NUTRITION

Senator HARKIN. Thank you, Senator Reid.

Dr. Gorden, as you know, the American public is bombarded by endless diet claims that may or may not work and may or may not be healthy for those that follow them. It just seems to me that there is more now than I can ever remember. I have followed some of these, and I am concerned that a lot of people are investing money in doing things that may not be entirely healthy for them. This committee last year asked that NIH and give the giving a study of nutrition greater organizational status at NIH, perhaps even creating a division for the study of nutrition or to give some research focus to evaluating the many diets that we hear about. Your Institute is charged with studying obesity and has the lead on nutritional questions as well.

Can you give us a rundown on your evaluation of giving a study of nutrition greater organizational status that we asked about last year?

Dr. GORDEN. There is sort of two parts. One is the issue related to obesity, which we feel is a terribly important issue. The easiest thing in the world to do is to lose weight, and the hardest thing is to sustain that weight loss. And this is a major concern for us. We have a task force at present at work attempting to make recommendations in this arena to the point where our knowledge base ends, and where we would very much like to inaugurate clinical studies to address this very important issue of how to sustain weight loss. This is a critical issue as obesity is a major risk factor for a whole variety of other problems, including diabetes and cardiovascular disease and perhaps other neoplastic diseases. That is one aspect.

We believe that we have an organizational structure that is capable of dealing with this issue. Nutrition research is vested in several institutes at the NIH. You have discussed some aspects of nutrition research already with Dr. Lenfant and Dr. Broder, and we are very pleased to cooperate with those institutes in furthering nutrition research and being sure that the resources are available for the kind of research that we need to be doing. So, we believe we have an organizational structure.

We believe there are some terribly important issues. We have focused on the issue of centers, which we refer to as Clinical Nutrition Research Units. We support five at the present time, and feel that this is a very important mechanism by which we can address these particular problems of nutrition. We would prefer to utilize this more direct mechanism of trying to deal with the issues that you refer to rather than sort of organizational changes within the NIH per se.

Senator HARKIN. So, you feel that this is getting adequate attention.

Dr. GORDEN. I believe it is getting adequate organizational attention.

Senator HARKIN. But your Institute is sort of the lead on this. Right?

Dr. GORDEN. Yes; we are.

Dr. RAUB. Mr. Chairman.

Senator HARKIN. Yes, Dr. Raub.

Dr. RAUB. May I add that we have a particularly strong central effort. There is not only a nutrition coordinating committee, but it has a full-time staff based in the NIH Director's office. That staff works very closely with Dr. Gorden, with colleagues in the Heart, Cancer, Child Health, and Aging Institutes, and the Nursing Center, and others to ensure a good flow of information, but in some cases it promotes certain initiatives. For example, going back several years, the concept of the Clinical Nutrition Research Units actually was launched under the umbrella of the central coordinating group. In addition to the five funded by Dr. Gorden's Institute, three others are funded by the National Cancer Institute. We believe we have a strong handle on the trans-NIH aspects of nutrition.

DIABETES

Senator HARKIN. My time is running out, but I do want to ask you one other question about juvenile diabetes. I understand that type I is the result of the immune system destroying cells in the pancreas. We have been told in the past that of the two types of diabetes, this type is most likely to result in a cure.

Last year this committee provided an additional $2 million to pursue promising research to find better treatments and a cure for type I diabetes.

Can you just give me a brief update on this on how we are proceeding?

Dr. GORDEN. Yes; there have been several important specific discoveries in the past year. One is the recognition of markers that precede the onset of the clinical disease and actually refinement of the chemical nature of these markers. We now have the opportunity to actually detect this disease at least 3 and perhaps 5 years before its clinical onset. It used to be that we believed that a child was perfectly well today, and tomorrow that child had juvenile diabetes. That is almost certainly not the case. The process is going on for months and years, and we now have the ability to detect that process by a chemical marker.

That provides a very important opportunity now to try to develop prevention strategies, and we are at the present time looking at several proposals that might be used to interdict the process at this very early stage. Our ability to detect it and our ability to use drugs or other pharmacologic agents to actually prevent it-agents that we can be certain are safe is something that we have under discussion. It is a difficult issue because we do not have what we would like to think of as a "magic bullet," so to speak, that is perfectly safe and perfectly effective. If we had that, it wouldn't be a matter of discussion at all. But this research certainly is an opportunity.

We have developed other ways of achieving immunologic privilege. Other studies have demonstrated that transplants of islet cells that produce insulin in particular areas of the body seem to be immunologically privileged. This raises further hope for transplantation types of therapies either from direct islet cells themselves or from whole organ transplants.

So, I think that we clearly have a focus on this disease that we have never had before, and we have now, I think, a real opportunity for prevention and, we hope, for understanding the cause and the cure.

QUESTIONS SUBMITTED BY THE SUBCOMMITTEE

Senator HARKIN. Thank you very much. There will be some additional questions which will be submitted for your response in the record.

[The following questions were not asked at the hearing, but were submitted to the Institute for response subsequent to the hearing:]

QUESTIONS SUBMITTED BY THE SUBCOMMITTEE

JUVENILE DIABETES

Question. I understand that Type 1, or juvenile diabetes, is the result of the immune system destroying cells in the pancreas. The Committee has been told in the past that of the two types of diabetes this type is most likely to result in a cure. Last year the Committee provided an additional $2 million to pursue promising research to find better treatments and a cure for Type 1 diabetes. Could you update the Committee on the progress in this area?

Answer. It is now well accepted that insulin dependent diabetes mellitus (IDDM or Type 1) is the result of the

inappropriate destruction of the insulin secreting beta cells of the pancreas by the immune system. Therefore, a major site of emphasis for research on this "auto-immune" disease is explaining why the immune system makes this mistake and how the mistake might be prevented or corrected.

In the last year or two we have seen several examples of how this enhanced exploration of immune functions has suggested potential clinical approaches to IDDM. When someone becomes ill with IDDM this signifies the culmination of a destructive immune process which has gone on silently for years within that patient. By the time they become sick it is generally too late to prevent or reverse the damage. Therefore, it is important to find markers for the process at an earlier stage. Recently, researchers have discovered the identity of one such marker. This blood-bourne antibody directed at beta cells had been called the "64k antibody" because it attacks a poorly understood constituent of beta cells called the "64k antigen." We now know that this antigen is an enzyme in the beta cell called by its initials, GAD (glutamic acid decarboxylase). With this knowledge, we may be able to develop more sensitive tests for the impending development of IDDM in individuals. In addition, the specific role of GAD in possibly instigating or enhancing the auto-immune process needs now to be elucidated.

The ability to identify individuals at high risk for IDDM by various tests (including anti-GAD antibodies and other immunologic or metabolic measures) will give us the opportunity to try immunologic interventions designed to inhibit or arrest the process. The NIDDK, with collaboration from our sister institutes, NIAID and NICHD, sponsored a workshop on Clinical Trials of Immunosuppression for the Prevention of IDDM in April, 1990. Participants for the meeting were drawn from the diabetes and immunology research communities. A consensus was reached that some high-risk individuals could be identified now and that clinical studies to explore the ability of immunomodulation to alter the occurance of IDDM in these individuals was timely and warranted. This group also pointed out that there was still much to be learned about identifying the majority of those at high risk and the best interventions to be tried. The NIDDK, NIAID and NICHD have released two Program Annoucements to encourage the submission of investigator-initiated research proposals in this area.

For those already with IDDM, the replacement of destroyed beta cells with transplants of islets has been a long term goal of the diabetes research community and the NIDDK. A major barrier to success continues to be the need for generalized immunosuppressive drugs by the transplant recipient which are frought with major untoward side-effects. A recent immunologic finding by a NIDDK supported investigator has raised a fascinating new approach to preventing transplant rejection. In experimental animals, the placement of a small piece of the transplanted islet tissue in the thymus gland (a gland that is known to play an important role in regulating the immune system) obviates the rejection of transplanted islet tissue placed anywhere else in the animal without continuous powerful immunosuppressive drugs. If this finding is confirmed and extended to man, then the possibilities for islet transplantation as a cure for IDDM will be markedly enhanced.

KIDNEY CLINICAL TRIAL

Question. I understand the NIDDK has underway a clinical trial which is attempting to determine the effect of low protein diets on slowing, or forestalling kidney failure. This clinical trial still has two more years to go and will require a final year of analysis before the results are known. Are there any

preliminary results from the first two years of clinical trials on this diet study?

Answer. The clinical trial, Modification of Diet in Renal Disease (MDRD) Study, will determine the effects of low protein and phosphorus diets and control of blood pressure, on loss of kidney function. The study has completed recruiting 800 men and women with mild to moderate loss of kidney function in the fifteen medical centers located throughout the U.S. The response from private physicians to patient recruitment in this clinical trial has been outstanding. Over one-half of the MDRD participants were referred to the study by community physicians. Early results of the dietary intervention are encouraging in that protein intake decreased by 30 percent to 60 percent in the two low protein groups. In addition, control of high blood pressure has been very good. Follow-up of study participants will be completed by December 1992. The final results of the study will become available during the summer of 1993.

INTERSTITIAL CYSTITIS

Question. IC, or interstitial cystitis, is a very painful bladder disease that afflicts primarily women. Last year the Committee provided additional funding for research in this area and requested that a National Registry be established. What progress has the Institute made in following up on the suggestions made by the Committee?

Answer.

NIDDK has issued two Requests for Applications in the field of Interstitial Cystitis. The first calls for investigatorinitiated research proposals. The second calls for the development of an Interstitial Cystitis database. The database is a scientific approach to a registry, and was developed in concert with the Interstitial Cystitis Association. Both Requests for Applications are scheduled for funding during FY 1991.