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soliciting additional research trainees in the nutrition sciences through publication of annual Requests for Applications. Two such solicitations have been issued, and a third will be published in 1991, which will specifically encourage applications for career awards and fellowships. During FY 1990, three new institutional training grants were awarded, which will enable institutions to offer support to promising individuals for pre- and postdoctoral training. In addition, an institutional Physician Scientist Award to support newly trained clinicians was made. Another excellent way in which physicians can learn about molecular biology as it applies to nutrition is through the Clinical Nutrition Research Unit (CNRU) program. The NIH supports eight CNRUs--five funded by the National Institute of Diabetes and Digestive and Kidney Diseases and three funded by the National Cancer Institute. These CNRUs provide support for long-term multidisciplinary programs of research in critical health problem areas, as well as provide an excellent environment for training new investigators.


Question. Can you describe the intramural aspects of the NIH program as related to problems of nutrition. Specifically, are there activities at your institute that involve the clinical center and studies of human nutrition?

Answer. The major focus of NIH-supported nutrition research is extramural. The NIH intramural program is carried out on the Bethesda, Maryland, campus primarily at the Warren Grant Magnuson Clinical Center. Exceptions are the programs of the National Cancer Institute, the National Institute on Aging, and the National Institute of Environmental Health Sciences, which are conducted in laboratories off campus. The Nutrition Department of the Clinical Center implements nutrition components of protocols generated by the various Institutes through collaborations between dietitians and clinical investigators. Implementation of protocol requirements includes provision of controlled nutrient intakes for various disease states and for drug-related studies. Test diets are provided, either as an integral part of a protocol or as a diagnostic procedure. Other research-related activities include obtaining anthropometric measurements to assess body composition, diet counseling for protocol-specific diets with subsequent determination of compliance, development and implementation of nutrition-education classes to support protocol requirements, development of questionnaires to assess dietary intake patterns, and provision of dietary regimens for studies requiring assessment of appetite in relation to specific drug therapies.

The intramural research activities supported by the NIDDK primarily include basic and clinical research on metabolism, endocrinology, hematology, digestive diseases, diabetes, and genetics. Studies in the Pima Indian population at the NIDDK Phoenix Epidemiology and Clinical Research Branch, supported at an annual rate of approximately $5 million, are aimed at unravelling the reasons behind the extraordinarily high prevalence of noninsulin-dependent diabetes mellitus (NIDDM) and obesity in this population. Studies among the Pima have revealed that the resting metabolic rate (RMR) is a familial trait, which may be linked to a single genetic defect, and that a low RMR may be predictive of body

weight gain. Several years ago, NIDDK intramural researchers constructed a human respiratory chamber to permit the measurement of daily caloric expenditure and its components, in humans. As with the RMR, a significant variability in the 24-hour metabolic rate also appears to be a familial trait. Continuing research on the genetic and metabolic factors related to NIDDM in the Pima may elucidate the disease process in other groups.


Question. I understand that the excellent laboratories in Phoenix, Arizona study problems of diabetes, and to a limited extent, problems of human obesity. Are there no similar activities on the Bethesda campus?

Answer. NIDDK Intramural researchers on the Bethesda campus of the NIH are examining how fat is metabolized by studying the genes, enzymes, and hormones involved in fat cell metabolism. They are studying the possible effects of hormone action on human fat distribution, which is reported to have major health effects, and have also determined a possible role for one enzyme in the wasting that occurs in tumor patients. In relation to obesity and diabetes, investigators are also focusing on glucose transporters-specialized proteins that convey sugar from outside the cell into its interior where it can be used to produce energy. In both diabetes and obesity, the number of such proteins stored by cells is markedly reduced.

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Question. Since there is only one NIH-funded Obesity Research Center, would it not be wise to consider creating more obesity centers either intra- or extramurally?

Answer. The existing Obesity Research Center funded by the National Institute of Diabetes and Digestive and Kidney Diseases is making valuable contributions to our scientific understanding of obesity. Additional centers would certainly strengthen our obesity program.


Question. Are the Clinical Nutrition Research Units now funded by NIH good vehicles for bringing physicians and medical students into high quality research in human nutrition?

Answer. The Clinical Nutrition Research Units (CNRUs) contribute enormously to the field of nutrition research, both in terms of promoting high quality research in clinical nutrition and in exposing young investigators to the importance of nutrition in health and disease. CNRUS are a bridging mechanism for basic and clinical research in the nutrition sciences. Advances in nutrition derive from many diverse scientific disciplines and clinical specialities. In order to transfer these scientific advances to physicians, other health professionals, and the public, a close interaction among the areas of research, health services, and education is essential. The CNRUS provide an optimal environment for this interactive exchange.

A large number of deficiency states, consequences of inborn errors of metabolism, and food-related diseases are better understood now, and may be treatable, or preventable. However, many unanswered questions remain on the relationship of diet to health and disease, particularly in cancer, other chronic diseases and aging. Locating CNRUS in medical school environments where they are associated with NIH-supported training programs in nutrition equips researchers to address these health issues effectively. This structure not only attracts promising scientists to the field but helps to establish nutrition as a discrete discipline in these institutions. The CNRUs build upon an established base of already funded research excellence in clinical nutrition research and make available core laboratories in areas such as metabolism and food intake to students, trainees, and investigators. CNRUs also provide start-up funding for pilot studies of new investigators, as well as broad educational programs for medical students, house staff, practicing physicians, and allied health personnel.

For example, at one NIDDK-supported CNRU, a major theme is the nuritional management of very low birth weight infants. Until recently, very little information has been available regarding vitamin requirements during parenteral feeding of children. Now, micromethods for analysis of specific levels of vitamins and nutrients have been developed and validated at this center. This advance has led directly to improved patient care and insights into other health implications for this at-risk population. A large study on diet and atherosclerosis is being carried out at another CNRU that examines the effect of different levels of fat content in the diet on cholesterol concentrations. These studies will help to show what level of decrease in fat content in the diet is important in lowering cholesterol and the risk of heart attack and stroke. As these few examples illustrate, CNRUS create a focus for nutrition research that would not exist otherwise.


Question. Is there a formal research plan for dealing with the most pressing issues in clinical nutrition such as: what is the molecular defect underlying the genetic influence on human obesity; what are the physiologic effects of the widely recommended reduction in fat intake; are there any biochemical or other markers to determine the fat intake or intake of other nutrients that can be used in evaluating the efficacy of diet; dietary change; how important are infantile or early childhood nutritional practices on guiding nutritional behavior in adult life; are there suitable animal models or other methods under investigation by NIH to analyze the scientific basis for any potential relationship of early nutrition and later adult nutritional behavior and health?

Answer. The annual report of the NIH Nutrition Coordinating Committee summarizes the ongoing research activities and plans of all of the various NIH components that fund studies in this field. The questions you list are among those that the NIH institutes are seeking to answer through their collective efforts in nutrition science research.



Question. The National Diabetes Advisory Board has recommended the establishment of a new program to promote the integration of new research methodologies of basic science into diabetes research. Can you tell us what is the status of this program?

Answer. In 1987, the National Diabetes Advisory Board (NDAB) formulated a National Long Range Plan to Combat Diabetes. One of their recommendations was to establish Diabetes Interdisciplinary Research Programs (DIRPs) to be supported by NIDDK. These programs would promote the integration of new research methodologies into diabetes research. Young as well as established diabetes oriented scientists would be given the opportunity to immerse themselves in new technologies at the cutting edge of modern science.

In response to the NDAB plan, the NIDDK convened several colloquia on various aspects of diabetes research. The discussions focused on interdisciplinary dialogue between investigators in the new and rapidly evolving research areas of biomedical research (i.e. molecular biology and immunology) and in research areas related to diabetes. Since those meetings the NIDDK has initiated support for a few investigator-initiated collaborative interdisciplinary research program projects that grew from the discussions begun at those colloquia.

Most recently, the NIDDK has issued a request for applications (RFA) that asks for proposals for DIRPs to be submitted by mid-May, 1991. This RFA is unique because it has been prepared in partnership with the Juvenile Diabetes Foundation International (JDFI). The JDFI has committed themselves to supporting DIRP proposals that the NIDDK determines are of high scientific and technical merit but are unable to fund.

We are excited about this new joint endeavor for at least two reasons. First, successful completion of this RFA will demonstrate that it is possible to maintain all NIH standards of proper grant application handling and appraisal while joining with non-NIH agencies to improve efficiency and coordination. Second, and most important, we will have accomplished a significant step in improving our efforts to discover the new knowledge that is necessary if we are to make an impact on the devastation caused by this disease.


Question. Now that we know insulin-dependent diabetes is an autoimmune disease, how is this knowledge being used in your institute's efforts to combat diabetes?

Answer. The knowledge that insulin-dependent diabetes (IDDM or Type 1 diabetes) is an autoimmune disease has directed current research toward an emphasis on elucidating how and why the immune system inappropriately attacks the insulin secreting cells of the pancreas. We know that this immune destruction takes place over

years before diabetes becomes clinically apparent. Therefore, the NIDDK is supporting investigations of how to detect this silent process at an early stage. When individuals can be identified who are apparently destined to become IDDM victims then interventions designed to inhibit or arrest the process can be tested to prevent disease occurance. The NIDDK with the collaboration of the NIAID and NICHD held a workshop on Clinical Trials of Immunosuppression for the Prevention of IDDM in April, 1990. Diabetes and immunology researchers jointly participated in the discussions. They reached a consensus that some high risk individuals could be identified and studies to explore the potential of immunomodulatory interventions to delay or inhibit the development of IDDM in these individuals was now timely and warranted. They also stated that more research was needed to identify the majority of those at high risk and to develop new interventions that target the specific process of autoimmune destruction of insulin-secreting cells that causes IDDM. have recently published two Program Annoucements to stimulate research applications in this research area.



Question. Can you tell us something about how genes are involved in diabetes and how understanding the genetics of diabetes will help in the treatment and prevention of this disease?

Answer. Diabetes is a genetic disease. The term "diabetes" encompasses a number of different diseases and hence a number of different genes may be involved. Specifically, diabetes can be divided into two clinically distinct forms: insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM). Researchers have identified a susceptibility gene in patients with IDDM and have shown a prevalence for NIDDM among ethnic/racial groups and within families. These results support the genetic classification of this disease.

The involvement of genes in this disease can be envisioned at all steps in the pathways leading from the production of insulin in the pancreatic beta cell to the responsiveness of the insulin target tissues (for example, muscle, fat, and liver), and also the sensitivity of the immune system in initiating an autoimmune attack on the beta cells. Genes that dictate any of the biochemical components that normally function to maintain blood sugar levels are candidates for the causative genes in diabetes. An alteration or mutation in any of these genes has the potential to elicit an aberrant response resulting in the body's inability to handle glucose.

The results obtained to date indicate the diversity of genes that may play a role in causing this disease. Within the last two years, a dramatic discovery has uncovered a diabetes susceptibility gene in IDDM (which affects 500,000 children and young people in the U.S.). This gene, which relates to the body's immune system, appears to be necessary but not completely sufficient to cause the disease. In animal models there is a suggestion that additional genes are involved, but as yet, no other gene has been identified in humans. Investigators interested in NIDDM have recently identified the location of a gene believed to be responsible for a rare form of diabetes which affects young people and has clinical

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