Congressional Report on NIH Implementation of the Recommendations of the Diabetes Research Working Group

On March 17, 2000, the Department of Health and Human Services transmitted the mandated "Congressional Report on NIH Implementation of the Recommendations of the Congressionally Directed Diabetes Research Working Group" to the chair and ranking minority of the Senate Labor/HHS Appropriations subcommittee, Senator Arlen Specter and Senator Tom Harkin. This report describes diabetes-related research activities at the NIH as of that date. The development of research goals and initiatives is a dynamic process based on several factors including: emerging scientific opportunities, new technologies, opportunities for collaboration, and available resources. The research initiatives presented in this report will continue to evolve based upon new research advances and other factors. Thus, the information contained in this report was current as of the date of transmittal, but is subject to continuous change.







Mar 17, 2000


The Honorable Tom Harkin
Ranking Minority Member
Subcommittee on Labor, Health
and Human Services and Education
Committee on Appropriations
United States Senate
Washington, D.C. 20510

Dear Senator Harkin:

I am pleased to transmit a report as requested in Senate Report 106-166, pages 178 and 179. This report is entitled "NIH Implementation of the Recommendations of the Congressionally Directed Diabetes Research Working Group."

Sincerely,

John J. Callahan
Assistant Secretary for
Management and Budget

Enclosure



The Honorable Arlen Specter
Chairman
Subcommittee on Labor, Health
and Human Services and Education
Committee on Appropriations
United States Senate
Washington, D.C. 20510

Dear Mr. Chairman:

I am pleased to transmit a report as requested in Senate Report 106-166, pages 178 and 179. This report is entitled "NIH Implementation of the Recommendations of the Congressionally Directed Diabetes Research Working Group."

Sincerely,

John J. Callahan
Assistant Secretary for
Management and Budget

Enclosure



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

National Institutes of Health

National Institute of Diabetes and Digestive and Kidney Diseases

Congressional Report on NIH Implementation of the Recommendations of the Congressionally
Directed Diabetes Research Working Group

 

Ruth Kirschstein, M.D.
Acting Director, NIH
March 2000

 
 

Allen Spiegel, M.D.
Director, NIDDK
March 2000

 

TABLE OF CONTENTS

Executive Summary

Introduction

Background

The Diabetes Research Working Group

NIH-Wide Diabetes Research Agenda

Examples of New and Expanded Initiatives

DRWG Extraordinary Opportunity: Genetics of Diabetes and its Complications

DRWG Extraordinary Opportunity: Autoimmunity and the Beta Cell

DRWG Extraordinary Opportunity: Cell Signaling and Cell Regulation

DRWG Extraordinary Opportunity: Obesity Research

DRWG Extraordinary Opportunity: Clinical Research and Clinical Trials

DRWG Recommendations Regarding Special Needs for Special Problems

DRWG Recommendations Regarding Resource and Infrastructural Needs

Summary

EXECUTIVE SUMMARY

The following report on NIH implementation of the recommendations of the congressionally directed Diabetes Research Working Group (DRWG) has been prepared by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), in response to a request from the Senate Committee on Appropriations on the Fiscal Year 2000 budget for the Department.

The Fiscal Year (FY) 1998 House and Senate appropriations report language for the NIH and the NIDDK called for the establishment of a Diabetes Research Working Group (DRWG) to develop a comprehensive research plan for the Congress for all NIH-funded diabetes research, including recommendations for future directions. In March 1999, the DRWG presented to the Congress its report, "Conquering Diabetes: A Strategic Plan for the 21st Century." The scientific recommendations in the DRWG Strategic Plan are divided into three main categories: (1) Extraordinary Opportunities, (2) Special Needs for Special Problems, and (3) Resource and Infrastructural Needs. Of particular importance are the five "Extraordinary Opportunities," which represent the professional judgment of the DRWG concerning which research avenues offer the brightest promise and technologic capability to yield major research advances rapidly--and thus deserve immediate pursuit through expanded and/or new funding.

The Office of the NIH Director has delegated to the NIDDK, the component of the NIH that has the lead responsibility for research on diabetes, the responsibility for providing operational leadership and coordination of NIH-wide diabetes research efforts and the trans-NIH response to the DRWG Strategic Plan. The NIDDK has consulted with other Institutes and Centers (ICs) in order to frame an NIH-wide diabetes research agenda that builds upon the scientific advice and recommendations of the DRWG, and other scientific and lay input from the broad diabetes community. This report outlines the many diabetes initiatives undertaken by the NIH relative to each of the "Extraordinary Opportunities" recommended by the DRWG, as well as to "Special Needs for Special Problems" and "Resource and Infrastructural Needs." The vast majority of these initiatives are either newly launched in FY 2000 or are major expansions of initiatives either planned or undertaken in a preliminary way in 1998-1999, as the NIH was closely following the DRWG's process of defining high priority research areas for special emphasis.

Over the last few years, the NIH has worked towards developing a trans-NIH diabetes research agenda which is both comprehensive and balanced. Each of the ICs mentioned in this report has developed research activities relative to its research mission. While some of these initiatives build upon existing programs, many are new and are intended to accelerate research progress in diabetes and its complications. The NIH understands the great burden that diabetes places on patients, families and communities. The NIH has important programs under way, but recognizes that formidable research challenges remain to be addressed in order to cure this costly and devastating disease.

 

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

National Institutes of Health

National Institute of Diabetes and Digestive and Kidney Diseases

DIABETES RESEARCH

Introduction

In its report on the Fiscal Year 2000 budget for the Department of Health and Human Services, the Senate Committee on Appropriations stated:

"The Committee believes that finding a cure for diabetes and its complications--a devastating disease affecting 16 million Americans--should be a top priority as NIH makes funding allocations. The Committee is pleased that NIH has focused more attention over the past few years on diabetes research and has provided sufficient resources in the bill for all NIH institutes with an interest in diabetes to expand substantially their research in this area. The Committee has reviewed the recently released Diabetes Research Working Group report and urges the NIH to implement the recommendations. The Committee held a hearing this year focusing on the needs of children with diabetes and recommends that NIH place a high priority on research that is focused on a cure for diabetes and its complications, in particular, research on type 1, or juvenile diabetes which is the most severe form of the disease. Given the tremendous research opportunities in the field, the Committee urges the Office of the Director to play the lead role by ensuring that a trans-NIH approach to diabetes research be developed at NIH and to review and implement where appropriate, the recommendations outlined in the DRWG report. Further, the Committee requests that NIH submit a report to the Committee before the fiscal year 2001 congressional hearings summarizing progress in fiscal year 2000 regarding the status of implementation of the DRWG recommendations, including initiatives that specifically impact type 1 diabetes." (Senate Report No. 106-166, page 178-179)

The following report has been prepared by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Department of Health and Human Services, in response to this request.

Background

In both human and economic terms, diabetes is an extremely costly disease. It is widely recognized as one of the leading causes of death and disability in the United States. Diabetes affects an estimated 16 million Americans. About half of them do not know they have diabetes and are not receiving care for the disease. Approximately 800,000 people are diagnosed with diabetes each year including both genders, the young and the old, all races and ethnic groups, the rich and the poor. Although diabetes occurs most often in older individuals, it is one of the most common chronic disorders in children in the United States. About 120,000 children and teenagers age 19 and younger have diabetes. It is the leading cause of kidney failure, new blindness in adults, and non-traumatic amputations. According to a 1997 study by the American Diabetes Association, diabetes and its complications of the eye, kidney, nervous system, heart and blood vessels cost an estimated $98 billion annually. Though there are several interventions currently available to help reduce the burden of this disease, there are no methods to cure it or prevent its onset.

Diabetes is a disease marked by the body's failure to produce or properly use insulin, a hormone that is needed to convert sugar, starches, and other food into energy essential for daily life. The causes of diabetes are not precisely known, although both genetic and environmental factors play a role. Diabetes occurs in several forms, and has complications that affect virtually every system of the body. The most common forms of this disease are type 1 and type 2 diabetes.

Type 1 diabetes--formerly known as insulin-dependent or juvenile-onset diabetes--most often occurs in children, but can appear at any age. It accounts for 5 to 10 percent of all diabetes in the United States. It occurs equally among males and females, but is more common in Caucasians than in non-Caucasians. Type l diabetes is considered an autoimmune disease, which occurs when the body's system for fighting infection--the immune system--turns against itself. In type 1 diabetes, the immune system attacks and destroys the insulin-producing cells in the pancreas. Thus, a person with type 1 diabetes needs daily injections of insulin to live. At present, the causes of the autoimmunity in type 1 diabetes are not known, but both genetic factors and an environmental trigger are believed to be involved.

Type 2 diabetes is the most common form of the disease. Once known as non-insulin-dependent or adult-onset diabetes, it affects about 90 to 95 percent of people with diabetes. In type 2 diabetes, the pancreas usually produces some amount of insulin, but for some reason, the body cannot use the insulin effectively. The end result is the same as for type 1 diabetes--an unhealthy buildup of glucose in the blood. Type 2 diabetes is more common in older people, especially older women who are overweight. Obesity is a major risk factor for this form of diabetes. It also occurs more frequently among minority groups, including African Americans, Hispanic Americans, Native Americans, and Native Hawaiians. Recently, a disturbing increase of type 2 diabetes has occurred in children, particularly minority children.

The Diabetes Research Working Group

The Fiscal Year (FY) 1998 House and Senate appropriations report language for the NIH and the NIDDK called for the establishment of a Diabetes Research Working Group (DRWG) to develop a comprehensive research plan for the Congress for all NIH-funded diabetes research, including recommendations for future directions.

Prior to establishment of the DRWG, the NIH leadership had focused attention on diabetes with a trans-NIH symposium on "Diabetes Mellitus: Challenges and Opportunities," held September, 1997. New research initiatives were formulated as a result of this symposium, and also with new funds provided by the Balanced Budget Act of 1997 for research specifically on Type 1 diabetes ($30 million annually for five years starting in FY 1998). When the DRWG was established, NIH leadership followed closely the deliberative planning process of this group of experts and began to lay "footprints" with FY 1998 and FY 1999 funds in areas of scientific opportunity and need that were being identified in meetings of the DRWG.

In March 1999, the DRWG presented to the Congress its report, "Conquering Diabetes: A Strategic Plan for the 21st Century." The scientific recommendations in the DRWG Strategic Plan are divided into three main categories: (1) Extraordinary Opportunities, (2) Special Needs for Special Problems, and (3) Resource and Infrastructural Needs. Of particular importance are the five "Extraordinary Opportunities," which represent the professional judgment of the DRWG concerning which research avenues offer the brightest promise and technologic capability to yield major research advances rapidly--and thus deserve immediate pursuit through expanded and/or new funding. The "Extraordinary Opportunities" are: Genetics of Diabetes; Autoimmunity and the Beta Cell; Cell Signaling and Cell Regulation; Obesity; and Clinical Research and Clinical Trials of Critical Importance. The NIH is using and will continue to use the DRWG Strategic Plan as a guidepost for framing diabetes initiatives, within the context of the agency's available resources and its overall research responsibilities.

NIH-Wide Diabetes Research Agenda

The Office of the NIH Director has delegated to the NIDDK, the component of the NIH that has the lead responsibility for research on diabetes, the responsibility for providing coordination of NIH-wide diabetes research efforts and the trans-NIH response to the DRWG Strategic Plan. The NIDDK has consulted with other Institutes and Centers (ICs) in order to frame an NIH-wide diabetes research agenda that builds upon the scientific advice and recommendations of the DRWG, and other scientific and lay input from the broad diabetes community. The following sections of this report discuss diabetes initiatives that are relevant to the scientific recommendations of the DRWG. Many of the initiatives described in this report are relevant to more than one main category as outlined by the DRWG; however initiatives are described only under the category identified as most relevant by the sponsoring IC(s). Appended is a list of abbreviations used throughout the report.

Examples of New and Expanded Initiatives

The NIH has undertaken many diabetes initiatives related to each of the "Extraordinary Opportunities" recommended by the DRWG, as well as to "Special Needs for Special Problems" and "Resource and Infrastructural Needs." The following are examples of many of these important initiatives. The vast majority of these initiatives are either newly launched in FY 2000, or are major expansions of initiatives either planned or undertaken in a preliminary way in 1998-1999, as the NIH was closely following the DRWG's process of defining high priority research areas for special emphasis.

DRWG Extraordinary Opportunity: Genetics of Diabetes and Its Complications

Both type 1 and type 2 diabetes have a genetic component. Diabetes-linked genes make some individuals more susceptible to developing diabetes than others. In addition, these genes may cause some people with diabetes to be more prone to developing the severe and often devastating complications associated with diabetes. Knowledge of the genetic defects underlying diabetes is critical for identifying individuals at risk for developing diabetes and its complications, as well as for identifying targets for effective treatment and prevention. Examples of recent NIH initiatives relative to the genetics of diabetes and its complications are outlined below.

International Type 2 Diabetes Linkage Analysis Consortium

  • The International Type 2 Diabetes Linkage Analysis Consortium has been established to facilitate joint analysis of data from groups seeking to map the genes responsible for type 2 diabetes. The Consortium has conducted a joint analysis of chromosome 20, mapping data from each of the participating groups as a pilot for analyzing the entire genome and has begun a similar analysis of chromosomes 10, 11 and 12. The Consortium has established a webpage at: http://www.sph.umich.edu/group/statgen/consortium. Partial funding for this Consortium is provided by the NIDDK.

Functional Genomics of the Developing Pancreas

  • The NIDDK is pursuing genetics research along several fronts. The Institute is sponsoring an initiative on the functional genomics of the developing endocrine pancreas. This initiative supports the production and sequencing of complementary DNA (cDNA) libraries based on multiple stages of pancreatic development. In addition, this initiative also provides for bioinformatics links to existing NIH-supported genomics databases. Another major goal of this initiative is to make pancreatic cDNA libraries available as microarrays to be used by researchers for gene discovery and functional studies in both the normal and diabetic pancreas.

Diabetes Genome Anatomy Project (DGAP)

  • The focus of DGAP is to obtain genomic information on the spectrum of genes expressed in tissues relevant to diabetes and its complications. The objectives are to develop libraries of full length cDNAs from tissues affected by diabetes and its complications; to identify "low copy number transcripts" relevant to diabetes; to discover novel genes in tissues affected by diabetes; to conduct expression profiling to determine patterns of gene expression in disease; and to perform functional phenotyping of expressed products in tissues affected by diabetes. Information obtained would be catalogued in a diabetes relational database with automated data mining and query support. This database will be developed and offered as a resource for investigators for use in the development of new assays, identification of potential therapeutic agents, and points of departure for new studies into diabetes and its complications. Information obtained through this initiative will further our understanding of the etiology and pathophysiology of diabetes and serve as a springboard for the development of future investigator-initiated, hypothesis-driven research. DGAP would build upon an ongoing initiative that focuses on functional genomics of the endocrine pancreas. DGAP is envisioned as a trans-NIH effort and the NIDDK would encourage collaboration among those Institutes with an interest in diabetes and its complications.

Genetics Advisory Group

  • The NIDDK will convene an advisory group to aid in further development and implementation of the genetics initiatives recommended by the DRWG.

Genetic Risk Factors

  • During the past several years, the ORMH has supported an innovative research collaboration between investigators from Howard University and scientists in the intramural research program of the NHGRI. The African American Diabetes Mellitus Study is investigating genetic risk factors for diabetes mellitus in Nigeria and Ghana, which are thought to be the founding populations for African Americans. The Coordinating Center at Howard University is collaborating with scientists in Nigeria and Ghana, as well as with NHGRI. This study has not only started to yield high-quality data, but has assisted in the recruitment of several exceptional scientists to the Center at Howard University.

  • The intramural program of the NHGRI is also supporting the "Finland-United States Investigation of Non-Insulin Dependent Diabetes Mellitus (FUSION)," which is studying a large group of siblings affected with type 2 diabetes in Finland. The purpose of FUSION is to look for genes that are risk factors for this condition in the Finnish population. In fact, the project has already identified two regions on chromosome 20 that seem to harbor susceptibility genes for diabetes. This population is particularly well suited to this kind of study, because it is not as genetically complex as the U.S. population and because Finland has been keeping detailed and comprehensive medical records of its citizens for a long time.

  • The NIDDK is also sponsoring an initiative to search for genes that confer susceptibility to kidney disease. The primary objective of this investigation will be identification of genes or genomic regions that are associated with differential risks for the expression and progression of kidney disease, particularly diabetic kidney disease.

Multiple Autoimmune Diseases Genetics Consortium (MADGC)

  • This is a registry and repository of genetic and clinical data, as well as resources collected from families in which two or more individuals are affected by two or more distinct autoimmune diseases. These resources, including DNA and immortalized cells, will be provided to investigators to promote research that advances the discovery of human immune response genes involved in autoimmunity. This collaborative resource, sponsored by NIAID, includes families with type 1 diabetes and other autoimmune diseases.

Diabetes in the Elderly

  • The NIA will provide support for the Hawaii Family Study of Diabetes Mellitus (HFS-DM). This study will conduct linkage and association studies of genes that may be linked to or associated with diabetes in Japanese Americans by establishing pedigrees of large, informative, well-characterized families with type 2 diabetes mellitus. This study will utilize interview and blood chemistry data from The NHLBI/NIA funded Honolulu Heart Program and Honolulu-Asia Aging Study (HAAS) exams. The high prevalence of diabetes in Japanese Americans in Hawaii, coupled with the extensive historical and familial data that are available for this elderly cohort, makes the establishment of pedigrees for the study of diabetes extremely beneficial. Detailed phenotyping of this "older generation" will become invaluable if future studies of diabetes genetics are to be conducted.

  • Type 2 diabetes is very common in elderly men and women and is associated with an increased risk of cardiovascular and microvascular complications. Up to 50 percent of the elderly have some abnormality of glucose metabolism. The NHLBI's Cardiovascular Health Study is providing important information on the natural history and clinical consequences of diabetes and milder glucose metabolic abnormalities in a cohort of over 5000 men and women above age 65 years.

DRWG Extraordinary Opportunity: Autoimmunity and the Beta Cell

Type 1 diabetes is an autoimmune disease in which there is destruction of the insulin-secreting beta cells of the pancreatic islets. For type 1 diabetes, current therapy is limited to replacement of insulin by daily injections. In the past decade, important research discoveries in basic immunology, cell biology and autoimmune disease have laid the groundwork for advances in strategies to block the immune response to prevent destruction of the beta cell and to preserve normal insulin secretion. To capitalize on these advances, the NIH has numerous initiatives under way that will lead to a greater understanding of the immunologic basis of type 1 diabetes and that will allow for the development of novel strategies to replace beta cell function through islet transplantation. The NIH is also undertaking initiatives to increase investigation in beta cell biology in order to gain essential knowledge for developing improved therapies for the treatment of diabetes. A brief description of some of these initiatives follows.

Transplantation

  • The NIDDK, in a collaborative effort with the NIAID and the JDF, issued a research solicitation to support trials of human islet cell transplantation.

  • The NIDDK Division of Intramural Research, in collaboration with the Department of Defense, the NIH Clinical Center, and the Diabetes Research Institute of the University of Miami, has initiated a clinical research program that will explore new approaches to both kidney transplantation and islet cell transplantation for diabetes.

  • The NIAID, NCRR and NIDDK have sponsored an initiative to evaluate existing and new tolerance induction treatment regimens and to elucidate the underlying mechanisms of the induction, maintenance, and/or loss of tolerance in non-human primate models of kidney and islet transplantation. Tolerance induction is a new means of "re-educating" the immune system to accept transplanted organs and cells.

  • In response to Congressional appropriations report language, NCRR proposes to establish three regional islet cell centers with core laboratory facilities that can isolate and characterize human islet cells according to Good Manufacturing Practice (GMP) guidelines. Following procurement of a donor pancreas, the islet cell center would be tasked with the isolation of islets using GMP standardized protocol(s), assays for physiologic function, immunologic markers, and HLA phenotype. Donor-specific data would be collected, such as age, gender, hospital course and treatment prior to organ harvest, exposure to medications, duration of brain death prior to harvest, and collection of blood samples for glucose, cortisol, cytokines, and other metabolic measurements. Aliquots of isolated islets would be shipped to investigators throughout the country once an appropriate recipient is identified. Additionally, aliquots of the same cell isolate would be reserved for basic research, with immediate isolation of cDNA for molecular and genomic studies, and cryopreservation of cells for future investigation.

    The three regional centers participating in this RFA would be identified by a number of factors. There must be a strong institutional commitment to transplantation, with considerable prior experience in the field. A GMP isolation facility must be located near the clinical facilities, such that freshly isolated islet cells could be transplanted on site, if it is determined that shipping or cryopreservation of islets reduces cell viability or function. Phase I protocols could be carried out using locally available resources at the regional center, and would include use of freshly isolated islet cells, transplantation of cells on site at the institution, and use of GCRC infrastructure for post-transplant follow-up and data collection. One of the three regional centers would be designated as a coordinating center with a bioinformatics core to collate data from ongoing trials and provide a database from which both clinical and basic scientific data could be correlated with transplantation outcome.

Transplantation Registries

  • In April 1999, NIDDK convened an advisory panel to review information collected by a pancreas transplant registry supported by the Institute to collect and analyze demographic and outcome information on all pancreas transplant recipients from institutions performing transplants in the U.S. This database serves as a research tool for the medical community. Implementation of the panel's recommendations will increase our knowledge of effective practices and outcomes of pancreatic transplantation in patients with diabetes in the U.S.

  • The objective of this NIDDK-supported initiative is to support the establishment of a North American islet transplantation registry. This registry will collect and analyze data related to transplantation into humans. Appropriate types of data to be collected by the registry would include patient and graft survival rates; patient demographic information; donor age; islet source; cold storage time of the pancreas; islet isolation procedure; islet storage procedure; number, purity, and viability of islets at time of transplant; islet implantation site; immunomodulation/immunoisolation procedure; post-transplant metabolic parameters; post-transplant morbidity and mortality; procedures to follow rejection episodes; and post-transplant autoimmune antibody levels. This database will serve as a research tool for the medical community to evaluate progress in the expanding area of human islet transplantation.

Beta Cell Biology

  • The NIDDK and the JDF sponsored a workshop in April 1999, on imaging and quantification of beta cell mass. As a result of this meeting, a research solicitation has been issued to stimulate the development of techniques or reagents leading to the ability to image, or otherwise non-invasively detect, pancreatic islet beta cells in vivo, and measure their mass, function, or evidence of inflammation. It is expected that this research will contribute to the eventual development of a clinical exam that can be used for monitoring disease progress and response to therapy in people who have diabetes, or are at risk for developing it.

Immunology Research and Clinical Trials

  • Initiatives for clinical trials and clinical research relevant to autoimmunity and the beta cell include Diabetes Centers of Excellence, Autoimmunity Centers of Excellence and a Collaborative Network for Clinical Trials in Immune Tolerance that will support development of novel immunotherapies. A more detailed description of these projects can be found under the section on "Clinical Research and Clinical Trials."

  • The NIAID, NHLBI, NIAMS, NIDDK, NINDS, NIA, and ORWH have developed an initiative to accelerate the award process for research funding of ancillary studies to clinical trials which seek to elucidate basic immune mechanisms. The applications received in response to this solicitation will undergo an accelerated assignment, review, and funding process, such that awards will be made within 13 weeks of submission.

  • A trans-NIH research solicitation has been issued to examine the genetic basis and molecular pathways of target organ damage in rheumatic and autoimmune diseases, such as type 1 diabetes. This initiative is sponsored by numerous Institutes, including the NIAMS, NIDCR, NIAID, NIDDK, NICHD, NIEHS, NIDCD, NEI, NHLBI, NINDS, NIMH, and ORWH.

  • An initiative sponsored by NIAID and NIDCR seeks to attract new investigators and novel research projects in order to advance understanding of the human mucosal immune system. These studies should increase our understanding of oral tolerance, which is being used in clinical trials for the prevention and treatment of type 1 diabetes. In addition, increased understanding of the mucosal immune response should lead to new approaches to prevent infection, including infections of the oral and craniofacial regions, genitourinary and upper respiratory tracts, skin, and bone, which are increased in incidence among patients with diabetes.

Vaccine Development

  • The 1999 Institute of Medicine report, "Vaccines for the 21st Century: A Tool for Decision Making," highlighted the need for vaccines for type 1 diabetes and other autoimmune diseases, and emphasized the societal benefits that would accrue with the successful development of such vaccines. The NIAID is continuing to emphasize research in this area, spurred by a scientific symposium it held on "Vaccines for the Prevention and Treatment of Autoimmune Diseases" to discuss the newest advances and approaches to induction of tolerance for autoimmune disease.

Stem Cells as a Potential Source of Islets

  • Type 1 diabetes results in the destruction of insulin-producing beta cells. Replacement of these cells through regeneration or transplantation could offer lifelong treatment for patients with diabetes. However, a major problem in implementing treatment is the lack of sufficient islet cell tissue and a lack of understanding about whether and how beta cells regenerate. Embryonic stem cells and other tissue-specific stem cells could potentially provide a limitless source of islets for transplantation therapies. An initiative on the development of the endocrine pancreas is intended to stimulate the application of advances in developmental biology, specifically in developmental genetics and embryology, to study pancreatic development. This initiative is sponsored by NIDDK and NICHD.

  • The NCRR currently supports research on non-human embryonic and other stem cells from various animal models. NCRR can play a crucial role in diabetes research by supporting studies on stem cells derived from both non-embryonic and embryonic, non-human sources with the goal of isolating and identifying pancreatic endocrine stem cell precursors. There is a need for improved methods to identify stem cells, control their differentiation, optimize culture conditions, and develop reagents to identify differentiated insulin-producing cells. Research projects should involve methods and reagents that are effective across animal models and would likely be effective in human tissues as well.

  • The NCRR is currently planning a stem cell repository for nonhuman species to bank and distribute stem cells and reagents for characterization of stem cells and differentiated derivatives. In addition, the repository will have a database/information component that will allow researchers access to shared data, techniques, and information on stem cells. A specific portion of this repository would be set up for exchange of material to support research that has the potential to lead to replacement of functions lost in diabetes.

  • The NIDDK, ADA and the JDF are sponsoring a workshop on "Stem Cells and Pancreatic Development." The objective of this workshop is to bring together investigators from multiple disciplines conducting state-of-the-art research in stem cell biology and the developmental biology of the pancreas. Presentations will highlight recent advances in the characterization of stem cells that have been isolated from a variety of tissues and organs; the pathway of pancreas development from the earliest steps of fate determination to islet cell differentiation; and cutting-edge technologies including genetic models such as zebrafish and mouse, functional genomics, imaging, and lineage analysis. It is anticipated that this workshop will provide insight into new research directions in the rapidly developing area of stem cell biology and pancreatic development, and will generate recommendations for future research initiatives.

DRWG Extraordinary Opportunity: Cell Signaling and Cell Regulation

A fundamental component of the regulation of all cellular functions is the ability of cells to communicate with each other, and more importantly, to carry signals within the cell itself. These processes are critical to virtually all functions of the body, including the ability of the beta cell to develop and secrete insulin and the ability of insulin to stimulate the breakdown and conversion of sugar, starches and other foods into energy essential for life. In addition to the initiatives described below, a number of initiatives described under the areas of "Autoimmunity and the Beta Cell" and "Complications" will explore aspects of cell signaling and cell regulation as they relate to the underlying mechanisms of onset and progression of diabetes and its complications.

Growth Factors

  • The NIDDK, NEI, NIDCR, NINDS, and NHLBI have issued a Program Announcement to stimulate research on the role of growth factors in the pathogenesis of complications of diabetes. Several growth factors are already being tested in clinical trials for the treatment and/or prevention of diabetic microvascular disease, but a systematic examination of the pathophysiologic role of growth factors in diabetic complications is lacking. An understanding of the tissue and cell specific expression of growth factors in the eye, kidney, mouth, nerves, vessels, and of the molecular action of these growth factors in the pathophysiology of complications will lead to improved and more specific therapies.

Mechanism of Insulin Action

  • The NIDDK is sponsoring an initiative to stimulate research on the role of cell signaling and cell regulation in diabetes. The initiative solicits novel and innovative approaches to address the role(s) of the insulin receptor in the development, progression and treatment of diabetes and its complications.

Signal Transduction

  • The NIDDK is launching an initiative intended to stimulate research on the mechanisms of action of nuclear receptors in the regulation of tissue-specific gene expression. This initiative will build upon a recent NIDDK workshop in molecular endocrinology entitled, "Co-Activators and Co-Repressors in Gene Expression." The workshop highlighted the importance of emerging information on the roles of nuclear accessory factors in the regulation of signaling at the level of transcription. Transcription factors or other factors recruited by hormone receptors are responsible for enhancing and/or supporting the expression of genes. This initiative is sponsored by numerous Institutes, including: NIDDK, NIEHS, NICHD, NIA, NIAMS, and NIMH.

Center for Research on Cellular Processes

  • The NCRR plans to establish a research center that would focus on cellular processes, especially those cellular activities related to diabetes. The NCRR proposes that such a center be supported as a Biomedical Technology Resource Center which would play a prominent role in the National Diabetes Technology Network (NDTN) discussed in the "Resource and Infrastructural Needs" section below.

DRWG Extraordinary Opportunity: Obesity Research

Obesity is a major risk factor for the development of type 2 diabetes and for insulin resistance. It is also a major cause of morbidity and mortality in the U.S. Obesity disproportionately affects minorities, including African Americans, Mexican Americans and Native Americans. Moreover, the prevalence of obesity in children and adolescents is increasing at an alarming rate--especially for minority groups--leading to the development of type 2 diabetes at an earlier age.

Prevention Research

  • A research solicitation issued by the NIDDK, NHLBI, NIA, NICHD, ODP, and ORWH will explore interventions for the prevention of obesity in high-risk individuals or populations.

  • Caloric restriction (CR) is the only intervention known to reliably extend the health- and life-span of rodents and other non-primate animal models. An important metabolic correlate of CR in both rodents and thus far, in non-human primate studies, is its ability to enhance insulin sensitivity and glucose tolerance in older animals, and significantly slow the development of type 2 diabetes in non-human primates. Thus, the CR model offers an exciting opportunity to explore underlying mechanisms in the prevention of type 2 diabetes, as well as prevention of the age-related increase in insulin resistance and glucose intolerance that can lead to significant health problems in older people. The NIA will support high quality research applications in this area.

Study of Health Outcomes of Weight Loss

  • The NIDDK and NHLBI are co-funding a clinical trial, the "Study of Health Outcomes of Weight Loss (SHOW)," in patients with type 2 diabetes. The SHOW trial is currently in the design phase. In late 2000, the trial will begin a three-year effort to recruit 6,000 obese patients with type 2 diabetes at approximately 15 clinical centers to determine whether sustained weight loss can be achieved in these patients. A goal of the trial is to have the overall ethnic and racial composition of the recruited populations reflect the prevalence rates for diabetes in the United States. Other sponsors include the NINR, ORMH, ORWH, and the CDC.

DRWG Extraordinary Opportunity: Clinical Research and Clinical Trials

In order to capitalize fully on the advances obtained through basic research, this knowledge must be extended to humans through clinical research programs. Studies conducted in test tubes, cells and animal models can answer important fundamental questions related to diabetes and its complications, and can provide a strong basis for the development and testing of novel interventions. However, it is only through clinical studies conducted in patients with diabetes that these fundamental observations can be validated. The NIH has a number of initiatives under way to develop and test strategies for treating and preventing type 1 diabetes and for developing methods to achieve normal blood glucose levels in patients with diabetes. Descriptions of initiatives follow.

Diabetes Prevention Trial--Type 1

  • The NIDDK, NIAID and NICHD have provided an administrative extension for the Clinical Centers involved in the ongoing Diabetes Prevention Trial (DPT-1) for type 1 diabetes, while a task force considers approaches to developing a TrialNet for future studies of prevention of type 1 diabetes, as recommended by the DRWG.

Diabetes Prevention Program

  • The NIH-sponsored Diabetes Prevention Program (DPP) is a multicenter clinical trial studying whether type 2 diabetes can be prevented in at-risk individuals through the use of medications or a regimen of diet and exercise. The DPP has recently met its recruitment goal of over 3,800 participants. A major success of the DPP has been recruitment of nearly 45 percent of the study participants from minority populations (African Americans, Hispanic Americans, Asian Americans, Pacific Islanders, and Native Americans--people at the highest risk for developing type 2 diabetes). Participants will be observed for at least three years, and up to six years, depending upon the date of enrollment.

Collaborative Network for Clinical Research on Immune Tolerance

  • The NIAID is spearheading a large initiative, co-sponsored by the NIDDK and the JDF, to develop new ways of inducing immune tolerance--selectively modulating the immune system by inhibiting harmful immune responses while keeping protective ones intact. This strategy promises to improve the success of transplants and treatments for autoimmune diseases that destroy the body's own cells and could lead to better management of type 1 diabetes, systemic lupus erythematosus, arthritis, and other immune system disorders. The project, known as the Collaborative Network for Clinical Research on Immune Tolerance, will involve nearly 40 research institutions internationally. Network researchers will conduct clinical trials to improve the success of kidney transplants using "tolerogenic approaches." Such therapies selectively prevent immune cells from attacking the body's own tissues while allowing them to function normally as defenders against invading bacteria, viruses, and cancer cells.

General Clinical Research Centers

  • The NCRR will enhance the infrastructure at institutions that have a General Clinical Research Center (GCRC) to permit increased research on type 1 diabetes. Protocols could utilize GCRC hospital beds and core lab resources to study complications of diabetes, such as diabetic neuropathy, autonomic neuropathy, atherosclerosis, and retinopathy. Likewise, the therapeutic interventions may require specialized patient care and lab evaluations performed within the GCRC.

Diabetes Centers of Excellence

  • In conjunction with the NIAID and the JDF, the NIDDK has initiated Diabetes Centers of Excellence. This initiative will foster the development of interdisciplinary programs to develop and test strategies of immune intervention for the prevention and treatment of type 1 diabetes; develop mechanical and/or cellular approaches to achieve normal blood glucose levels in patients with type 1 diabetes; and develop and test strategies for the prevention of complications in type 1 diabetes. These Centers will replace the Diabetes Interdisciplinary Research Programs, which have benefitted from the collaborative support of the NIDDK, NIAID, and JDF for more than ten years.

  • In FY 2000, the number of Diabetes and Endocrinology Research Centers supported by NIDDK increased from six to eight. These Centers provide shared resources for scientists within an Institution or in collaborating Institutions and foster multidisciplinary approaches to diabetes research. They also support pilot and feasibility projects to explore novel approaches to diabetes research and to attract researchers outside the area of diabetes to diabetes research.

Autoimmunity Centers of Excellence

  • Autoimmunity Centers of Excellence will support integrated basic, pre-clinical and clinical research to conduct single site and multi-site cooperative clinical trials and studies of mechanisms of action of tolerance induction and new immune modulation interventions in autoimmune diseases. This initiative will also facilitate the translation of basic research findings into clinical applications, enhance the exchange of information among basic scientists and clinicians, and encourage collaborations among clinical and basic researchers. This initiative is sponsored by NIAID, NIDDK, NIAMS, and ORWH.

Increasing Insulin Secretion

  • Exendin-4 is an agent that induces an increase in insulin secretion by augmenting the production of insulin from pancreatic beta cells and by inducing beta cell differentiation in the pancreas. The NIA plans to expand the clinical testing of exendin-4 during FY 2000. The initial phase I clinical study of exendin-4 demonstrated excellent glucose control as a consequence of a single daily injection. It is hoped that this agent will improve the treatment of diabetes in the elderly.

New Therapeutic Approaches

  • The NIDDK, NIAID, and NICHD have developed an initiative for clinical studies of new approaches to therapy for type 1 diabetes. The focus of this initiative includes studies of cell-based therapies; mechanical devices such as glucose sensing devices, insulin pumps, or an artificial pancreas; gene therapy; immunomodulation; and methods to detect and prevent hypoglycemia.

DRWG Recommendations Regarding Special Needs for Special Problems

The problem of diabetes is made more complex by the fact that it is not a single disease, but occurs in several forms, and has complications that affect virtually every system of the body. Diabetes spares no group, attacking men, women, children, the elderly, and people from every ethnic and racial background. Groups most at risk for developing diabetes type 2 diabetes are individuals over the age of 60 and minority populations. African Americans, Hispanic Americans, Native Americans and Asian Americans are particularly vulnerable. Known risk factors for type 2 diabetes--such as family history of diabetes, obesity, decreased physical activity, and "westernization" of lifestyle--are associated with an increased risk for the development of diabetes. This suggests that a combination of genes, environment and lifestyle increases susceptibility to developing diabetes and its associated complications. The complexity of diabetes therefore creates special needs and challenges for the research conducted and supported by the NIH. To address these needs, the NIH has initiatives in a number of categories, including microvascular and macrovascular complications; optimization of glucose control; diabetes and the environment; special needs in women, children and the elderly; special needs in minority populations; genetic engineering; behavioral and health services research, and the oral complications of diabetes. There are also initiatives on diabetes in HIV-infected individuals and the relationship of drugs and alcohol to diabetes. Some examples of these initiatives are provided below.

Microvascular Complications of Diabetes

  • In September 1999, the NIDDK, in conjunction with NINDS and JDF, convened a symposium entitled, "Advances in Neurobiology: A Key to Understanding Diabetic Neuropathy." As a result of this meeting, the NIDDK and NINDS issued a research solicitation to study the mechanisms by which diabetes results in painful and disabling neuropathies and other neurological complications. This information will help the development of interventions to prevent, limit, or reverse these complications.

  • The NIDDK, along with the NINR, released a research solicitation on new therapies for diabetic foot disease. Goals of this initiative are to stimulate research on the etiology and pathogenesis of diabetic foot ulcers and to develop effective prevention and treatment modalities. Despite advances in wound care, the incidence of diabetic foot ulcers, and of amputations, remains high. New diagnostic, prognostic and therapeutic strategies need to be developed to reduce the burden of diabetic foot disease. New insights into the etiology and pathogenesis of ulceration in the diabetic foot will help develop more effective measures for prevention and treatment.

  • In March 1999, in conjunction with the JDF and the National Aeronautics and Space Administration (NASA), the NIDDK, NINDS and NEI, held a meeting on diabetic retinopathy.

  • The NEI is collaborating with the NCI and NHLBI on an angiogenesis cooperative program and has issued a joint research solicitation. The principal pathologic mechanism underlying catastrophic visual loss in patients with diabetes is the abnormal proliferation of new blood vessels (angiogenesis) in the retina or the iris. Vascular endothelial growth factor and insulin-like growth factor-1 have been implicated in angiogenesis. This finding represents a new direction for diabetic retinopathy research. Vision scientists are poised to make rapid progress in research on angiogenesis because of the availability of very good animal models, the ability to visualize microvascular alterations at very early stages in both animals and humans, the ability to sample vitreous repetitively, and the ability to introduce drugs and biologics directly to the retina.

  • The NIDDK has issued a research solicitation to explore the kidney disease of diabetes. The aim of this initiative is to stimulate research to further the understanding of the pathogenetic mechanisms and genetic determinants of diabetic kidney disease, as well as to address issues concerning risk factors, co-morbidity, and causes of excess incidence of diabetic end-stage renal disease (ESRD) in certain minority populations.

Macrovascular Complications of Diabetes

  • The NHLBI is initiating a program intended to advance the understanding and prevention of microvascular and macrovascular complications in people with diabetes. The "Action to Control Cardiovascular Risk in Diabetes (ACCORD)" is a multi-center, randomized clinical trial to prevent major cardiovascular events in persons with type 2 diabetes. The trial, slated to last 9 years, will compare the effects on diabetes, hypertension, and lipids of a number of therapeutic approaches to diabetes combined with various blood pressure and lipid treatment approaches. This initiative is co-sponsored by NIDDK.

  • The NHLBI, in conjunction with the NIDDK and the NIA, has issued a research solicitation entitled, "Cellular and Molecular Mechanisms of Diabetic Cardiomyopathy." The aim of this four-year program is to understand the basic genetic, molecular and cellular processes responsible for the observed pathophysiology of diabetic cardiomyopathy and ultimately discover new interventions that effectively reverse or prevent disease progression.

Microvascular and Macrovascular Complications

  • The NIDDK has an initiative to study the role of endothelial alteration or dysfunction in the etiology and pathogenesis of the microvascular and macrovascular complications of diabetes. Endothelial function is known to be abnormal in diabetes and may be one early step in the development of atherosclerotic lesions. Recent work has also focused attention on the role of endothelial function in the pathogenesis of microvascular complications. This solicitation is intended to stimulate the application of new molecular technologies to this area. Understanding the pathogenesis of endothelial dysfunction in diabetes at the molecular and cellular level will provide new targets for pharmacologic or genetic manipulations to prevent the complications of diabetes.

Oral Complications

  • Clinicians have long known that a major disease complication in diabetic patients (both type 1 and type 2) is diminished capacity of wound healing. An initiative sponsored by NIDCR will support research to determine the importance of salivary-derived growth factors on wound repair. Studies arising from this initiative may provide insight into treatment strategies to combat the complications of diabetes that may result from a problem in wound repair mechanisms.

  • To help understand the state of early diagnosis in periodontal and other oral diseases in diabetes, the NIDCR is supporting a study to examine the oral health status, use of dental services, and cost of dental care between diabetics and non-diabetics. Other research is focused on the prevention, early diagnosis, and therapies of periodontal disease in patients with diabetes. Research topics in these areas include: periodontitis and the role of inflammation on the development of insulin resistance; diabetic neuropathies of the mouth and craniofacial area; oral diagnostics for diabetes; management of periodontitis and diabetes in Native Americans (through an Interagency Agreement with the Indian Health Service); oral wound healing in the diabetic; and the pathogenesis and treatment of diabetes complications in the oral mucosa.

  • In December 1999, the NIDCR and the NIDDK held a workshop on the major oral complications associated with diabetes.

Other Complications of Diabetes

  • The NINDS will participate, with NIDDK and the JDF, in a workshop on hypoglycemia designed to foster interactions between basic neuroscientists and investigators studying diabetes. It is hoped that this workshop will broaden insights into the varied effects of low blood glucose on the brain, especially on the developing brain.

  • The NIDDK has solicited research to enhance the understanding of the molecular and cellular changes that occur in the urinary bladder and penile erectile function of the person with diabetes.

  • The NIDDK has solicited research to enhance the understanding of gastrointestinal motility disorders associated with diabetes.

Optimizing Glucose Control

  • The NIDDK developed a trans-NIH initiative on pilot studies for new therapies to optimize glucose control in type 1 diabetes. This initiative is also sponsored by NCRR, NEI, NHLBI, NIAID, NICHD, and NIDCR.

Role of Environmental and Infectious Agents

  • Multiple NIH Institutes have issued a research solicitation to encourage basic or population-based research to determine the role of environmental and infectious agents in the initiation and/or exacerbation of autoimmune diseases, such as type 1 diabetes. The specific areas of interest in this solicitation are: (1) the role of exposure to environmental and/or infectious agents in the development of autoimmune diseases; (2) the role of genetic factors in causing the induction of autoimmune diseases by environmental or infectious agents; (3) and the interaction of hormones and gender differences with environmental or infectious agents in development of autoimmune diseases. This initiative is co-sponsored by the NIEHS, NIAID, NIDDK, NIAMS, NICHD, NIDCD, NEI, NHLBI, NINDS, NIMH, NIDCR, and ORWH.

  • The NIEHS is setting up a clinical office and research space at the main NIH location in Bethesda, Maryland, to focus on environmental influences in autoimmune diseases. Among the studies to be started will be an analysis of twin cohorts for type 1 diabetes. The emphasis on the diabetes-related aspects will be on the autoimmunity itself, and the environmental factors leading to diabetes discordance in identical twins.

  • The NIEHS is also investigating whether the Agricultural Health Study (AHS) has a sufficient number of cases of type 1 diabetes to study the risk of developing type 1 diabetes from nitrate exposure in well water. In a study from the United Kingdom, the incidence of childhood diabetes was found to be higher in rural areas in which nitrate levels in water were up to four times higher than in urban locations. This preliminary result could be pursued in a more rigorous prospective study with the AHS. The AHS is a large NIEHS/NCI epidemiological study of farmers and pesticide applicators, as well as their families, that examines how their environmental exposures affect disease risk. If a sufficient number of cases are located within this large cohort, follow-up interview and environmental nitrate measurements could be made to determine if nitrate exposure increases the risk of developing type 1 diabetes.

Interaction of Genetic and Environmental Factors

  • As a result of program announcements issued in FY 1998, the NIGMS expects to increase its support for research that will provide a better understanding of how genetic and environmental components interact to result in complex diseases such as diabetes. Research projects will develop better statistical models for studying gene-gene and gene-environment interactions, investigate DNA sequence variation and its evolution, and optimize sampling strategies.

  • The NIGMS has also recently developed an initiative to create a Pharmacogenetic Research Network and Database, and issued a related research solicitation entitled, "Mechanisms Underlying Individual Variations in Drug Response." Although it is too early to know whether any of the successful projects will focus on diabetes, it is likely that a better understanding of how individuals vary in their response to drugs will have direct bearing on the treatment of diabetes and its complications.

Racial and Ethnic Differences in Diabetes and Diabetes Complications

  • The NIDDK issued a Program Announcement to solicit research to expand our understanding of the underlying mechanisms that contribute to the ethnic variations in the etiology of type 2 diabetes.

  • The NIDDK issued a research solicitation to evaluate differences among contemporary populations in the United States, categorized by race-ethnicity and other factors, in risk factors for complications of diabetes and in rates of these complications. The solicitation will also investigate the extent to which factors--including inherent metabolic and genetic variations, medical care, socioeconomic status, and behavior--account for these differences.

  • The NCRR is developing Centers of Clinical Research Excellence (CCRE) at Research Centers in Minority Institutions (RCMI) to augment and strengthen their clinical research capabilities. Research areas will focus on diseases that disproportionately affect minority populations served by the RCMI institutions. One of these CCREs would focus on diabetes in minority populations, particularly on the epidemiology, genetics, and treatment of diabetes; provide support to develop the research infrastructure, including the recruitment of magnet investigators; and provide support for pilot projects that will allow faculty to obtain preliminary data that can be used to compete for independent research support. This Center could collaborate on efforts between RCMI grantees and existing diabetes centers.

Type 2 Diabetes in Children

  • In July 1999, the Diabetes Mellitus Interagency Coordinating Committee convened a group of epidemiologists and pediatric endocrinologists to address the alarming increase of type 2 diabetes in children, especially children from minority populations. Based on data presented at that meeting, the NIDDK and the NICHD have released an initiative to stimulate research on the pathophysiology, prevention and treatment of type 2 diabetes in children.

Gene Therapy Approaches

  • In November 1999, the NIDDK, in conjunction with the NHLBI, NCRR, NIAID, JDF, and the ADA, sponsored a workshop on gene therapy approaches for diabetes. The purpose of this workshop was to assess the current developments using gene therapy to treat diabetes in both animal models and patients. The results of this workshop will help the NIH to identify the most promising approaches for gene therapy for diabetes, as well as identify technological areas that need further improvements in order to achieve successful treatment for diabetes.

Behavioral Research

  • In November 1999, the NIDDK, in conjunction with the OBSSR, sponsored a meeting on behavioral science research in diabetes. The goal of this conference was to focus on the contribution of behavioral science to diabetes and to identify key research opportunities in which the application of behavioral research would contribute to reducing the burden of diabetes.

  • The NIDDK supports both basic and clinical behavioral research on diabetes, including research on enhanced care for African American children with diabetes; preventing depression in diabetes; interventions for diabetes dietary self-management; and on self-care programs for diabetes management.

  • Much of the responsibility for managing diabetes falls on the patients themselves. They must follow strict regimens of diet, exercise, blood sugar monitoring, and, in many cases, self-medication to maintain blood sugar levels in the normal range. The report of the trans-NIH symposium, "Diabetes Mellitus: Challenges and Opportunities," suggested that insight into the behavioral barriers that prevent application of effective therapies and the development of the means to reduce those barriers will help in the implementation of current and future therapies. In line with this recommendation, the NINR proposes to extend its research on adherence to treatment and other aspects of disease self-management to assist individuals with diabetes control. Research will focus on the application of behavioral strategies to diabetes self-management, with attention to cultural, ethnic, and age-related differences. Ways to enhance communications between patients and care providers will be stressed to improve patients' understanding of the disease process and treatment goals. Prevention and treatment of obesity will also be emphasized.

  • The NIMH will focus its efforts at increasing the Institute's diabetes-related grant portfolio in two areas. First, NIMH supports research to develop and evaluate age-appropriate interventions for a wide range of co-morbid, pediatric mental and medical disorders, symptoms, and related disability. In particular, Institute initiatives aim to understand the causes and limit the development of disorders such as depression, anxiety, conduct disorders, and eating disorders that may co-occur with a range of medical disorders in children and adolescents. The other focus of activity for the NIMH is neurobiological studies of diabetes as a risk factor for brain changes underlying certain types of depression. Such studies would be pursued in aging populations who present with diabetes or other medical conditions and are thought or known to be at increased risk for depression.

Predicting Risk for Diabetes

  • In addition to research focusing on the relationship between diabetes and periodontal disease, NIDCR is also supporting studies that provide insights into the pathogenesis of diabetes. For example, NIDCR scientists have been looking for markers to predict who is likely to develop diabetes years before the appearance of clinical disease. Recent advances in this area have led to diagnostic tests to determine who is at risk for developing diabetes.

Outreach to Special Populations

  • The National Diabetes Education Program (NDEP), a uniquely co-sponsored effort of the NIH and the CDC, was developed to promote the message that improved blood sugar control in people with diabetes can reduce complications--such as eye, kidney, and nerve damage--associated with the disease. The goal of NDEP is to reduce the morbidity and mortality associated with diabetes and its complications. The NDEP specifically targets education messages to minority groups who bear a disproportionate burden of type 2 diabetes. The NDEP plans to develop a campaign to alert health care providers to the alarming increase of type 2 diabetes in children, especially children from minority populations.

  • The NLM, as part of its outreach program for health professionals and the American public, has plans for three diabetes-related projects serving special populations. In the Pacific Northwest, there is a "tribal connections" program to improve Internet access for Native Americans. NLM could build upon this successful connectivity work to emphasize diabetes-related information for this population, which is especially vulnerable to type 2 diabetes. Similarly, NLM is planning to provide technical consultation for the use of smart-card technology to improve both diabetes care and adherence to preventive measures recommended by the American Diabetes Association among Latino and African Americans living in five low-income Los Angeles County health districts.

  • The NLM also proposes to collaborate with the Diabetes Center at Columbia Presbyterian Hospital in New York City. This collaboration will study whether a diverse population of type 1 diabetic children and adolescents, given access to electronic information resources, will be empowered to manage their diabetes and avoid costly and debilitating complications.

Diabetes in HIV-Infected Individuals

  • The NIDDK supports basic and clinical studies of diabetes and obesity relevant to the alterations in body composition and lipid and glucose metabolism now emerging as complications of HIV-infected individuals. To this end, the NHLBI and the NIDDK are cosponsoring an initiative to support research on the effects of HIV protease inhibitors on lipid metabolism leading to hyperlipidemias and altered body fat redistribution, the onset of insulin resistance, and the development of accelerated atherosclerosis.

  • The NIDDK also supports a multi-center, cross-sectional study of body composition and metabolic changes in a randomly selected cohort of HIV-infected individuals and normal controls. Data collected in this study has the potential to affect drug therapy of HIV infection and to provide valuable tools to assess the lipodystrophy syndrome in clinical practice, as well as to suggest mechanistic hypotheses for future investigation.

  • Recent advances in drug therapy allow patients infected with HIV to live longer without manifestations of clinical HIV infection. With this longer life span, other complications, such as diabetes, may develop due to metabolic consequences of HIV infection. An initiative co-sponsored by NIDA and NIAID will support research on metabolic disorders in drug abusers with HIV infection. It is anticipated that this initiative will involve pre-clinical and clinical research on diabetes, as well as other metabolic disorders among drug abusers (including intravenous drug users) with or without infections, including HIV.

Relationship of Drugs and Alcohol to Diabetes

  • The NIAAA continues to expand research in fundamental and clinical science areas that is focused on, or relevant to, diabetes. Cross-cutting research activities include working to determine the relationship of fatty acid composition of fresh blood components to the insulin resistant state in type 2 diabetics; defining the role of delta-5-desaturase in the etiology of insulin resistance in the diabetic state; evaluating the nutritional impact of ethanol on the risk of developing type 2 diabetes; and exploring possible mechanisms for the disruption of glucose homeostasis by ethanol, including how alcohol exposure alters the response of the fetus to insulin. The Biomedical Research Branch, Division of Basic Research, NIAAA, plans to sponsor a research solicitation in FY 2000 in the area of alcohol consumption and insulin resistance. Alcohol can interfere with the actions of insulin by several possible mechanisms, raising a question of whether some chronic patterns of alcohol consumption might lead to conditions resembling type 2 diabetes.

Relationship of Taste and Smell to Diabetes

  • The NIDCD and NIDCR will support basic and clinical studies of diabetes mellitus in the areas of taste and smell. Taste preferences for sweet-tasting substances play a crucial role in the development of insulin and non-insulin-dependent diabetes. The genetic basis for such taste preferences is being studied in human and animal models. The adverse metabolic consequences of diabetes require a heightened awareness of the importance of a balanced diet. Studies in the olfactory system demonstrate that the altered insulin levels and poor nutrition accompanying diabetes compromise the powerful regenerative capabilities of olfactory receptors, ultimately leading to a diminished quality of life due to the loss of the sense of smell.

Fundamental Research

  • The NIGMS will continue to support basic research that focuses on underlying mechanisms and principles that are expected to shed light on both normal and disease processes and to lead to the development of new modes of treatment and prevention.

  • Research studies supported by the NIA provide intriguing evidence that metabolic regulation is one mechanism involved in longevity determination and maintenance of health span in yeast, nematodes, and calorie-restricted rodents. It now remains to be determined whether such pathways have similarly critical roles in mammals.

DRWG Recommendations Regarding Resource and Infrastructural Needs

In order to conduct research efficiently, there must exist a supportive infrastructure. This includes not only the appropriate facilities in which to conduct research, both clinical and basic, but a cadre of talented and trained researchers; research programs to train and support investigators; mechanisms to harness new technologies; and the development of appropriate animal models to study diabetes and its complications. Some examples of newly initiated programs are outlined below.

Research Training

  • The NIDDK supports a number of mechanisms to increase research training. For example, the NIDDK sponsors initiatives designed to support the costs of training students in biomedical research at the predoctoral and postdoctoral levels; career development awards to newly trained or independent scientists in the early and formative periods of their careers; and fellowships that provide the opportunity for experienced scientists to make major changes in the direction of their research careers to broaden their research capabilities, or to enlarge their command of an allied research field.

  • The NIDDK is sponsoring an initiative to increase the number of individuals from under- represented minority groups committed to scientific careers in research areas served by the NIDDK, including diabetes.

  • The NIGMS, in collaboration with multiple institutes, has issued program announcements encouraging predoctoral and postdoctoral training emphasizing statistical and computational skills and workshops to provide additional training in statistical methods to biologists.

  • The NCRR is interested in increasing the number of scientists trained to conduct high-quality pathobiology research on selected strains of genetically altered mice, including those that have diabetes-related anomalies. This solicitation is intended to relieve mouse pathobiologists from time consuming service obligations and administrative responsibilities, thereby increasing the opportunities for their own research and for mentoring the next generation of mouse pathobiologists. This initiative is in response to pressures created by the great increase in the numbers of genetically altered mice being used and to the burgeoning opportunities for mouse diabetes pathobiology research.

Harnessing Technology

  • The NCRR proposes the establishment of a National Diabetes Technology Network (NDTN) within appropriate existing NCRR-supported Biomedical Technology Resource Centers. Each center within the NDTN would focus on one or two technologies critical to diabetes research. The network would also promote collaboration among the resources to create technologies not yet imagined.

  • The NIDDK is sponsoring an initiative on Biotechnology Cores. The purpose of this initiative is to foster development of core resources to support research related to diabetes and obesity by providing microarray chip or other gene expression analysis technology to investigators.

Animal Models

  • The NIDDK has an initiative to establish national centers for the purpose of detailed metabolic phenotyping of knock-out mice and other mouse models potentially useful for understanding diabetes and its complications. These facilities are expected to provide a range of standardized procedures to characterize metabolism, body composition, feeding behavior, activity, tissue pathology, and other physiologic, anatomic or pathologic alterations that may occur in these mice.

  • Nonhuman primate models are genetically, physiologically, and behaviorally more similar to humans than other laboratory animals. Like humans, primates are outbred species, with significant intra-species genetic variation. Although diabetes has not been studied to a great extent in the baboon, approximately five percent of the population appears to develop diabetes spontaneously. Some animals may be predisposed to diabetes, and diabetes can be experimentally induced with drugs. The baboon animal model could be used to study the link between atherosclerosis, hypertension, and type 2 diabetes. Furthermore, gene mapping could be directed toward finding and characterizing genes involved in insulin regulation. The baboon has frequently been utilized in xenotransplantation studies and could be the model for pancreatic islet cell transplantation research. Furthermore, excess accumulation and regional deposition of body fat has been implicated as a common risk factor for type 2 diabetes. Characterization of obesity genes will further our understanding of genetic factors in hyperinsulinemia. The NCRR proposes to establish baboon colonies to make this large animal model available to the diabetes research community.

  • An NIH-wide research solicitation will establish a facility for large-scale mutagenesis and phenotyping of developmental defects in the mouse. The immediate objective is to produce and characterize mouse strains harboring mutations that affect normal developmental processes. Ultimately, the mutant mice produced are expected to help elucidate the basic cellular, molecular, and genetic mechanisms that direct embryonic and post-embryonic growth and function, as well as yield insights into the mechanisms of human disease. This initiative is sponsored by numerous Institutes, including: NICHD, NIGMS, NIA, NIAMS, NIDCR, NIDDK, and NHLBI.

  • An increasing number of mouse animal models, including standard inbred and hybrid mice, as well as mice with spontaneous and induced mutations, are being developed for studies of diabetes and obesity. The maintenance and supply of the many strains useful for research in type 2 diabetes, hyperglycemia and hyperinsulinemia, plus various endocrine deficiency models, currently require a significant commitment of resources. The NCRR is initiating an expansion of mouse animal model resources by creating a network of centers to ensure that the future needs for these valuable research animals can be met. The diabetes-related mouse models are a significant component of the overall biomedical research needs.

  • Begun in FY 1998, the ongoing Trans-NIH Zebrafish Initiative has a goal of improving the genomic resources for the zebrafish, a potentially valuable model for diabetes. This initiative is sponsored by NICHD, NIDDK, NCI, NCRR, NEI, NHGRI, NHLBI, NIA, NIAAA, NIAID, NIAMS, NIDCD, NIDCR, NIDA, NIEHS, NIGMS, NIMH, and NINDS.

Coordination Mechanisms

  • The NIDDK chairs the Diabetes Mellitus Interagency Coordinating Committee (DMICC). This Committee was authorized by Public Law 93-354. The specific charges to the DMICC are as follows: to coordinate the research activities of the National Institutes of Health relating to diabetes and its complications; to coordinate those activities of all Federal programs that are related to diabetes and its complications; and to contribute to the adequacy and technical soundness of these activities by providing a forum for communication and exchange of information. The committee includes representatives from 23 Federal organizations whose programs are relevant to diabetes and its complications and includes representatives from the ADA and the JDF. A key function of the DMICC is to provide a forum for exchange of information necessary to maintain effective coordination of Federal activities related to diabetes and its complications. The NIDDK plans to use the DMICC in the future as one mechanism to coordinate Federal diabetes research efforts relative to the recommendations of the DRWG.

  • The NIAID chairs the NIH Autoimmune Diseases Coordinating Committee, established in FY 1998 at the request of Congress, to increase collaboration among the many NIH Institutes and private groups interested in autoimmune diseases and to facilitate the development of a coordinated research plan. The Committee includes representatives from most NIH Institutes, Centers, and Offices, as well as other Federal agencies and private organizations, such as the JDF. This group was instrumental in the development, issuance, and administration of a series of collaborative autoimmunity initiatives in FY 1999 after Congress increased NIAID's appropriation for autoimmunity research. The Committee has formed a series of collaborative Working Groups, to encourage prospective development of further collaborative initiatives in this area.

Summary

When the DRWG was established, the NIH leadership followed closely the deliberative planning process of this group of experts and began to lay "footprints" with FY 1998 and FY 1999 funds in areas of scientific opportunity and need that were being identified in meetings of the DRWG prior to official release of the DRWG's formal Strategic Plan in March 1999. The NIH continues to use the DRWG Strategic Plan as a guidepost for framing diabetes initiatives, within the context of the agency's available resources and its overall research responsibilities.

Over the last few years, the NIH has worked towards developing a trans-NIH diabetes research agenda which is both comprehensive and balanced. Each of the ICs mentioned in this report has developed research activities relative to its research mission. While some of these initiatives build upon existing programs, many are new and are intended to accelerate research progress in diabetes and its complications. The NIH understands the great burden that diabetes places on patients, families and communities. The NIH has important programs under way, but recognizes that formidable research challenges remain to be addressed in order to cure this costly and devastating disease.

Appendix
List of Abbreviations

ADA    American Diabetes Association
CDC    Centers for Disease Control and Prevention
DRWG    Diabetes Research Working Group
JDF    Juvenile Diabetes Foundation International
NCI    National Cancer Institute
NCRR    National Center for Research Resources
NEI    National Eye Institute
NHGRI    National Human Genome Research Institute
NHLBI    National Heart, Lung, and Blood Institute
NIA    National Institute on Aging
NIAAA    National Institute on Alcohol Abuse and Alcoholism
NIAID    National Institute of Allergy and Infectious Disease
NIAMS    National Institute of Arthritis and Musculoskeletal and Skin Diseases
NICHD    National Institute of Child Health and Human Development
NIDA    National Institute on Drug Abuse
NIDCD    National Institute on Deafness and Other Communication Disorders
NIDCR    National Institute of Dental and Craniofacial Research
NIDDK    National Institute of Diabetes and Digestive and Kidney Diseases
NIEHS    National Institute of Environmental Health Sciences
NIGMS    National Institute of General Medical Sciences
NIH    National Institutes of Health
NIMH    National Institute of Mental Health
NINDS    National Institute of Neurological Disorders and Stroke
NINR    National Institute of Nursing Research
NLM    National Library of Medicine
OBSSR    NIH Office of Behavioral and Social Science Research
ODP    NIH Office of Disease Prevention
ORMH    NIH Office of Research on Minority Health
ORWH    NIH Office of Research on Women's Health

Page last updated: October 18, 2007

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