February 29, 2000
Statement of Dr. Allen M. Spiegel
Director, National Institute of Diabetes and Digestive and Kidney Diseases
Mr. Chairman and Members of the Committee:
I am pleased to testify on behalf of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This year is the NIDDK's 50th anniversary. I have been with the Institute for nearly 27 of those 50 years--for the past 3 months as Institute director. Throughout this time I have had the privilege of conducting and directing basic and clinical research, often in collaboration with superb investigators at many academic centers and at NIH. The unique juxtaposition of laboratories and patient facilities in the NIH Clinical Center has afforded me a valuable perspective on the connections between basic and clinical research.
As NIDDK director, one of my main goals will be to strengthen those connections in order to accelerate progress toward relieving the burden of the many chronic and costly diseases within our mission. The challenges posed by these diseases are enormous. Significant gaps in our knowledge concerning their causes leave us as yet unable to prevent or treat them as effectively as we would wish. Yet, we are poised as never before to make dramatic progress in closing these gaps. New, powerful tools are becoming available to propel our progress. The support provided to NIH and NIDDK has been greater than ever before.
Thus, it is with great scientific excitement and optimism that I have accepted the challenge, as director of NIDDK, of leading the effort to alleviate the burden of diabetes; endocrine and metabolic diseases; digestive and nutritional disorders; and kidney, urologic, and blood diseases.
Powerful Research Tools
Shortly, we will have in hand the sequence of the entire human genome. Merely knowing the sequence, however, does not allow one to utilize this powerful tool. This sequence or "book of life" is not written in English and lacks obvious punctuation marks.
An NIDDK intramural scientist has recently discovered gene "insulators," a type of punctuation mark that allows a gene to be expressed without interference from surrounding regions. This discovery is already finding wide application in the biotechnology industry. Within the "book of life" are genes that either cause or contribute to many of the diseases within our mission. Our task in making full use of the human genome sequence is to identify all the genes within it, discover their function, and understand how changes in these genes cause disease. New tools such as microarray technology allow simultaneous measurement of changes in expression of thousands of genes. Bioinformatics methods allow us to analyze vast amounts of sequence information. These tools will help us to apply new genetic knowledge to revolutionize diagnosis, prevention, and treatment of many diseases.
Bioinformatics methods have revealed that many human genes have counterparts in the genomes of yeast, roundworm, and fruitfly. The function of these genes can thus be studied at the cellular level in these experimentally simpler model organisms. Vertebrate models such as zebrafish and mouse, while more difficult to study than worms or flies, are closer in organ structure and genetic sequence to humans. Zebrafish mutants with disorders of red blood cell formation or of appetite regulation have been discovered. Mouse mutants expressing too much or too little of almost any gene in any organ can now be created. Such models not only help clarify the function of genes and their role in causing disease, but also provide systems for testing possible treatments and preventions in ways not feasible in humans. Powerful imaging methods are being developed that will allow detection of subtle changes at the cell and organ level, thereby helping to elucidate the causes of disease, monitor disease progression, and assess preventive or therapeutic measures not only in animal models but in humans. Bioengineering approaches to cell and organ replacement hold great promise as well.
Research Advances: PKD, Hepatitis C, and Diabetes
Polycystic kidney disease (PKD) is one of the most common inherited disorders and the fourth leading cause of end-stage kidney failure, according to the U.S. Renal Data System. A long hunt led to identification of the gene responsible for the most common form of PKD, and shortly thereafter, researchers found a second gene responsible for a rarer form. The molecular function of these two gene products is still incompletely understood, but the recent surprising discovery in the roundworm--that mutations in one of the corresponding genes leads to defects in the functions of sensory neurons--opens up new avenues to understand the basic defect in PKD. Studies of PKD genes in humans have established that cyst formation is an abnormal growth process, analogous to benign tumor formation. Indeed, just last month, NIDDK-supported investigators reported that treatment with an inhibitor of a cellular receptor for a growth factor in a mouse model of PKD prevents cyst formation and dramatically enhances survival. Of course, further studies are needed before human trials, but NIDDK is already supporting research to develop noninvasive imaging methods to monitor cyst growth. Such methods will be critical in evaluating the effectiveness of new treatments.
The CDC estimates that 4 million Americans are infected with the hepatitis C virus. Hepatitis C is the most common cause of chronic hepatitis and the most common reason for liver transplantation in the United States. Epidemiologic studies show that 70 to 80 percent of infected individuals fail to clear the virus and as many as 20 percent of these develop chronic liver disease. Intramural NIDDK studies first showed that interferon, an antiviral agent, is effective in treating hepatitis C, but it completely clears the virus in only a small minority of patients. Recently, NIDDK investigators reported a major advance in treatment; by combining interferon with another antiviral, ribavirin, they were able to clear the virus in up to 40 percent of patients. Developing even more effective treatments and a vaccine to prevent infection remain as major challenges.
According to data compiled by the congressionally established Diabetes Research Working Group, diabetes affects an estimated 16 million Americans. It is a chronic and costly disease both in human and financial terms. The complications of uncontrolled elevation in blood sugar make diabetes the leading cause of end-stage kidney failure, adult blindness, and non-traumatic amputations and a major risk factor for heart disease.
Type 1 diabetes affects primarily children and young adults, with more than 13,000 new cases per year in the United States. This form of the disease is characterized by autoimmune destruction of the insulin-secreting beta cells of the pancreatic islets.
Type 2 diabetes affects primarily adults and is increasing in the United States at an alarming rate: nearly 800,000 newly diagnosed cases per year. It is caused by both reduced insulin secretion and resistance to insulin action.
Genetic abnormalities contribute to both forms of diabetes, but unlike single gene disorders such as PKD, most cases of diabetes are thought to be due to subtle abnormalities in multiple genes. Even before completion of the human genome sequence and full deployment of new genetic tools, significant progress has been made in identifying genes that cause diabetes. Why is such information important?
In type 1 diabetes, knowledge of which genes predispose one to the disease should allow identification of those at risk and to whom preventive measures should be targeted. Advances in understanding the immune basis for type 1 diabetes have identified candidate interventions to "re-educate" the immune system to prevent beta cell destruction. One such intervention is being tested currently in an NIDDK-supported multi-center trial. For those with type 1 diabetes in whom beta cell destruction has progressed to the point where little or no function remains, preventive measures are too late.
The focus must be on maintaining excellent control of blood sugar, as the landmark Diabetes Control and Complications Trial showed clearly that intensive treatment with insulin can prevent or delay the onset of kidney, eye, and other complications. Trying to maintain tight control of blood sugar with insulin treatment, however, can be difficult and frustrating, particularly in children. (See figure.) For this reason, NIDDK is committed to supporting research both to improve existing insulin treatment and to find innovative, new treatments that will represent a true cure for this disease.
Recent improvements in glucose-sensing devices that can eliminate the need for multiple finger sticks represent a small step toward the goal of an artificial pancreas. Recent animal studies using novel methods to block the immune system have demonstrated the feasibility of pancreatic islet transplantation. These promising results are being carefully extended to studies of kidney and islet transplants in humans in a newly opened NIDDK branch in the NIH Clinical Center.
In type 2 diabetes, genetic studies have shown that rare forms of the disease with onset at younger than usual age can be caused by single gene mutations. At least five such genes, each involved in some aspect of regulation of insulin secretion, have already been identified. A striking example is the gene termed insulin promoter factor-1, in which different degrees of mutation result in different conditions. Mutation of both copies of this gene leads to failure of the entire pancreas to develop. A severe mutation in one copy of the gene is one cause of the rare forms of early onset type 2 diabetes. Recent studies have shown that more subtle mutations of the same gene contribute to the more common form of type 2 diabetes by impairing insulin secretion. Identification of disease genes is important in providing novel targets for drug development and in enabling individualized therapy that is optimally effective for each patient.
Another recent advance illustrates how information about a drug target can be used to identify a new diabetes gene. A new class of diabetes drugs that increase insulin sensitivity was shown to act on a cell receptor protein termed PPAR-gamma. This led investigators to search for mutations in the gene for PPAR-gamma in type 2 diabetes patients. Such mutations were found in rare patients with an early onset form of diabetes characterized by insulin resistance, high blood pressure, and abnormal blood lipids. Because all of these features are frequently seen in patients with type 2 diabetes, more subtle defects in the PPAR-gamma gene may be responsible for more common forms of type 2 diabetes. Thus, understanding the genetic basis of even rare forms of type 2 diabetes is important, not only for care of patients with those forms of the disease, but also for what it can tell us about the causes of more common forms.
Future Research Plans
While these advances are indicative of the important progress we have made, clearly extraordinary challenges remain for virtually all the diseases within the NIDDK mission. Indeed, the congressionally established Diabetes Research Working Group identified five extraordinary diabetes research opportunities: genetics, autoimmunity and the beta cell, cell signaling and regulation, obesity, and clinical research and trials. The NIDDK intends to seize each of these opportunities.
To take full advantage of the soon available human genome sequence, we will bolster a consortium formed to identify type 2 diabetes genes and try to form a similar group to identify type 1 diabetes genes. We will form a diabetes trial network to do pilot studies of innovative methods to prevent type 1 diabetes, as clues emerge from studies of the mechanism of beta cell destruction. We will stimulate research using the most advanced methods to image islet beta cells, so that effectiveness of diabetes preventions can be sensitively monitored and more rapidly tested. We will expand our support for studies of islet transplantation in humans by establishing a consortium and an islet transplant registry so that progress may be maximized.
We will form a "Virtual Center" of interdisciplinary investigators whose goal will be a complete understanding of the biology of the beta cell. This will include identification of every gene expressed at every developmental stage and their regulatory interactions, so that we would ultimately know how a stem cell differentiates to become a beta cell. It would include elucidation of all the signaling pathways regulating insulin secretion, so that we would know every step at which this process can malfunction and identify new targets for correction. We will form a consortium of investigators who will create new mouse models to understand the causes and test possible treatments for the complications of diabetes. We will launch a major new trial to study whether sustained weight loss can be achieved in obese individuals with type 2 diabetes, and if it can, to determine whether this is in fact beneficial to health. We also plan an obesity prevention initiative building on recently successful pilot programs.
Health disparities pose a particular challenge for NIDDK, because minorities are disproportionately affected by many of the diseases for which we have research responsibility including type 2 diabetes, hepatitis C, and end-stage kidney failure. Our major type 2 diabetes prevention trial has enrolled nearly 50 percent of its patients from minority groups, and we will be supporting a new initiative directed at the alarming incidence of type 2 diabetes in children, especially from minority groups. We are supporting efforts to understand why certain groups such as African Americans and Native Americans show increased susceptibility to the kidney complications of diabetes, so that we can learn how to prevent them. We are planning a clinical trial of interferon treatment in African Americans to determine why they are less responsive to treatment. This should lead to improved therapies. In addition to these areas, NIDDK will be emphasizing basic and clinical studies of prostate disorders, such as BPH and prostatitis; bladder disorders such as interstitial cystitis; inflammatory bowel disease and irritable bowel syndrome; progressive kidney failure; food-related illnesses; and other health problems within our research mission.
In developing our future research agenda, we have the benefit of input from our National Advisory Council, from our many constituency organizations both lay and scientific, and from investigators attending the scientific workshops convened by our staff. As the new NIDDK director, I have already met with many of these groups and will continue actively to reach out to them, so that we may effectively collaborate in framing future research directions. Working together, we can take full advantage of this unique time of scientific momentum to mobilize the national biomedical research enterprise for the benefit of all the people of this country.
I am pleased to present the President's non-AIDS budget request for the NIDDK for FY 2001, a sum of $1.186 billion, which reflects an increase of $66.8 million over the comparable Fiscal Year 2000 appropriation. Including the estimated allocation for AIDS, total support requested for the NIDDK is $1.209 billion, an increase of $67.8 million over the Fiscal Year 2000 appropriation. Funds for the NIDDK's efforts in AIDS research are included within the Office of AIDS Research budget request.
The NIH budget request includes the performance information required by the Government Performance and Results Act (GPRA) of 1993. Prominent in the performance data is NIH's first performance report, which compares our FY 1999 results to the goals in our FY 1999 performance plan. As our performance measures mature and performance trends emerge, the GPRA data will serve as indicators to support the identification of strategies and objectives to continuously improve programs across the NIH and the
