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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?

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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. We 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

manifestations similar to NIDDM. The actual function of this gene has yet to be determined, however, and awaits further


Additionally, researchers have identified several mutations in the gene for insulin receptors in patients with rare but severe forms of NIDDM. Finally, a variety of other genes may be related to the long-term complications suffered by those with all forms of diabetes. In these areas, we do not yet know which genes are involved. Thus, the diversity of genes that may be involved in diabetes is presently an extremely active area of research.

Understanding the genetics of diabetes will provide at least two valuable results. Since each individual has his/her genes from birth, those genes that put them at risk for diabetes could be identified early in life. This would allow those individuals to undertake potentially preventive interventions which are now being developed before the disease occurs. Second, identification of relevant genes will help us understand what goes wrong to cause diabetes and, thereby, suggest promising new ways to treat and prevent this disease.



Question. Dr. Gordon, last year this Committee requested that the Institute consider establishing research centers to study Kidney and Urological Diseases in children. What action has the Institute undertaken regarding this initiative? In your professional judgment, is there a need for additional centers?

Answer. I am pleased to report that the NIDDK issued a Request for Applications for a Research Center of Excellence in Pediatric Nephrology and Urology in January 1991. The receipt date for the applications is April 2, 1991. We anticipate funding one center in 1991. The National Kidney and Urologic Diseases Advisory Board recommended that the number of research centers directed toward adult urologic and nephrologic diseases be increased from 6 to 18. I agree with this estimate. Many urologic and nephrologic diseases begin in the pediatric age group. Therefore, there is a definite need for research in the pediatric population, if we are to prevent or treat kidney and urologic diseases of young adults.



Senator HARKIN. Dr. Alexander, welcome back to the subcommittee. I look forward to hearing your plans for the Institute because the research programs are targeted on some of the most urgent public health issues in the United States today. I believe the work done by your Institute is critical to improving the health and well-being of our children in the future. And when we talk about prevention and early intervention, that is your backyard.

Doctor, we have your request for $520.6 million, an increase of about 8.7 percent from last year. Would you begin by highlighting the major programs included in your budget request?

Dr. ALEXANDER. Thank you, Mr. Chairman.

In 1989, more than 4 million babies were born in the United States, but of these almost 39,000 died before their first birthday. Although our infant mortality rate is at an all-time low, the pace of our progress in reducing it has slowed. Our scientists are trying to determine why the Nation's rate of low birthweight has remained constant and why low birthweight is twice as prevalent among black women as compared to white women.

An important advance was made this year in the treatment of children infected with the AIDS virus. NICHD-supported investigators found that monthly monthly administration of intravenous immunoglobulin, a solution that contains concentrated antibodies, significantly reduces the number of serious bacterial infections, reduces the number of hospitalizations required, and prolongs by as much as 1 year the time free from serious bacterial infections in children who are afflicted with symptoms of HIV infection.

In other research related to pediatric AIDS, the NICHD, in a joint effort with the National Institute of Allergy and Infectious Diseases, is beginning clinical trials in pregnant women to attempt to reduce transmission of the virus from mother to fetus.

Sudden Infant Death Syndrome continues to resist revealing its causes. Now, new technologies are allowing us to investigate factors that may hold the key to our being able to predict or prevent apnea or SIDS.

The Food and Drug Administration recently licensed the first vaccine effective in infants against Haemophilus influenzae type b. As Dr. Fauci indicated, this conjugate vaccine is based on the work of Dr. John Robbins in the NICHD intramural research program and was further developed with both NIAID and NICHD support. This vaccine, once it is widely used, should nearly eliminate H. flu meningitis as a cause of mental retardation and deafness.

Assuring that research advances are transferred from the laboratory bench to the health-care system is an Institute priority.

Evidence of this commitment is NICHD's recent establishment of a national program of child health research centers. We also plan to fund several new centers over the next year related to women's health issues. At least one center will focus on infertility research and as many as three will concentrate on contraceptive development. These centers will become part of the Institute's historically strong research centers program.


Millions of Americans are encumbered by physical disability resulting from birth defects, injuries, or diseases. Helping these individuals regain their physical or functional ability to the fullest extent possible is the objective of a new National Center for Medical Rehabilitation Research established within NICHD. The new center will conduct and coordinate research and research training related to rehabilitation of individuals with physical disabilities. our fiscal year 1992 budget request is


Mr. $520,584,000.

I will be pleased to answer any questions. [The statement follows:]

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