The National Institute of Diabetes & Digestive & Kidney Diseases

Minutes

Speakers

Nell Armstrong, Ph.D., R.N.
National Institute of Nursing Research

Elaine Collier, M.D.
National Institute of Allergy and Infectious Diseases

Peter Dudley, Ph.D.
National Eye Institute

Richard Eastman, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases

Judith Fradkin, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases

Robert Goldstein, M.D., Ph.D.
Juvenile Diabetes Foundation International

Gilman Grave, M.D.
National Institute of Child Health and Human Development

David Harlan, M.D., MC, USN
Naval Medical Research Institute

Joan Harmon, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases

Richard Kahn, Ph.D.
American Diabetes Association

John Lanigan
Health Care Financing Administration

Paul Nichols, Ph.D.
National Institute of Neurological Disorders and Stroke

T.G. Patel, M.D.
Veterans Health Affairs

Peter Savage, M.D.
National Heart, Lung, and Blood Institute

David Stevens, M.D.
Health Resources and Services Administration

Charles Wells, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases

WELCOME BY DR. EASTMAN

Dr. Eastman, Director of Diabetes and Endocrinology at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), welcomed attendees to the meeting and introduced Charles Wells, Ph.D., as the meeting's emcee.

Setting Priorities for Use of Funds for Type 1 Diabetes

Judith Fradkin, M.D., who is Deputy Director of Diabetes, Endocrinology, and Metabolic Diseases, NIDDK, presented an overview on the process of setting priorities for the use of funds allocated for the study of Type 1 diabetes. In September 1997, President Clinton announced an initiative to expand research on Type 1 diabetes and pledged $30 million a year, for 5 years, of which, $27 million would be used by the National Institutes of Health (NIH) and $3 million by the Centers for Disease Control and Prevention (CDC). Shortly after the President's announcement, Drs. Varmus and Gorden, along with eight other NIH directors, convened a major conference of over 200 leading researchers to generate recommendations for future research and develop an effective plan to use the newly allocated funds for research on Type 1 diabetes.

The chairpersons of four conference subgroups, relevant to Type 1 diabetes, prioritized their recommendations and four Requests for Applications (RFA) were issued for fiscal year (FY) 1998:

• Cellular and molecular approaches focusing on islet transplantation and bioengineered data cells;
• Noninvasive or minimally invasive glucose sensors and the development of closed loop systems for regulated and mechanical insulin delivery;
• Complications of Type 1 diabetes, particularly focused on the role of growth factors in pathogenesis, and new approaches to therapy; and
• Immunopathogenesis of Type 1 diabetes.

To preserve some of the funds for future RFAs and initiatives, $8 million of the $27 million was reserved for 1-year awards and all awards were limited to 3 years. In addition, 2 year pilot feasibility awards were encouraged in each RFA.

NIH received 302 applications in responses to the RFAs. RFAs were cosponsored by two to six institutions. With additional funding provided by the Juvenile Diabetes Foundation International (JDF), NIH made 87 awards. The overall success rate for the researchers submitting RFAs averaged 29 percent. Twenty-six percent of the principal investigators were first-time grantees; 37 percent of the researchers were new to diabetes; and about 30 percent of the awards were R21s.

For FY99, NIH has approximately $8 million available for new initiatives and the plans for this money were developed largely from the recommendations made by the 1997 conference subgroups and from ongoing deliberations of the congressionally-directed Diabetes Research Working Group. Three RFAs were issued to utilize these funds:

• Pilot studies on new therapies for Type 1 diabetes and its complications;
• Neurologic complications of diabetes; and
• Determination of EST databases and cDNA libraries from islets and other relevant diabetes tissue.

National Institute of Allergy and Infectious Diseases

Elaine Collier, M.D., who is Chief, Autoimmunity Section, National Institute of Allergy and Infectious Disease (NIAID), discussed NIAID's work in the area of diabetes. Since NIAID's focus is on immunology, the Institute is primarily interested in Type 1 diabetes, but it also has other interests that overlap with autoimmunity. Dr. Collier addressed three areas in her presentation: (1) Current initiatives in Type 1 diabetes, (2) The Autoimmune Disease Coordinating Committee, and (3) Last minute appropriations for autoimmune disease added to the NIAID budget.

NIAID has several important programs for research on Type 1 diabetes that are in solicitation, currently being reviewed, or are forthcoming. One such program is the Autoimmunity Centers of Excellence, which is cosponsored by NIDDK and several other Institutes. Applications for this program are now being reviewed. This program will focus on the development of clinical and basic centers of research for the purpose of conducting pilot trials with immunotherapies.

The Human Immunology Centers are program projects in human immunology, many of which are related to autoimmunity and Type 1 diabetes. Under a contract mechanism, NIAID has received applications for clinical trials and the development of clinical markers for Type 1 diabetes and autoimmunity.

Another program NIAID is excited about is a collaborative network on tolerance, which has been one of the Institute's emphasis areas for the past 2 years. The program has been jump-started with some extra funding and will initially focus on islet and kidney transplantation. Some additional funding may allow NIAID to incorporate the autoimmune portion of the collaborative network as well. NIAID is also hoping to internally fund a tolerance assay program for the purpose of developing assays of tolerance. Finally, along with other Institutes, NIAID is participating in an accelerated mechanism to fund clinical trial basic research.

Dr. Collier next discussed the Autoimmune Disease Coordinating Committee. Mandated by Congress, the Committee was established in 1998, and meetings were held in June and October. The Committee has gathered information on NIH-funded research and programs in autoimmune diseases and the current initiatives in this area at NIH and in private organizations. This information helped NIAID to make decisions about spending the $30 million added to its budget at the end of the fiscal year. The Institute has decided to spend the money on research on multiple autoimmune diseases and research that crosses multiple autoimmune diseases, and will fund the gamut from basic to clinical research. Other areas that will be covered include environmental research, infectious diseases, genetics, islet and kidney transplantation, human islet transplantation, basic organ research, and new technologies. In addition, several clinical trials will be funded, both contracts and RFAs.

National Institute of Diabetes and Digestive and Kidney Diseases, Naval Medical Research Institute

Captain David Harlan, M.D., M.C., USN, who is Director, Immune Cell Biology, Naval Medical Research Institute, gave a presentation on an initiative, currently in the process of being developed, that is a partnership between NIDDK and the Navy to establish a new branch called the Transplant and Autoimmunity Branch. This branch is being developed to understand tolerance and how it is broken in patients with T cell mediated autoimmune illnesses.

For the past 10 years, the Navy Medical Research Institute, as well as other people around the country, have been studying the two-signal model for T cell activation that was initially proposed by Laferty and Cunningham about 25 years ago. Dr. Harlan used a series of slides to explain the basic concepts of this model. It is known that the T cell plays a cental role in the pathogenesis of Type 1 diabetes mellitus (T1DM). Prior to Lafferty and Cunningham, it was thought that the process through which a T cell recognized a target (e.g. a cell) was sufficient to activate the T cell. Lafferty and Cunningham proposed that target recognition alone however, was not sufficient to activate the T cell. Rather, they proposed that there had to be another receptor to provide a second T cell signal to activate it. A corollary of this hypothesis was if a drug could interfere with the second signal while the T cell recognition process was occurring, that particular T cell was either killed or permanently inactivated.

The leading candidate for that receptor was a T cell receptor called CD28. Researchers now know that CD28's natural ligand is the class of receptors collectively called B7, comprised of two members named CD80 and CD86. It is also known that the B7 molecules can interact with another receptor on the T cell, called CTLA4 (or more recently CD152). In 1992, Linsley et al. developed a reagent called CTLA4-Ig by linking the CTLA4 extracellular domain with the immunoglobulin heavy chain. They found that CTLA4-Ig could block CD28 signaling by effectively competing for B7 and thus preventing the B7 CD28 interaction.

Also in 1992, Lenschow et al. published the first paper demonstrating that the two-signal model had some relevance in vivo. They transplanted human islet cells under the kidney capsule of diabetic mice, and the mice were cured of diabetes for about 7 days until the immune system recognized the islet cells as foreign and killed them. When the researchers administered the co-stimulatory receptor blocker CTLA4-Ig every other day for 14 days, the mice never rejected the islet cells. They also showed that if the kidney with the transplanted islet cells was removed, the mice always became diabetic again, demonstrating that the human islet cells were producing the insulin. Most importantly, they showed that islets from the original human donor could be transplanted under the remaining kidney's capsule and not be rejected while islets from an unrelated human donor were normally rejected. These exciting results suggested that the mouse immune system had "learned" to recognize islets from the original human donor as self, and yet retained the ability to respond against other foreign tissue.

With the publication of several other papers, it became widely recognized that CD152 (CTLA4) was somehow mediating a down regulatory signal to prevent T lymphocyte activation. In the simplest terms, CD28 turns things on and CD152 (CTLA4) turns things off, and they both interact with B7. The most widely studied rodent model for T1DM is the NOD mouse. In a study published a few years ago, researchers administered CTLA4-Ig and found that if the agent was administered to young mice, the mice usually did not develop diabetes. Interestingly, when the researchers administered an anti-CD80 antibody, mice developed disease earlier than did control mice. These data suggested that B7 interactions with T-cell counter-receptors can down-regulate some immune responses (presumably via the CTLA4 receptor) and activate others (presumably via CD28).

In 1995 Navy researchers began studying costimulatory pathway modifying reagents in a rhesus monkey kidney transplant model developed at the University of Wisconsin. The researchers performed a bilateral nephrectomy on adolescent rhesus monkeys, then transplanted a purposefully mismatched kidney and administered one of the immune modulating therapies to see if it had any effect on graft survival. In the group of transplanted monkeys who did not receive any immune modulating therapy, it did not take very long for their immune systems to recognize that the allografted tissue was foreign. As a result, within 10 days the monkey's creatinine level rose, the animal stopped producing urine and died. Human CTLA4-Ig was administered to another group of monkeys and while it did prolong graft survival to 20 and 30 days, the monkeys eventually rejected their kidneys.

Also around 1995, reports of another agent which appeared to act via a costimulatory receptor mechanism began to appear in the literature; the anti-CD154 antibody. Initially, it was thought that anti-CD154 acted by preventing B7 up-regulation on antigen presenting cells. Parker et al. reported that diabetic mice given islet allografts and anti-CD154 administered as a single agent resulted in a long-term cure in half of the recipients. They also found that the co-administration of donor specific lymphocytes along with anti-CD154, allowed long term islet allograft survival in all the transplanted mice.

Balasa et al. administered anti-CD154 to young NOD mice and followed them for the onset of diabetes. They found was that if the anti-CD154 was given to young NOD mice, they were protected. However, if they waited until the mice had already developed insulitis before administering the antibody, it was not effective. The researchers concluded that anti-CD154 appeared to play a role in the pathogenesis of diabetes in the NOD mouse.

Larsen et al. then reasoned that if anti-CD154 was indeed working through its ability to prevent B7 up-regulation on the antigen presenting cell, that the co-administration of anti-CD154 along with a drug that would block B7 (CTLA4-Ig) should be especially effective in preventing allograft rejection. To test this theory, the researchers used a mouse skin allograft model. They found the combination of CTLA4-Ig and anti-CD154 could result in long-term skin allograft survival, however, both agents were required as neither agent was effective alone. More dramatically, when the researchers administered cyclosporine A along with these agents, it abrogated the graft- sparing effect. Since cyclosporine A works by preventing proper signaling through the T cell receptor, these results suggested that alloantigen recognition was required for the graft-sparing effect observed.

The Navy began testing, in collaboration with researchers at the University of Wisconsin, whether the CTLA-Ig plus anti-CD154 combination would prevent kidney allograft rejection in the rhesus monkey model. The first two monkeys that were transplanted with completely mismatched kidneys and given these agents in 6 doses over 30 days maintained normal kidney function for the first six months following transplantation. The experiments were repeated, but the researchers gave the monkeys only anti-C154 and found it quite effective as a single agent. The monkeys had a normal creatinine for at least 95 days, and when the kidney began to reject, re-administration of the drug reversed the rejection process.

Because the researchers saw rejection episodes at day 90, they decided to alter the treatment regimen and administer 6 doses of the drug over the first month, and then monthly. This has been done in four animals to date, and none have suffered even one episode of rejection (submitted for publication). In the anticipation of clinical trials, the researchers wondered if the agent could be administered with currently used immunosuppressive therapies. To test this, the researchers administered the agent with mycophenolate mofetil, and those monkeys have not rejected their allografts, while other combinations have not prevented allograft rejection.

Dr. Harlan also reported that these drugs appear to have no apparent toxicity. The researchers have been closely following the animals' blood counts, chemistries, and liver function tests. The monkeys grow normally and their wounds have healed normally.

Finally, Dr. Harlan reported that Navy investigators have been collaborating with researchers at the University of Miami (Drs. Kenyon and Ricordi) to test anti-CD154 therapy for its ability to prevent islet allograft rejection in pancreatectomized rhesus monkeys. These monkeys are all insulin independent and gaining weight.

In response to audience questions, Dr. Harlan pointed out that despite the fact that researchers have seen no toxicity from this therapy, the mechanism underlying its remarkable effectiveness is not yet well characterized and almost certainly is more complex than the two-signal model implies. Researchers are now hoping to characterize the molecular mechanism of action and determine the optimal therapy for the prevention of autoimmune illness and allograft rejection. Therefore, kidney and pancreatic islet transplant clinical trials are being planned for initiation at NIH in Summer 1999. A ward at the NIH Clinical Center is currently being renovated for these trials. The researchers will initially study patients with long-term insulin dependent diabetes and patients getting single kidney transplants.

In response to a question about rejection, Dr. Harlan explained that some monkeys were purposefully underdosed with anti-CD154, and when they did reject, the researchers have been able to rescue them with traditional rescue therapies used for patients now receiving kidney transplants.

National Institute of Diabetes and Digestive and Kidney Diseases

Joan Harmon, Ph.D., who is Senior Advisor for Diabetes, NIDDK, presented the initiatives and research support for Type 1 diabetes within NIDDK. She first described the FY98 NIDDK initiatives, which included three RFAs related to Type 1 diabetes:

• Cell Biology: The Pancreatic Beta Cell--$4 million was set aside for this solicitation that invited applicants to study the growth and differentiation factors responsible for the development and maintenance of the beta cells in the pancreas. Out of the 54 applications received by NIDDK, 17 were funded. Of those funded, seven grants relate to transcriptional control of pancreatic development; nine relate to the control of beta cell differentiation and propagation, and one relates to the toxic effects of glucose on the beta cell.
• Diabetic Nephropathy Mechanisms, Genetic Determinants, and Interventions--This RFA sought applications to pursue basic and applied investigations to better understand the physiology of diabetic nephropathy, genetic determinants of susceptibility, cellular and molecular factors, mechanisms of glomerular sclerosis, interstitial fibrosis, and renal scarring. For this RFA, $2.5 million was set aside, and out of the 53 applications received by NIDDK, 7 were funded. These grants included two studies on the genetics of nephropathy; four studies related to the mechanism of disease onset; and one study related to glycosylated albumin in diabetic nephropathy.
• The Effects of Diabetes on Urinary, Bladder, and Erectile Function--This RFA sought applications for studies to increase basic knowledge of the effects of diabetes mellitus on the lower urinary tract. Specifically, studies were sought of vascular, neurological and smooth muscle functions, and interactions of the normal urinary bladder and penile erectile function and the changes that occur with diabetes. Total funding was set at $1.5 million, and NIDDK received 24 applications and funded 3 of them. Two of the grants relate to bladder dysfunction and one relates to erectile dysfunction.

NIDDK's second FY99 solicitation, Human Islet Cell Transplantation in Humans, is also cosponsored by NIAID and JDF. Applications are being sought to investigate the potential modulation of the immune response in humans to transplanted islet cells. NIDDK expects to see applications proposing clinical studies using new methods to induce immune tolerance to prevent the recurrence of the autoimmune destruction of beta cells in the islet and to prevent transplant rejection. This RFA has a set aside of $5 million and a submission date of March 10, 1999.

Dr. Harmon also presented a comparison of FY97 to FY98 spending in the areas of Type 1 diabetes. The areas that showed the greatest increase in spending included beta cell growth and development, which increased by $4 million. Other areas of increase included:

• Etiology and epidemiology (approximately $4.2 million);
• Transplantation and glucosensors ($1 million); and
• Complications of diabetes, including nephropathy, which includes bladder and erectile dysfunction (approximately $4.5 million).

National Heart, Lung, and Blood Institute

Peter Savage, M.D., who is Deputy Director, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute (NHLBI), presented an overview on diabetes and its relationship to cardiovascular disease, talked about NHLBI initiatives and how they relate to Type 1 diabetes, and discussed the need to acquire critical information about how microvascular complications in people with Type 1 diabetes may differ from those in people with Type 2 diabetes.

More than 30 million Americans have some form of glucose intolerance. Among middle-aged and older people who are diabetic, studies show that the risk of cardiovascular disease is substantially different for people who have evidence of subclinical cardiovascular disease, even if they've had no clinical events, than in people who do not have subclinical disease. NHLBI is attempting to develop a better assessment of subclinical disease and look at how it modifies the risk in patients with diabetes. Currently, many of the methods of measuring subclinical disease are relatively crude. However, as assessment methods improve, it may enable a greater focus on people who have the highest risk of subclinical disease, which is the major cause of death in people with diabetes.

There also is a series of cardiovascular problems that are associated with acute cardiovascular disease. An issue that has been raised in one clinical trial is how patients with diabetes may have different responses to attempts at coronary surgery or angioplasty versus bypass surgery and so forth. It is a fact that the rate of congestive heart failure in diabetics exceeds that of nondiabetics. Although congestive heart failure is in part explicable by traditional atherosclerotic cardiovascular disease, there appears to be an excess of unexplained congestive heart failure.

How does diabetes cause an increase in cardiac and vascular disease? There is an increasing amount of data showing that hyperglycemia, in both Type 1 and Type 2 diabetes, causes an alteration in other known cardiovascular risk factors. If the risk factors and abnormalities that are independent of glucose abnormalities are treated, the evidence suggests the risk of at least coronary heart disease can be substantially reduced.

Other issues related to cardiovascular disease (CVD) in diabetics include the direct toxicity of sustained hyperglycemia, the question of whether or not there is an interaction between the diabetic abnormalities in other risk factors, and the relationship of Type 2 diabetes with syndrome X or the multiple risk factor syndrome. In addition, the evidence that controlling glucose reduces microvascular complications is much stronger than the evidence that the same degree of control will produce the same relative benefits in terms of macrovascular disease. Some insulin studies have shown that people who are aggressively treated with insulin tend to gain weight and may have some adverse changes in some of their other cardiovascular risk factors.

Among patients with diabetes, what are the factors that predict premature macrovascular disease and poor outcomes? The risk of cardiovascular complications is not equal in all patients with Type 1 diabetes, and it has been known for a long time that these variations in risk between different populations are only partially explained by differences in other cardiovascular disease risk factors. There also is some evidence on new cardiovascular disease risk factors associated with diabetes abnormalities and the hemostatic system, increases in inflammatory markers, and oxidation of low density lipoprotein cholesterol. Moreover, a series of new techniques, mostly in ultrasound, are being developed for looking at subclinical disease.

The total number of dollars spent by NHLBI in FY97 on macrovascular complications is difficult to estimate because databases were not set up to pull out this information. As of this year, the total amount of money being spent by NHLBI on macrovascular complications will have doubled over the past 2 years.

Dr. Savage then began a discussion on the differences and similarities of cardiovascular complications in Type 1 and Type 2 diabetics. Both groups of patients have hyperglycemia, and from what is known, hyperglycemia, or something related to it, has potentially adverse effects in both groups of diabetics. Both groups tend to have an excess of hypertension as compared to similarly aged nondiabetics. In Type 1 diabetics, hypertension may be more related to the development of renal disease, which may alter the risk. However, the adverse effects of hypertension appear to be similar in both groups of diabetics, and the response to deterioration in glucose control, in terms of shifting upward several of the CVD risk factors, has some common elements.

In looking at the two groups of diabetic patients, the amount of preexisting vascular disease is much greater in people who develop Type 2 diabetes in middle age verus someone who develops Type 1 diabetes in youth. Because injected insulin is administered into the peripheral tissue rather than coming from the pancreas, all Type 1 diabetics have circulating hyperinsulinemia. Type 2 diabetics will have a variety of levels of insulin, depending upon their level of insulin resistence, whether they are using endogenous insulin, and whether they have injected insulin.

Of primary importance is to find better ways to reduce macrovascular complications. Once that is accomplished, researchers need to look at how some of the differences and similarities between Type 1 and Type 2 diabetics might help prevent cardiovascular complications in Type 1 diabetics. This is an important research area because cardiovascular complications are a major cause of death in Type 1 diabetics during their sixth decade. Currently, it is one of the leading causes of premature cardiovascular disease in the United States.

The NHLBI has a set of five projects that are cosponsored by the JDF and seven recently funded small grants on diabetic complications. The five programs funded in conjunction with the JDF are examining a series of different aspects of diabetes. An RFP has also just been issued for a clinical trial on prevention of cardiovascular disease to examine glucose lowering.

In terms of the difference between Type 1 and Type 2 diabetic patients' risks of macrovascular complications, Dr. Savage reported that data are being gathered that are applicable to Type 1 patients. Smaller, shorter trials using surrogate endpoints, rather than hard clinical events as endpoints, may be feasible to provide some specific information on Type 1 diabetic patients.

In response to questions from the audience, Dr. Savage talked about the association between markers of some infectious diseases and some increase in risk of cardiovascular disease. Diabetes has been known for a long time to be associated with some blunting of the response to infection. Diabetics may have more periodontal disease than nondiabetics, and dentists have found that certain types of gum disease seem to be more associated with the risk of atherosclerotic disease.

National Eye Institute

Peter Dudley, Ph.D., who is with the Retinal Disease Program, National Eye Institute (NEI), presented an overview of the Institute and its involvement in diabetes research. His presentation touched on four areas: NEI's strategic plan, NEI funding devoted to diabetes and related research, trans-NIH initiatives, and cooperative activities with private organizations.

Dr. Dudley provided a historical overview of NEI's interest in diabetes and diabetic retinopathy. In 1975 the Institute's first formal strategic plan, "A Vision Research: A National Plan, 1978-1982," identified research priorities that included physiological studies of blood flow, mechanisms of edema, protein transplant across the retina, and mechanisms and metabolic relationships between neurons and glia in the retina. Moreover, clinical investigations were an important feature of that plan. At the same time, the Diabetic Retinopathy Study (DRS) was in its infancy and preliminary reports on the effects of photocoagulation therapy appeared in the literature. Other landmark clinical trials followed the DRS, including the "Early Treatment of Diabetic Retinopathy Vitrectomy Study," which began recruitment in 1976 and the "Early Treatment of Diabetic Retinopathy Study," which began in 1979. Since then, the Institute has issued a series of 5-year plans.

NEI's strategic plan continues to highlight diabetic retinopathy and vascular problems in the retina. The current plan, "A Vision Research: A National Plan," covers 1999-2003 and cites several areas of progress that have occurred in research on diabetic retinopathy such as the identification of vascular endothelial growth factor as a major candidate contributing to the etiology of neovascularization, possible roles of insulin growth factor 1 in proliferative retinopathy, and the benefits of tight control of glycemic levels.

In FY98, NEI devoted $23 million, or 7.9 percent of its extramural grants budget, to diabetes and diabetes-related research and programs. In FY99 that figure will increase to almost $26 million, with further increases projected for the year 2000. Recently, the Diabetes Research Working Group completed its work on a plan soon to be submitted to Congress. NEI was able to share information from its own program planning effort with the Diabetes Research Working Group to help them think about the priority areas for microvascular complications of the eye.

Dr. Dudley emphasized that the NEI strategic plan is and continues to be a community plan. That is, NEI solicits input from the community, including a major scientific organization, for example, the Association of Research and Vision in Ophthalmology. In addition to research on molecular and genetic factors in diabetic retinopathy, NEI considers epidemiologic and health services research to be important areas. More attention needs to be given to the design of effective screening strategies for eye diseases, education of eye care providers and the public in treating eye disease, and the identification of factors associated with the most effective delivery and use of vision care services. These areas all have important implications for diabetes.

Another program within NEI is the National Eye Health Education Program (NEHEP). This program, mandated by Congress in 1968, aims to find new ways to prevent, diagnose, and treat eye diseases. NEHEP has formed a partnership with a wide variety of public and private organizations devoted to eye health. NEHEP serves as a vehicle for educating professionals, patients, and the public, and treating diabetic retinopathy.

NEI has been joined by other NIH Institutes in sponsoring two RFAs related to diabetes. The first RFA funded nine vision-related projects related to the pathogenesis of and therapy for complications related to diabetes. In addition, NEI funded two additional projects and is in the process of making two other awards in collaboration with JDF. The second RFA is for pilot studies of new therapies for diabetes and its complications, and applications are due on March 30, 1999.

NEI is also working with the diabetes community in several other areas. Several years ago, the Institute joined JDF in a cooperative research program on diabetic retinopathy with the aim of increasing the funding of R01 type applications. This program has resulted in the co-funding of several grants. The NEI and Eli Lilly & Company have entered into a memorandum of understanding whereby NEI advises in the design, coordination, and oversight of a large scale clinical trial with a protein kinase inhibitor for the treatment of diabetic retinopathy.

National Institute of Neurological Disorders and Stroke

Paul Nichols, Ph.D., who is Program Director, National Institute of Neurological Disorders and Stroke (NINDS), presented an overview of the grants supported by NINDS that are specifically related to diabetic neuropathy. Currently, the Institute is supporting 12 grants in this area, with half of them being funded only recently as a result of last year's appropriations for research on diabetic complications. The largest study being supported by NINDS is an epidemiological study of diabetic complications in a well-defined population in Rochester, Minnesota. The principal investigator of this study has found with tests such as nerve conduction, two-thirds of all diabetic patients showed some signs of neuropathy. However, only 20 percent of patients exhibit symptoms of neuropathy. Therefore, this investigator concluded that diabetic neuropathy might be less of a problem than people believe and is certainly a less serious problem than diabetic nephropathy or diabetic retinopathy. Dr. Nichols also recommended a new book on diabetic neuropathies written by this investigator, which is scheduled for publication in 1999.

NINDS has funded six new grants, and of these, three were R21 pilot studies, one was a small R01, and two were regular R01s. The Institute expects to have up to $2.5 million available from the RFA that was issued in December 1998 to fund about 12 more grants. NINDS has also been working on publicizing the availability of the grants.

Dr. Nichols also discussed a literature search that he conducted. He found only 134 articles on diabetic neuropathy published within the last year as compared to 350 articles on diabetic nephropathy and 530 articles on diabetic retinopathy. Upon further analysis of the 134 articles on diabetic neuropathy, Dr. Nichols found that only 36 were published by people doing research in the United States. Among all of the articles, there were 22 different studies on the pathogenesis of diabetic neuropathy and 8 of these were conducted in the United States. Interestingly, 3 of the 22 studies dealt with genetic factors, showing evidence of 3 specific genes being involved in diabetic neuropathy.

Of the 134 articles, there were 14 animal studies that focused on a drug or compound's effect on nerve conduction. In addition, there were 13 clinical studies that involved human subjects. In one of these studies, patients were treated with acupuncture and some of their symptoms cleared up completely.

In response to a question from the audience about the number of diabetics who have diabetic neuropathy, Dr. Nichols stated that the literature reports a 60 percent incidence. However, when glycemia is controlled as well as possible, only 20 percent of those with neuropathy have any symptoms.

National Institute of Child Health and Human Development

Gilman Grave, M.D., who is Chief, Endocrinology, Nutrition, and Growth Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, based his discussion on the point that NICHD has a rather small program and does not have enough diabetes grants. Dr. Grave talked about the complete overlap of programs between NICHD and NIDDK and gave several examples of this overlap. Upon joining the NICHD in 1972, Dr. Grave learned that the Institute did not have a program in juvenile diabetes because the topic belonged under NIDDK's program area. However, NICHD could study diabetes and pregnancy and in 1977, four major research programs were begun in this area. Two of these studies are now in their 21st year. The highest the total yearly budget for diabetes at NICHD has ever been is $15 million.

One of the most interesting studies supported by NICHD was the Diabetes in Early Pregnancy Project, which enrolled 1,000 women who were Type 1 diabetics in 5 different centers across the country. The women who did not receive intensive preconception care had a 9 or 10 percent rate of congenital defects. However, the women who received intensive care both preconceptionally and during pregnancy had approximately a 3 percent rate of congenital defects. As a result of decreasing the congenital defect rate by two-thirds, intensive preconception and pregnancy care have become standard obstetrical practice.

As a result of a meeting, "Early Detection of Potential Diabetics: The Problems and the Promise," NICHD began to seriously study markers and predictors of diabetes by conducting a study of 100 multiplex families. This study revealed the genetic linkage between the DR4 allele and Type 1 diabetes. In a 13-year study (1984-1997), "The Florida Natural Study of Type 1 Diabetes," supported by $6 million from NICHD, researchers studied genetic and immunological predictors of diabetes in 7,000 first degree relatives of diabetics and 9,000 school children.

NICHD recently funded a large new study called the Hyperglycemia and Adverse Pregnancy Outcomes Study (HAPO). Gestational diabetes is a major, worldwide problem and affects 2 to 3 percent of women who get pregnant. Nearly half of all women with gestational diabetes will develop Type 2 diabetes within 15 years. Newborns of mothers with gestational diabetes are sometimes affected with severe hypoglycemia within the first day of life because their pancreas has been producing large amounts of insulin to combat the high blood sugar that crosses the placenta. These babies also become macrosomic and often reach a birth weight of 14 pounds. As a result, it is hard to deliver these large infants without risk to the mother. There is usually a very high rate of cesarean section among women with gestational diabetes because of the risk of injury to both the mother and infant during a vaginal delivery.

Until the initiation of the HAPO, gestational diabetes has never been studied systematically with a blinded prospective research design. This project will cost $10 million over the next 5 years and NICHD is hoping that other Institutes will contribute to its funding. This study is being conducted around the world at 16 centers, 4 of which are in the United States. Researchers hope to enroll 25,000 pregnant women over the next several years to follow them for pregnancy outcomes.

Other NICHD initiatives include clinical obesity in childhood and basic research. For example, one researcher is studying transcription factors that determine tissue specificity in the expression of the insulin gene. Another area of research within the Institute is on polycystic ovarian syndrome. Women who develop this syndrome become obese and hirsute and have hyperandrogenism and infertility. They are also extremely insulin resistant to the point of becoming hyperglycemic. Yet for some reason, these women do not get the macrovascular complications that are typical of other Type 2 diabetics.

NICHD is also very interested in the epidemic of Type 2 diabetes that is occurring among obese Mexican Americans, Hispanics, and young, African American adolescents, especially females. Within the Institute's intramural program, a researcher has been successful at making a model of Type 2 diabetes by eliminating the insulin receptor and also the gene that makes insulin receptor substrate, which controls signaling traffic through the IGF-1 pathway and the insulin receptor pathway.

Dr. Grave ended his presentation with the message that NICHD wants the CSR to assign more diabetes grants to the NICHD. The NICHD wishes to expand its diabetes program and is working with the JDF to cofund grant applications on Type 1 diabetes. The Institute is ready to do more research in the area of diabetes, if additional funding is received.

Recommendations of Juvenile Diabetes Foundation Task Force

Robert Goldstein, M.D., Ph.D., who is Vice President, Juvenile Diabetes Foundation International (JDF), presented the recommendations of the JDF Task Force. JDF was founded in 1970 by the parents of children with diabetes with a very targeted mission: to find a cure for diabetes and its complications through the support of research. The Foundation continues to maintain this goal and has done very well, particularly in more recent years. JDF's 1998 fiscal year (ending in June 1998) research portfolio was about $45 million and is expected to be about $65 million for fiscal year 1999.

Two years ago, JDF started a Task Force that was charged with the mission of accomplishing the goal of curing diabetes. The Task Force includes scientists, as well as business professionals, as JDF wants to use a business approach in achieving its goals. Moreover, JDF does not want to simply duplicate NIH's efforts. The Task Force is focusing on three areas: primary and secondary prevention; achieving euglycemia; and complications.

Dr. Goldstein provided examples of how JDF approached the issues. Although genetics was thought to be extraordinarily important and JDF funds research in this area, it was much too expensive for JDF to tackle alone. Similar considerations apply to investigating possible viral triggers of autoimmunity. Likewise, JDF feels that it cannot make a big impact in the area of insulin pumps because they are basically a commercial enterprise.

JDF would like to focus its resources on taking key, basic science observations from the "bench to the bedside." Examples of areas of emphasis include islet transplantation, gene therapy, and studies dealing with the complications of diabetes. The Task Force created a model for research that includes evaluation mechanisms. Regular research grants are funded at $100,000 a year for 2 years. In addition, JDF funds postdoctoral fellowships, career development awards, and innovative grants that are similar to a mini-version of a R21. A special grant category was created for researchers who would like to apply for more than $100,000 a year for more than 2 years. JDF receives many grant applications from both academia and industry. Most recently, JDF funded a team of 32 researchers at Harvard to study islet transplantation.

JDF reviews all grant applications with a NIH-like process of scientific review with critiques and a second level of review by a panel of lay JDF volunteers. Dr. Goldstein invited the audience to attend a JDF grant review session.

JDF also has many partnerships with other organizations including NIDDK, NIAID, NICHD, NHLBI, NASA, and the Knut and Alice Wallenberg Foundation in Sweden. Most of the partnerships are for co-funding projects and last year, JDF spent about $15 million co-funding partnerships worldwide.

Dr. Goldstein next discussed JDF's results-oriented evaluation process. Most organizations, including NIH, conduct what Dr. Goldstein calls a passive-evaluation-of-research process. A passive evaluation is one in which the investigator provides a progress report at the end of the year and somebody reads it.

JDF believes it is giving out research money that fits a problem and so it needs a different way to evaluate research. To communicate this active results-oriented research process to investigators, the JDF Task Force relied heavily on a process of mapping. JDF has about 40 pages of maps that start with Type 1 diabetes from its beginning to complications--something that looks like a serious textbook of pathogenesis that takes a person from the beginning to the end pathways. JDF does not distribute these maps because their half-life is too short and they would need to be constantly updated.

Using slides, Dr. Goldstein showed an example of a map and how it is used to accomplish islet cell transplantation. Researchers are required to answer the questions, "What am I trying to accomplish in this project," "What are my year one goals," "What do I expect to accomplish in the first 6 months and in 12 months." In the case of large special grants, such as the Harvard islet transplantation initiative, a small group of JDF volunteers accompanied by an external scientist (who is unrelated to the grant), conduct monthly site visits to review different parts of the project. Moreover, JDF conducts a second level of review of its entire yearly portfolio. Using these evaluation methods, JDF can begin to have a discussion about managing the future, just as the business community does.

National Institute of Nursing Research

Nell Armstrong, Ph.D., R.N., who is a Program Director in the office of Extramural Programs, National Institute of Nursing Research (NINR), presented an overview of the impact of nursing research and reasons for keeping funding in a variety of Institutes. NINR's mission is to support both clinical and basic research. The NINR is a small organization that has always had a strong interest in diabetes research. The goal to find a cure for diabetes is of vital importance; however, if the past is prelude to the present and future, people will be walking around with diabetes for the next 50 to 100 years. NINR supports the basic science and clinical science research necessary to cure diabetes. In the meantime, people have to be helped in living with the disease. The Institute, therefore supports research to understand and ease the symptoms of acute and chronic illness and prevent or delay the onset of diabetes complications or disability. Some of the topic areas supported by NINR are medication, exercise, burden of care, quality of life, and social support. The Institute also supports interdisciplinary studies.

Dr. Armstrong provided an example of a current study in which the research team has immersed themselves in a particular culture of an American Indian tribe in South Dakota. Out of this study will come a model for implementing interventions in other unique cultures. NINR focuses on young to elderly and have known for many years that social support makes a difference in adherence in many chronic diseases, particularly diabetes. One investigator is looking at renal transplant in Type 1 diabetics and other types of subjects and the quality of life before and after transplantation.

Another investigator is looking at the implementation of combined intensive therapy and coping skills training in young diabetics. Both groups of subjects, who received intensive therapy, have shown improvement in their hemoglobin A1, but the group that also received the coping skills training had better improvement over time. The researcher now plans to follow the original cohort over the next four years to determine if this intervention is sustained. If this is the case, the study results can impact the clinical care given to children and teenagers with diabetes.

In terms of future research, NINR wants to study larger samples and a more diverse population to see which strategies really make a difference over time in self-management. For this reason, the Institute has developed a FY2000 initiative to lay the groundwork for clinical trials in intervention strategies. NINR also wants to study intervention strategies in all cultures.

Research Funding in Type I Diabetes: American Diabetes Association

Richard Kahn, Ph.D., who is Chief Scientific and Medical Officer, American Diabetes Association (ADA), presented an overview of ADA's programs. In the area of research directly related to only Type 1 diabetes, ADA is uniquely funding approximately $3 million for projects. This represents about 18 percent of the 217 projects funded by ADA. Additional funding is provided for the study of the complications of diabetes, which apply to both Type 1 and Type 2 diabetics. Thus, ADA funds a little over $12 million in diabetes research, which is called Type 1 research and represents 77 percent of the 217 funded programs. These funds also include modest support ($200,000/year) for the Type 1 Diabetes Prevention Trial.

ADA attempts to be unique in its award of funds rather than duplicating, adding on, or supporting existing awards that are being given by NIH. However, this is very difficult to actually do. ADA has created a mentor-based postdoctoral fellowship program in which they award a postdoctoral fellowship not to the student but to the mentor. The mentor then chooses a fellow to train for 1, 2, or 3 years. ADA believes if good scientists with long track records of success are selected as mentors, they will subsequently turn out good investigators.

ADA also will be significantly increasing the number of awards given to physicians to encourage them to become clinicians. The organization will be giving some unique support to physicians entering a Ph.D. program--those physicians who would like to take a full year off of medical school to do diabetes research as a way to stimulate physician-scientists.

Health Care Financing Administration's Initiatives in Type 1 Diabetes

John Lanigan, who is a Health Insurance Specialist, Health Care Financing Administration (HCFA), presented an overview of HCFA's initiatives in Type 1 diabetes. HCFA has one of the largest budgets in the United States, second only to that of the military. The Administration has been reorganized 2 or 3 times in the last 3 years and staff roles are changing. Mr. Lanigan normally serves as a liaison with the American Medical Association and the medical speciality groups and as the administrative officer for the Secretary Practicing Physicians Advisory Council.

In preparation for today's meeting, Mr. Lanigan contacted HCFA's press office to find out what new and exciting diabetes initiatives were being written about or worked on. He prepared a packet that contains a press release, dated June 22, 1998, and titled, "Diabetes Self-Management Benefits: More than 16 Million Americans Have Diabetes and Nearly 750,000 New Cases Are Reported Every Year." Minorities make up a disproportionate share of those suffering from diabetes, especially African Americans, Native Americans, and Latinos.

As of July 1, 1998, more Medicare benefits are available to diabetics. These newly expanded benefits will help provide people with the skills and resources that most diabetics need to control their diabetes. Another press release in the packet announces that all medicare beneficiaries with diabetes, whether or not they use insulin, will have coverage for blood glucose monitors and testing strips so they can monitor their own blood glucose levels. In the past, medicare covered blood glucose monitors and testing strips only for insulin dependent diabetics.

HCFA is also in the process of developing expanded coverage for outpatient diabetes self-management training services. This new program will benefit 2.25 million beneficiaries and has a 5-year cost projection of hundreds of millions of dollars. This program is a proposed rule that is being prepared right now and will be published sometime in the next month.

Mr. Lanigan then read the following from, "HCFA Diabetes Initiatives":

"HCFA has selected diabetes as one of the nation's top priorities. The goal of HCFA's diabetes initiative is to improve outcomes of care for the over 3.5 million patients with diabetes covered by medicare and medicaid programs. It will occur through several mechanisms."

• The development of a Diabetes Quality Improvement Project (DQIP) Measure. A national coalition initiated and funded by HCFA to develop performance measures for the care of diabetes. Six measures have been adopted by the National Council of Quality Assurance for HEDIS reporting for 2000. Several other organizations have gotten behind this effort. The measures addressed glycohemoglobin test frequency, control lipid testing, lipids control nephropathy monitoring, and dilated eye examinations.
  
• Additional DQIP Measures. Patient education, health status, patient satisfaction and access to be developed as part of the continuation DQIP. The second step was under managed care programs that we hear so much about in the country.
• Managed Care (MC) Data Collection and Reporting. Managed care plans will be required to collect, and HCFA will report the Diabetes Quality Improvement Measures in the year 2000. Beginning in 1999, as part of the new quality improvement standards by medicare and medicaid managed care, all plans will be required to work on quality improvement projects in diabetes. For any new diabetes project, the DQIP measures will be baseline for reporting. HCFA expects plans to demonstrate improvement in care for patients with diabetes during the 3-year evaluation period. Peer Review Organizations (PRO) will be available to assist plans with quality improvement efforts.
• Fee-For-Service (FFS) Data Collection and Reporting. In the fee-for-service setting, a national monitoring system based on the DQIP measures derived from administrative data is being developed. Statewide data for all patients with diabetes will be provided to each peer review organization. These data will provide informational performance of four of the DQIP measures by physicians who bill for the care of medicare patients with diabetes. PROs will have data that will allow them to do small area analyses, link data to groups or individual physicians. Additionally, all PROs will be required to develop projects for diabetes quality improvement as part of the next contract cycle which begins in 1999. PRO evaluations will be based on the statewide FFS monitoring data and individual projects in both FFS and MC, and the PRO's ability to bring about improved care for medicare beneficiaries in their States. PROs will collaborate with physicians in their state to develop and implement quality improvement projects on a voluntary basis.
• Development of Tools and Plans for Providers. HCFA contracted with one of the peer review organizations to develop standardized paper and software tools for medical records abstraction of the DQIP measures. HCFA has contracted with a second PRO organization to test these tools and specifications for the DQIP measures. Managed care plans and physicians will be able to use these tools and results of these studies to optimize their collection of data for DQIP and HEDIS.
• Identification and Dissemination of Best Practices. HCFA will be awarding a contract to evaluate the literature on best practices in improving diabetes care, to evaluate unpublished nonproprietary programs and projects, and to evaluate PRO diabetes care improvement projects. The contractor will develop a compendium of successful projects, will analyze commonalities of successful projects, and will organize a national conference on Best Practices in Diabetes Care for PROs, plans, groups, and individual physicians.
• Comparisons of Medical Care in Cross Settings. Comparison will be possible in the year 2000 due to availability of the DQIP measures. The fee-for-service monitoring system can be used to compare the results of the DQIP/HEDIS measures to those reported by all managed care plans. HCFA requires an extensive audit of all of the HEDIS measures collected by the plans prior to reporting, so that the DQIP measures collected by the plans will be audited and quality of the measures in both the FFS and MC setting will be determined prior to any public use of the measures.
• Identification and Dissemination of BUS Practices. HCFA will be awarding a contract to evaluate the literature on BUS practices in improving diabetes care, to evaluate unpublished nonproprietary programs and projects, and to evaluate care improvement projects.
• Federal Efforts Linked to DQIP. Diabetes will be a topic of focus for intergovernmental effort at quality improvement. All Federal agencies will work together to identify opportunities for improvement using the DQIP measures. The agencies will then share strategies for intervention to improve care and will work together to achieve defined improvement goals.

Mr. Lanigan also reported that on December 30, 1998, HCFA released some materials on the Year 2000 compliance to assist health care providers and suppliers in getting ready for the computer changes that are necessary to receive payments.

One of the audience discussion points following Mr. Lanigan's presentation related to the fact that a physician must certify that a patient needs diabetes education under a comprehensive plan of care, which seems overly burdensome. The concept of defining precisely who can give education, what it is, where it can be given, and how one evaluates the results is very difficult. For example, there are about 150,000 pharmacists in the country, many of whom claim they are educators and, therefore, should be able to educate people with diabetes and bill for it. Such an effort may cost the United States a half million dollars. HCFA is on pretty solid ground when it says it's the physician who can bill for education because ordinarily payments go to physicians, with some exceptions. It is quite an eye-opener to see how many people petition HCFA to get reimbursement under medicare for a huge variety of things and this is why the medicare trust fund is in jeopardy.

Initiatives by Health Care Centers to Improve Diabetes Care to the Underserved High-Risk Persons: Health Resources and Services Administration

David Stevens, M.D., who is Chief, Clinical Branch, Division of Community and Migrant Health, Bureau of Primary Health Care, provided an overview of the Bureau's programs. There are about 8 or 9 million underserved people in the United States and about two-thirds of these are below the poverty level and 15 percent are about the 200 percent poverty level. About one-third of this population has no health insurance at all, including Medicaid. About 30 percent of the underserved population are African American, 35 percent are white, and about 7 percent are Asian. These figures are actually out of date as they are climbing all of the time.

The Bureau of Primary Health Care has over 700 health centers. The Bureau does not actually run the centers but provides about one-third of their funds to cover uninsured care. The centers are community based and have community boards. The Bureau also has a National Service Core Center that serves about 10.4 million low income, minority people.

The Bureau has started, related to the President's Racial Initiative, a Health Disparities Initiative that includes diabetes. In diabetes, the aims are to increase the quality of diabetes care of the uninsured population and delay complications of the disease. To implement this initiative, the Health Resources and Services Administration (HRSA) has divided the country into five geographical clusters. In each state are primary care associations that are the membership organizations of all the health centers. In each cluster, HRSA has asked one of the States to take the lead, and HRSA is supporting a full time coordinator for approving diabetes care in each of the clusters.

Dr. Stevens then spoke about the model that is being used for providing care. In this model are the health centers with their four main areas. The first area is self-management support. The second area is delivery redesign. For example, many centers have found that group patient visits are extremely helpful, which is a redesign. Another area is decision support for clinicians so that they are able to follow the outcomes they are looking to achieve. HRSA wants informed, active patients and a proactive clinical team.

In addition to CDC, The Institute of Health Care Improvement is partnering with HRSA and has developed something called a "Breakthrough Series." The Institute chooses a well-known, clinically important subject for which knowledge is not being applied. Experts are called together and they determine the basic things that need to be done, outcome measures, and some of the models that can be applied and used. A set of evidence-based concept or models are developed and used for coaching. Participants get together for four learning sessions over a 6 to 8 month period and produce monthly reports. In the area of diabetes, the aims or goals are in the areas of patient self-management, control of blood glucose, prevention of cardiovascular complications, and prevention of microvascular complications. Each center is choosing areas they want to work in. This program will include a National Congress, open to everyone, which will be held in October 1999 in St. Louis.

In the past, the Breakthrough Series involved 33 to 40 organizations. The series that began in September 1998 involves 33 organizations. Each of the HRSA clusters nominated a lead health center and 100 centers will be meeting shortly in Washington, D.C. for a 2-day learning session. Health centers will be choosing an area they want to work on, starting monthly reports, and interacting with the faculty and HRSA coaches, which include HRSA coordinators, regional office staff and diabetes control program staff. HRSA has additional resources from its partner, CDC, for all 15 of the States that are participating in the program. This is HRSA's approach for Type 1, Type 2, and gestational diabetes.

Dr. Stevens mentioned that HRSA has sponsored projects using a similar model. For example, using a similar approach, data from 10 States shows an increase in child immunization rates.

Defining the Underlying Mechanism of Early Vascular Defects: Department of Veterans Administration

T.G. Patel, M.D., who is Program Chief, Renal Diseases, Veterans Health Affairs, gave a presentation on the three research centers funded by the Veterans Administration (VA) and JDF. These centers are located in Iowa City, Nashville, and San Diego, and Dr. Patel spoke mainly about the work being conducted in Iowa City. All three centers focus on the effects of diabetes on the vascular system and study the cellular and molecular processes by which intensive therapy reduces insulin resistance.

The center in San Diego focuses on the mechanism of insulin action to gain a better understanding of the causes of insulin resistance and the complications of the vascular system and diabetic nephropathy. The center's most relevant accomplishment during its first year has been the establishment and operational success of patient recruitment. It will take about 2 years for contributions to emerge from this study, but the results are expected to benefit both Type 1 and Type 2 diabetics as well as people with vascular disease, obesity, and hypertension.

Dr. Patel described several projects that are being carried out in Iowa City. The first project concerns metabolic interaction of insulin and leptin and the regulation of synthetic sympathetic nerve activity and vascular reactivity. This project has demonstrated that insulin administration to both normal and streptozotocin diabetic rats results in a marked and rapid increase in plasma leptin. Intravenous and intracranial ventricular leptin increases sympathetic activity to several peripheral nerves. In addition, administration of leptin to fasting rats decreases basal insulin, glucose levels, and IGF-1. Study investigators have published eight articles about this project, and the study results should have an impact on the understanding of several common, but difficult to explain, clinical phenomena in Type 1 and Type 2 diabetes.

The second project dealt with microvascular changes in humans with diabetes. The third project was in the area of hypoglycemia insulin resistance and endothelial function in human diabetes. There are four protocols for this project and studies have been initiated for three of the protocols. Vascular physiology studies are being conducted in diabetic subjects; however, preliminary data are not yet available.

A fourth project is being carried out to study the mechanism of diabetic endothelium and platelet dysfunction. Study investigators have published eight articles describing results that may lead to targeted drug therapy for diabetic patients. The fifth project relates to circulating factors in the etiology of diabetic vascular disease. It has been shown that the serum of diabetic rats contains a protein that causes endothelial cell dysfunction, which could have an impact on diabetic vascular disease. Five articles have been published on this study.

Project six was on the role of IGF-1 and altered endothelial function in diabetes mellitus. The researchers have nearly completed animal studies assessing the effect of IGF-1 on several blood vessels using vascular rings. If IGF-1 improves or normalizes the early vasodilatory effects of diabetes, then it is likely that people with diabetes will benefit because supplies of IGF-1 for human use are already available.

Dr. Patel also commented that the etiology of diabetes in immigrant populations has not received much discussion. He mentioned a study conducted in Hawaii on the Japanese American that found a higher incidence of coronary artery disease among this population than found in Japanese living in Japan. The results of the study showed that the food habits and lifestyle of the Japanese Americans contributed to the higher incidence of coronary artery disease.

Future Directions for the Diabetes Mellitus Interagency Coordinating Committee

Richard Eastman, M.D., Director, Division of Diabetes. Endocrinology, and Metabolic Diseases, NIDDK, closed the meeting by discussing strategies for future Diabetes Mellitus Interagency Coordinating Committee (DMICC) meetings and plans to put the minutes from the meeting onto a Federal Web page. With increasing attention on diabetes and a greatly expanding budget, Dr. Gordon perceives that the function of the DMICC becomes more important to avoid the duplication of efforts.

Approved by:___________________________________ Date:__________________
Richard Eastman, M.D., Chairman
Diabetes Mellitus Interagency Coordinating
Committee, NIDDK

Approved by:___________________________________ Date:__________________
Charles A. Wells, Ph.D., Executive Secretary
Diabetes Mellitus Interagency Coordinating
Committee, NIDDK