquiry because: 1) children with T1DM and their parents appear to be far less accurate than adult patients in symptom and BG detection; 2) As a group, pediatric patients are more likely to suffer from negative clinical sequelae (e.g., severe hypoglycemia (SH) and DKA); and, 3) Early intervention could have greater public health care benefit by achieving more reductions in acute and long-term complications, health care utilization, and disability. Phases 1A and 1B of the proposed project will provide the first systematic and comprehensive study of symptom recognition, BG detection, decision-making, and subsequent clinical sequelae in schoolaged children with T1DM and their parents. A theoretical model of co-regulation of pediatric diabetes is proposed and tested, in which the behaviors of both parent and child influence the sequence of events that determine avoidance or occurrence of negative outcomes, such as extreme hypo- and hyperglycemia. Based on the findings of these studies and our current BGAT for adults, Phase 1 C will pilot test a translation of this intervention designed for parents of school-aged children with T1DM, BGAT for parents (BGAT-P). This intervention will take advantage of the critical role parents play as the primary teachers of children about diabetes management by including training activities for parents to do with their children designed to improve children's ability to recognize BG symptoms, detect extremes in BG, and make appropriate self-treatment decisions. Based on the findings from this pilot study, and feedback from parents, in Phase 2 BGAT-P will be further refined and tested in a controlled clinical trial to assess its short-term efficacy. Phase 3 is a 12-month follow-up study to determine whether the improvements found in Phase 2 are maintained over time and also to assess the impact of BGAT-P on future clinical negative events, including frequency of SH and DKA experienced by children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOBIOLOGY OF MACROVASCULAR DISEASE IN DIABETES Principal Investigator & Institution: Chait, Alan; Professor of Medicine; Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-SEP-1976; Project End 31-MAR-2002 Summary: The overall objective of this research program is to gain understanding of the genetic, cellular, biochemical and molecular nature of premature atherosclerosis in diabetes mellitus. There are five interrelated projects: (1) The role of hyperglycemia, diabetic nephropathy and the development of central obesity with intensive insulinization in determining the levels, distribution and composition of lipoproteins: It is proposed that part of the excess incidence of premature disease is related to the dyslipidemia that results from these variables in diabetes; (2) Therole of diabetes on the interaction between lilpoproteins and proteoglycans of the artery wall: It is hypothesized that alterations in lipoprotein and or proteoglycans as a results of diabetes will facilitate their interaction in such a manner that would result in the retention of lipoprotein in the artery wall in diabetes; (3) The effect of diabetes on HDL-mediated cholesterol efflux: This project will evaluate how modifications of lipoproteins affect two distinct pathways of cholesterol efflux from cells, passive desorption and apolipoprotein-mediated efflux, and will focus on how changes in HDL structure in diabetes affects HDL function; (4) The role of non-enzymatic glycation of endothelial cell matrix proteins on the signaling pathways activated by physiologic fluid flow: The major hypothesis is that nonenzymatic glycation of extracellular matrix proteins makes them "slippery" and unable to participate normally in the transduction of physicochemical signals in response to fluid flow, which is the primary determinant of the production of endothelial-derived nitric oxide, a critical mediator of vascular homeostasis; (5) Molecular mechanisms of oxidation damage in diabetes: The hypothesis is that oxidant stress due to glucose autoxidation and/or protein glycation results in highly specific biologically active reaction products that can be used to detect glucose-mediated oxidative damage in vivo. This focus on the effects of diabetes on basic biological mechanisms of atherosclerosis should help establish which alteration are preventable or reversible, and will provide a rational basis for the prevention of this major complication of diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATIENT-PROVIDER RELATIONSHIP AND DIABETES SELF-CARE Principal Investigator & Institution: Ciechanowski, Paul S.; Assistant Professor; Family Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2007 Summary: (provided by applicant) Clinicians, researchers and policy planners have recognized that despite the availability of effective medications and self-monitoring methods, normal metabolic control for a great proportion of patients with diabetes remains elusive, in large part because of non-adherence to treatment. Models of care, which focuses on improving patient-provider interactions, have been shown to be effective in improving adherence to therapies in patients with chronic illness. The goal of this 5-year Mentored Patient-Oriented Research Career Development Award is to enable the applicant to obtain the necessary skills and training to become an independent investigator in improving diabetes self-management by focusing on the health care relationship. This career development award will consist of coursework, mentorship, and supervised investigations focusing on: 1) understanding patientprovider relationship influences on diabetes self-care, using attachment theory as a

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model; 2) assessing cost and utilization and societal implications of poor patientprovider communication in diabetes care; and 3) developing and testing of high quality clinical interventions using relationship-based theoretical models to improve health care utilization, treatment adherence and outcomes in diabetes. Career development activities will be applied to four mentored research studies. In study 1, analyses of existing data sets from primary and tertiary care diabetes patients will test the hypothesis that the quality of the patient-provider relationship is associated with diabetes self-management. In study 2, a large longitudinal epidemiological study of primary care patients with diabetes will assess the impact of patient-provider communication on clinical outcomes and health care costs and utilization. In study 3, indepth qualitative and quantitative assessment of type 2 diabetes patients will be conducted to assess how treatment adherence is influenced by patterns of patientprovider interactions. In Study 4, data from the first three studies will be integrated with career development training to develop and pilot test clinical interventions for improving care of diabetes. Study 4 will test the feasibility of conducting such interventions focusing on the patient-provider relationship in preparation for a clinical effectiveness trial (R-01 study). This award will help the applicant bridge the gap between theory-based research on the patient-provider relationship and dissemination of clinical and population-based interventions designed to improve the quality of the patient-provider relationship and self-care in diabetes. This K-23 award will provide crucial support for the applicant's ongoing development as an investigator, clinician, and educator in the area of diabetes care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PGS-2 IN THE PATHOGENESIS OF IDDM Principal Investigator & Institution: Clare-Salzler, Michael J.; Associate Professor; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-JUL-2006 Summary: Type 1 diabetes, a Th1 mediated autoimmune disease, resulting from poorly defined interactions between susceptibility genes, the environment, and the immune system. A feature of T cell-mediated autoimmune diseases, including type 1 diabetes, is a reduced capacity of antigen presenting cells (APC) to activate T cells. Low levels of activation may predispose to autoimmune because apoptotic death of autoreactive T cells or generation of regulatory T cell responses requires quantitatively highly levels of activation than are needed for T cell survival. We have defined an APC defect, the constitutive expression of the normally inducible cyclooxygenase, prostaglandin synthase 2 (PGS2), which is common to monocytes (MO) of subjects at risk for type 1 diabetes and macrophages (MP) of NOD and NODscid mice. We determined in congenic mice that an NOD gene in a defined region of chromosome 1 controls the PGS2 phenotype, but is not the PGS2 gene. PGS2 expression allows high-level production of inflammatory PG and contributes to defective APC function. Our natural history studies in humans demonstrate healthy controls express low levels of PGS2, whereas high levels are present; 1.) Early in life as infants with high-risk HLA genotypes, 2.) In high risk autoantibody positive subjects, and 3.) in 80% of type 1 diabetics. Preliminary studies of patients with other established autoimmune disease demonstrate similar aberrant PGS2 expression and suggest this MO defect may be common to autoimmunity. Furthermore, omega-3 fatty acids which reduce PG metabolism appear to reduce the risk for autoantibodies, suggesting the PGS2 defect is regulatory by dietary environment. PG production appears to play a major role in diabetes pathogenesis as treating NOD mice with drugs that block both PGS activity significantly reduces diabetes incidence.

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Ongoing prospective studies demonstrated 12/17 (71%) high risk subjects who progressed to diabetes expressed high levels of PGS2. Preliminary, risk analysis suggests MO PGS2 expression increases the chance of developing diabetes by approximately 40%. In order to further define the etiology of PGS2 expression and its role in type 1 diabetes pathogenesis we will address the following specific aims, 1.) determine whether MO PGS2 expression is a risk factor for developing autoantibodies and type 1 diabetes, and establish whether it is similarly expressed in other autoimmune diseases, 2.( Determine the NOD gene(s) encoded on chromosome 1 which contribute to abnormal PGS2 expression and 3.) establish whether PGS2 specific inhibitors and supplementation of dietary omega-3 fatty acids reduce disease in NOD mice. The overall goal is to establish the utility of PGS2 as risk factor for type 1 diabetes and as a potential target for human diabetes prevention trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREDICTION OF CARDIOMYOPATHY IN TYPE I DIABETES BY MRS Principal Investigator & Institution: Pohost, Gerald M.; Director; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2007 Description (provided by applicant): Congestive heart failure is a leading cause of morbidity and mortality in the United States and diabetes has been recognized as a major risk factor for the development of this disease. However, there is a lack of consensus regarding the existence of a diabetes-specific cardiomyopathy as well as the importance of vascular and non-vascular alterations in the development of diabetesrelated cardiac disease. We recently demonstrated a transient decrease in cardiac phosphocreatine (PCr)/ATP with handgrip stress, indicative of ischemia, in women with chest pain but no artery disease. The most likely explanation for these results was the presence of microvascular disease. Thus, given the sensitivity of changes in bioenergetics to ischemia and the lack of any direct, non-invasive measurements of microvascular disease, we will use 31P-NMR spectroscopy to evaluate the effects of diabetes on cardiac metabolism. Specifically, we will test the hypothesis that patients with diabetes will exhibit reversible, exercise-induced decreases in PCr/ATP and PCr/inorganic phosphate consistent with an imbalance in energy supply and demand. Furthermore, we propose that these changes will be present only in those diabetic patients with evidence of systematic microvascular disease and will be accompanied by evidence of contractile dysfunction as assessed by cine MRI. Finally we anticipate that the observation of metabolic functional abnormalities will be predictive of short- and long-term outcomes. We will test these hypotheses by determining the effects of handgrip exercise on cardiac bioenergetics and cardiac function in diabetic patients with and without evidence of systematic microvascular disease. We will also evaluate the utility of abnormal cardiac bioenergetics and function as predictors for the development of overt cardiac disease in patients with diabetes. Cardiac bioenergetics will be assessed using 31P-NMR spectroscopy at 4.1T and cardiac function will be measured using cine MRI at 1.5T. Type 1 diabetic patients aged 40 and under with a duration of diabetes greater than 10 years will be studied and grouped based on the presence or absence of systemic microangiopathy. These studies will enable us to assess whether the presence of microvessel disease is a prerequisite for the development of cardiac dysfunction in diabetic patients. This investigation will provide an unprecedented insight into the impact of diabetes on cardiac function and bioenergetics in humans. This will provide

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valuable information for the development of novel therapeutic interventions and improved management of diabetic patients with cardiac disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION OF TYPE 1 DIABETES WITH MMP INHIBITORS Principal Investigator & Institution: Bleich, David; City of Hope National Medical Center Duarte, Ca 91010 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Lymphocyte infiltrates in the islets of Langerhans, "insulitis", is a characteristic hallmark of immune-mediated diabetes in rodent models and human beings. Strategies to prevent invading lymphocytes from reaching the pancreatic beta-cells have been effective in preventing diabetes in non-obese diabetic (NOD) mice. Recently, much attention has been focused on the regulation of matrix metalloproteinases (MMPs) in diseases ranging from metastatic breast cancer to rheumatoid arthritis because these key enzymes regulate tumor cell migration and lymphocyte migration to sites of inflammation. At present, several broad-spectrum MMP inhibitors are being tested in human phase II and Ill trials to determine whether these drugs can prevent tumor metastasis and rheumatoid arthritis. Similarly, we postulated that MMPs play a role in insulitis in NOD mice and possibly human type 1 diabetes. The studies presented here will determine whether a novel broad-spectrum MMP inhibitor can prevent insulitis and diabetes in NOD mice. Six week-old and eighteen week-old NOD mice will be treated with intraperitoneal injections of an MMP inhibitor and followed for development of diabetes. We will evaluate an early treatment protocol (6 weeks of age) to see if MMP inhibition can prevent insulitis and a late treatment protocol (18 weeks of age) to see if MMP inhibition can prevent diabetes once insulitis has progressed. Furthermore, splenic and pancreatic lymph node T cells will be obtained from NOD mice and challenged in vitro with glutamic acid decarboxylase 65. We will assess the Thl/Th2 profile of lymphocytes isolated from these two anatomic sites and whether MMP inhibition can alter the cytokine profile. In collaboration with the University of Arizona, we will evaluate the role of MMPs and their inhibitors in Tlymphocyte development and migration using an in vitro fetal thymic organ culture (FTOC) model. This system has been called "in vitro IDDM" because NOD thymic T lymphocytes can target and infiltrate NOD pancreatic islets when the two organs are cocultured. Since MMP inhibition not only regulates cell migration, but apoptosis, we will perform dose and time courses with MMP inhibitors to determine whether this strategy can alter thymic T-lymphocyte selection and maturation. Finally, TNF-alpha can regulate the production of diabetogenic T-cells and regulatory NKT cells bearing both natural killer and T-cell phenotypes (DX5+ cells) in the FTOC model. Cell membrane bound metalloproteinases called ADAMs (A Disintegrin And Metalloproteinase) process membrane-bound pro-TNF-a to the biologically active cytokine. Thus, we will determine whether MMP inhibition can downregulate intrathymic TNF-a production and increase the levels of NKT cells. We will determine levels of CD4+,CD8+, and NKT cells using flow cytometry. We anticipate that these studies will give us supporting data to initiate a human trial to treat pre-type 1 diabetic patients with a broad-spectrum MMP inhibitor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: R21 PROJECT: ANTI-DIABETIC EFFECTS OF PANAX GINSENG Principal Investigator & Institution: Yuan, Chun-Su; Anesthesia and Critical Care; University of Chicago 5801 S Ellis Ave Chicago, Il 60637

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Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 31-JAN-2004 Summary: Diabetes mellitus or diabetes is a chronic metabolic disease that can cause blindness, kidney failure, nerve damage, and confers an increased risk of ischemic heart disease, stroke and peripheral vascular disease. Diabetes is divided into two major categories: type 1 or insulin- dependent diabetes mellitus (IDDM), and type 2 or noninsulin dependent diabetes mellitus (NIDDM). In this country, the incidence of diabetes is approximately 4.5%, of which 90% is type 2 diabetes. In 1992, diabetes care required roughly 14.6% of the total U.S. health care expenditure ($105 billion). Many of these patients also suffer from diabetic complications. Considering the heterogeneity of this disease, and the limitations of current therapies, such as high secondary failure rates and side effects, there is an urgent need to explore new anti- diabetic agents. This research project is related to the development of useful products in the field of complementary and alternative medicine. This proposal will focus on our studies on anti-diabetic effects of Panax ginseng, and this project is a continuation of our previous ginseng pharmacological studies. Recently, in our preliminary studies, we observed exciting results on anti-diabetic actions in ob/ob mice using Panax ginseng berry (or fruit) extract, other than the commonly used root extract. The ob/ob mice is a genetic model for type 2 diabetes, and these animals are extremely insulin resistant and have fasting blood glucose levels that are significantly higher than that of lean mice. Data from our pilot observation showed that extract of Panax ginseng berry normalized hyperglycemia and increased insulin sensitivity in ob/ob mice. In addition, we analyzed the constituents of the ginseng berry by HPLC analysis and found that, compared to ginseng root, the ginseng berry has a distinctive profile of ginsenosides, the vital constituent of ginseng. In this revised proposal, we will test the hypothesis that Panax ginseng berry extract has significant anti-hyperglycemic activity. The project aims to identify the anti-hyperglycemic constituents of Panax ginseng berry, and synergistic effects between these constituents. We will also investigate mechanisms of action of these active component(s). Our strategy is to use an in vivo-guided chemical fractionation method to isolate the pure, biologically active, anti-hyperglycemic compound(s) from Panax ginseng berry using the ob/ob mouse. Improvements in glucose homeostasis, glucose tolerance, and in vivo insulin sensitivity will be tested. The results of the proposed project will also help fill gaps in our knowledge before therapeutic agents can be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RACE AND LONG-TERM DIABETES SELF-MANAGEMENT IN AN HMO Principal Investigator & Institution: Ross-Degnan, Dennis; Harvard Pilgrim Health Care, Inc. 93 Worcester St Wellesley, Ma 02481 Timing: Fiscal Year 2002; Project Start 15-JAN-2002; Project End 31-DEC-2004 Summary: (provided by applicant): This project will examine the complex relationships between race, diabetes self-management (including self-monitoring of blood glucose and diabetes drug therapy), glycemic control, and diabetes complications in a managed care setting over a nine-year period. African Americans with diabetes are less likely to be in glycemic control, a major risk factor for development of complications, including nephropathy, retinopathy, and peripheral vascular disease. Randomized controlled trials suggest that diabetes self-management including patient education, drug therapy, changes in diet, and regular exercise can improve glycemic control in the African American population. However, there is little epidemiological evidence regarding the role of race/ethnicity as a determinant of adherence to recommended diabetes self-

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management practices, or regarding the relationship between self-management, glycemic control, and subsequent clinical outcomes. Further, previous studies of race and diabetes self-management have been limited by short study periods, inadequate sample size, and reliance on self-reported measures of self-monitoring of blood glucose. The clinical setting for this study is Harvard Vanguard Medical Associates (HVMA), a large multi-site, multi-specialty group affiliated with Harvard Pilgrim Health Care. HVMA consists of 14 health centers serving over 300,000 people in the Boston area. We will use an open cohort design to enroll all adult (l8 years) patients between 1991 and 1999 who have 24 months or more of uninterrupted enrollment in HVMA following ascertainment of non-gestational diabetes, defined by (1) hospital discharge diagnosis of diabetes mellitus, (2) outpatient diagnoses of diabetes mellitus, HbAlc lab test result 8.0, or use of a diabetes drug (insulin, sulfonylurea, or metformin). We estimate that the cohort will include approximately 1,800 adults identified as African American and 5,000 identified as Caucasian. Access to HVMA computerized medical records, hospital emergency room and inpatient claims, lab, and pharmacy data will allow us to create reliable, objective measures of self-monitoring (home glucose monitor test strip use), drug therapy. glycemic control (HbAlc lab results), and diabetes complications (as measured in outpatient visits, emergency room visits, and hospitalizations). Stratifying by type of drug therapy (insulin/combined therapy vs. oral therapy), we will use descriptive analyses, generalized linear mixed models, and proportional hazards models to (1) identify racial differences in self-management practices and diabetes-related health outcomes over time; (2) assess whether African American race is an independent predictor of self-monitoring practice or adherence to drug regimen; and (3) whether there are racial/ethnic differences in the association between self-management and specific clinical endpoints, including glycemic control (HbAlc