Griffin P. Rodgers M.D., M.A.C.P.
National Institute of Diabetes and Digestive and Kidney Diseases
Recent Advances and Future Opportunities in Type 1 Diabetes Research
The Committee on Homeland Security and Governmental Affairs
United States Senate
Wednesday June 24, 2009
Chairman Lieberman, Senator Collins, and Members of the Committee, as Director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), I thank you for your invitation to testify at this hearing on type 1 diabetes. On behalf of the NIDDK and the other Institutes and Centers of the National Institutes of Health (NIH) within the U.S. Department of Health and Human Services (HHS), I am pleased to report that we are vigorously pursuing research on type 1 diabetes and its complications—along with research partners with whom we share important goals. Such partnerships have helped to synergize and propel research to combat this disease. In FY 2008, NIH invested over $1 billion on diabetes research. Through collaborative and coordinated research efforts, we are gaining important insights into the molecular mechanisms underlying disease development, testing promising therapies to prevent and treat the disease and its complications, and striving for a cure. Today I will discuss recent advances and future opportunities in type 1 diabetes research, including research supported by the Special Statutory Funding Program for Type 1 Diabetes Research.
Type 1 diabetes strikes mainly in childhood and adolescence. It is an autoimmune disease, in which the body’s own immune system attacks and destroys the insulin-producing beta cells found in clusters called islets within the pancreas. To survive, people with type 1 diabetes require daily administration of insulin in the form of injections or via an insulin pump. They must also monitor their food intake and physical activity in order to manage their blood glucose levels. Even with continuous and vigilant management, patients are still susceptible to developing serious, long-term complications that can damage the eyes, kidneys, nerves, heart, and other organs. Moreover, we now know that type 1 diabetes diagnoses are on the rise, and that the disease is occurring in younger children than before—often appearing during infancy.
Today, I will be describing some of the strides that we have made in improving the lives of people with type 1 diabetes. Importantly, because of continued improvements in therapy, people with type 1 diabetes are living longer, healthier lives than ever before. For example, improved therapy is reducing rates of diabetic kidney disease in people with type 1 diabetes. Further improvements in health and well-being are expected, as new continuous glucose monitoring technologies are helping patients better control their blood glucose levels, which is key for preventing disease complications. Blood tests can predict the risk of developing the disease in relatives of people with type 1 diabetes; this knowledge has enabled the launch of clinical trials testing new prevention strategies. We are working to build on these successes and continue basic and clinical research to further improve patients’ quality-of-life and to seek ways to prevent and cure type 1 diabetes.
How are we going about this? The NIH is focused on six broad goals in type 1 diabetes research, which are: (1) to understand the genetic and environmental causes of type 1 diabetes; (2) to prevent or reverse the disease; (3) to develop cell replacement therapy as a cure; (4) to avert hypoglycemia (low blood sugar), which limits tight control of blood glucose; (5) to pre-empt complications; and (6) to harness new technologies and empower talented researchers to pursue these opportunities.
Through this multifaceted approach, we can achieve a comprehensive understanding of the disease process, and form the foundation for future advances in treatment, prevention, and approaches to a cure.
Pursuit of the six goals I just mentioned has involved not only partnerships among scientists with complementary expertise from many academic institutions, but also partnerships among many of the Institutes and Centers of the NIH, HHS’s Centers for Disease Control and Prevention (CDC), and patient-advocacy groups, which have played an instrumental role in facilitating and in contributing support to many of these collaborative research endeavors.
Of course, the most important partners in these efforts are those people with or at-risk for type 1 diabetes who participate in clinical research to help improve diabetes care, not only for themselves but for future generations. The clinical research we conduct would not be possible without their enthusiastic participation and dedication.
I would now like to tell you about some of the exciting progress that has been made in type 1 diabetes research.
Understanding the Genetic and Environmental Causes of Type 1 Diabetes
Type 1 diabetes is caused by a combination of genetic and environmental factors, and it is the genetic arena that has seen some of the most impressive advances in recent years. Today, at least 40 genes are known to influence the likelihood of developing type 1 diabetes--four times as many as were known only two years ago. Why is this important? Identifying genes may lead to potential avenues for therapeutic or preventive treatments, and even on a personalized or customized basis. Moreover, because we have identified genetic variants that account for more than half of the genetic risk for type 1 diabetes, we can identify these high-risk individuals for entry into prevention trials. Since the sequencing of the human genome a few years ago, a new research method called “genome-wide association” has emerged, where specialists in genetic research scan the DNA of patients and search over 500,000 common genetic variations for markers of disease. Most genes influencing the likelihood of developing type 1 diabetes were discovered using this technology.
In addition, our understanding has grown deeper as well as broader by studying genes that are already known, such as through the fine mapping of the HLA locus (also known as MHC), the gene which has the greatest single impact on susceptibility to type 1 diabetes. Such research is helping to explain how it is that HLA exerts its strong effect on type 1 diabetes susceptibility. Other research has shown that a different diabetes gene, PTPN22, influences progression from autoimmunity to full-fledged type 1 diabetes in people who have a family history of the disease, while the gene CTLA-4 plays a similar role in children without a family history of the disease. A drug directed at CTLA-4 is now in clinical trials to slow progression of type 1 diabetes. Indeed, the next great strides in the genetics of the disease are likely to come from understanding the roles of the diabetes genes we already know, and leveraging that knowledge to fight the disease. A new initiative, “Fine Mapping and Function of Genes for Type 1 Diabetes,” seeks to do just that. The Type 1 Diabetes Genetics Consortium, a group of researchers from around the world who have come together to collect samples and information from families with type 1 diabetes, has helped to drive these recent advances, and will be in the vanguard to answer key remaining questions about diabetes genetics.
We know much less about the environmental factors that trigger onset of type 1 diabetes in genetically-susceptible individuals. The rise in rates of type 1 diabetes around the world is presumably the result of a change or changes in the environment, which we hope to identify through research. The discovery of a precipitating viral infection could lead to a diabetes-preventing vaccine; the identification of a dietary trigger or protector could be addressed through a dietary intervention. To address this crucial issue, an international consortium is identifying infants at high-risk for developing type 1 diabetes and following them through adolescence to search for environmental factors that may trigger disease. This long-term NIDDK-led study, called The Environmental Determinants of Diabetes in the Young, or TEDDY, has screened almost 350,000 newborns for the presence of the most important genetic risk factor for type 1 diabetes, identifying over 17,000 with this risk factor and enrolling over 6,670 of the children in the study. This achievement represents tremendous progress toward amassing the largest set of data and samples anywhere in the world on newborns at risk for autoimmunity and type 1 diabetes. To maximize the return on the investment in TEDDY, samples from the study will be made widely available to researchers worldwide. Importantly, TEDDY may also contribute to understanding the development of celiac disease, which is an autoimmune disease primarily affecting the gastrointestinal tract. Some genes confer susceptibility to both celiac disease and type 1 diabetes, and many people have both diseases. Thus, TEDDY may benefit not only people with, or at-risk for, type 1 diabetes, but also people with celiac disease and other autoimmune diseases. As the powerful research tool that the TEDDY samples will represent continues to be assembled, new data are beginning to shed some light on environmental variables that can affect incidence of diabetes. Among the most striking of these findings in the last year is the discovery that healthy bacteria in the gut can potentially help blunt the autoimmune attack that causes diabetes in an animal model.
A clearer understanding of why diabetes strikes will also come in part from a fuller perspective on where, when, and how often it does. Thus, CDC and NIDDK support the Search for Diabetes in Youth Study, an epidemiologic effort which has recently reported the most complete picture to date on the incidence and prevalence of both type 1 and type 2 diabetes in five major racial/ethnic categories in the United States. These data show that type 1 diabetes is present at significant rates in youth under age 20 in all of these groups. In Colorado, where data exist for the period of 1978-1988, we now know that incidence of type 1 diabetes climbed 2.3 percent per year over the past three decades, rising both among Hispanic and non-Hispanic white children. We also know that the largest part of that increase came among children diagnosed very early, within their first 4 years. This research will also help to evaluate key risk factors for the disease, and for its complications.
Preventing or Reversing Type 1 Diabetes
To spur the testing of promising new strategies to prevent type 1 diabetes in those at elevated risk of the disease, and to slow or reverse its course in those recently diagnosed, the NIDDK leads a clinical trials network, the Type 1 Diabetes TrialNet. TrialNet researchers have just reported exciting data that rituximab, a therapeutic agent currently in use for non-Hodgkin’s lymphoma and rheumatoid arthritis, can substantially preserve the function of insulin-producing beta cells in people with recently diagnosed type 1 diabetes. Patients taking the drug had better glycemic control and required less insulin than those who took a placebo over a one year follow-up to their treatment. Other TrialNet studies include a trial to test whether oral insulin administration can prevent type 1 diabetes in a group of people who have high levels of anti-insulin antibodies, a certain marker of pre-clinical type 1 diabetes. The TrialNet infrastructure is critically important for testing emerging therapies for disease prevention and early treatment.
The Immune Tolerance Network (ITN), sponsored by NIH’s National Institute of Allergy and Infectious Diseases (NIAID), is also conducting several clinical trials to test therapies to reverse disease in newly-diagnosed patients with type 1 diabetes. ITN and TrialNet work in partnership, and currently between the two have nine trials in progress, with several others scheduled to launch soon.
Evidence from observational studies suggests it may be possible to use dietary interventions to lower the risk that people born with the genetic predisposition to developing type 1 diabetes will go on to develop the disease. Indeed, TrialNet is currently doing a pilot trial of omega-3 fatty acid supplements to help lower the odds of developing type 1 diabetes in those at elevated genetic risk. NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) leads an effort, called the Trial to Reduce IDDM [insulin-dependent diabetes mellitus] in the Genetically At Risk, or TRIGR, which is examining a specific environmental factor, cows’ milk, in development of type 1 diabetes. That international study has recently completed recruitment of 2,160 newborns at high risk for type 1 diabetes and is comparing standard formula with a formula in which cows’ milk proteins are broken down into smaller pieces.
NIDDK also leads an international effort to standardize autoantibody measurements, which has helped to characterize childhood diabetes and distinguish between type 1 and type 2 diabetes. Increasingly, beta cell inflammation, and in some cases autoimmunity, is being recognized as contributing to type 2 diabetes. Standardizing antibody measurement is important to help understand this phenomenon as well as to identify participants at high risk of type 1 diabetes for participation in TrialNet trials.
Developing Cell Replacement Therapy
Insulin therapy for type 1 diabetes is a less than ideal substitute for the body’s exquisitely precise regulation of blood glucose by insulin-producing pancreatic beta cells. In contrast to insulin administration, a real cure could emerge from cell-based therapy, such as the transplantation of insulin-producing cells. Developing this type of therapy has proven challenging: clinicians must have an adequate supply of healthy islets for transplantation; they must inhibit the autoimmune attack that destroyed a patient’s original islets; and they must inhibit the body’s defense mechanisms that can lead to graft rejection. This last point is a particular challenge in the case of diabetes, because many of the best medications for preventing tissue rejection are toxic to beta cells. However, researchers are collaborating to achieve this goal. For example, scientists from the Clinical Islet Transplantation Consortium, a network of clinical centers sponsored by NIDDK and NIAID to conduct studies of islet transplantation in patients with type 1 diabetes, are comparing the current state of the art procedure for islet transplantation with several new protocols that may yield improved insulin production over the longer term with fewer side effects. The Collaborative Islet Transplantation Registry, initiated and supported by NIDDK, is tracking approaches to and outcomes of such procedures. Scientists are hard at work overcoming technical difficulties to islet transplantation, and increasing the available supply of transplantable islets. A powerful new tool recently developed through the Beta Cell Biology Consortium, established by NIDDK to facilitate interdisciplinary approaches that will advance our understanding of pancreatic islet development and function, is a mouse model that facilitates testing of medications used in people with diabetes to find those that are benign in their effects on islets.
Recent research from the Beta Cell Biology Consortiumalso suggests that an exciting alternative therapy may one day replace beta cells without the need for transplants: converting exocrine cells in a patient’s own pancreas into insulin-producing cells. Scientists found that this was possible in diabetic mice by infecting the exocrine cells with a virus carrying genetic signals that trigger the cells to act like beta cells and produce insulin in response to rising glucose levels. In the mice, the insulin production was sufficient to “cure” them of their diabetes. There are a considerable number of technical hurdles and safety questions that must be addressed before such an approach can be tested in people with type 1 diabetes, and an additional intervention may be required to keep the immune system from attacking the new insulin-producing cells just as they attacked the patient’s original islets. But this exciting approach could avoid some of the problems associated with immune rejection of transplanted tissue.
Such research also provides fundamental new insights into the biology of the beta cell, which is of great importance not only to help improve treatment for patients with type 1 diabetes, but also for millions of Americans with type 2 diabetes or with pancreatic cancer. Thus, research projects such as these, made possible by the Special Statutory Funding Program for Type 1 Diabetes Research, have a broader impact on biomedical research than some may realize.
By studying the beta cell in detail, scientists are also gaining new insight into the autoimmune process that leads to type 1 diabetes and discovering new biomarkers that can predict disease onset. Biomarkers are measurable molecular, biological, or physical characteristics that indicate a specific underlying physiologic state. Biomarkers are critically needed to predict disease risk, to monitor disease, and to monitor autoimmune responses during therapeutic intervention. Autoantibodies, which are antibodies that react with the cells, tissues, or native proteins of the individual who produce them, are the most important biomarkers used for detecting the earliest stages of autoimmunity, and recent research has identified a new autoantibody that improves the sensitivity and specificity of such predictive tests. Better testing for autoimmunity before onset of diabetes can identify those at risk, help catch the disease before blood glucose gets dangerously high and could lead to interventions that prolong beta cell life, reduce the need for injected insulin, and lower the risk of complications. As therapies improve, autoantibody screening may one day make it possible for health care providers to reverse the course of diabetes entirely in patients whose diabetes risk is caught early enough.
Preventing or Reducing Hypoglycemia in Type 1 Diabetes
Research is pointing the way to exciting new interventions that may one day lead to prevention or reversal of type 1 diabetes or to the development of an artificial pancreas. But just as important are key findings that give patients and their families practical solutions to the problems posed by the disease every day. Perhaps the most distressing acute complication in people with type 1 diabetes is hypoglycemia—low blood sugar. It is caused by greater-than-necessary treatment with insulin relative to food intake and physical activity. The potential for hypoglycemic episodes has challenged the use of intensive insulin therapy even though major clinical trials have shown that intensive therapy can significantly reduce the risks of longer-term diabetic complications. Another worry has been the fear that recurrent episodes of hypoglycemia might lead to a decline in cognitive skills. Again, good news comes from NIH research. Scientists have found that tight control of blood glucose does not lead to cognitive decline, even when it is accompanied by recurrent episodes of hypoglycemia, and in fact is significantly associated with better preservation of fine motor control.
Nevertheless, hypoglycemia remains a serious concern for people with diabetes and their loved ones, and the NIH is deeply committed to helping ease the difficulties of glucose control. Within the last few years, continuous glucose monitors have been developed and approved for use, which can help remove some of the guesswork from insulin therapy. Research from the DirecNet Consortium, led by NICHD, has yielded practical suggestions for people with diabetes and their parents or caregivers to help maintain healthy glucose levels more safely and effectively by managing diet and exercise. To better understand the way patients and caregivers utilize continuous glucose monitors, the NIH has developed an initiative to study the way data from the monitors is used.
Having supported the research that led to development of continuous glucose monitors, the NIH is committed to capitalizing on this technology to achieve a new option in diabetes clinical care: an “artificial pancreas” that will tightly control a person’s blood glucose, like the biological pancreas naturally does in people without diabetes. Strides in improved accuracy of continuous glucose monitoring, together with new algorithms to predict insulin requirements based on trends in glucose levels, have allowed researchers to begin careful studies to “close the loop” and link insulin delivery to continuous glucose measurements. The NIH is working with the business community to help bring about the required technology through the Small Business Innovation Research to Develop New Therapeutics and Monitoring Technologies for Type 1 Diabetes initiative, a new grant program that will award its initial funding later this year.
Preventing or Reducing the Complications of Type 1 Diabetes
The complications of diabetes affect virtually every system of the body; diabetes and its complications can shorten average life expectancy by up to 15 years. Recent studies have brought good news: people with type 1 diabetes are living longer and healthier lives than ever before. The landmark NIDDK-supported Diabetes Control and Complications Trial (DCCT) demonstrated that intensive control of blood glucose levels is extremely effective in preventing complications affecting the eyes, kidneys, and nerves. Long-term results from the follow-on study to the DCCT now show that intensive therapy also dramatically reduces the risk of heart disease, which is the leading cause of death in people with diabetes. Results also showed that a finite period of good glucose control provides benefits years down the road, with enduring protection from complications of the eyes and kidneys, and from cardiovascular disease. Thus, patients and physicians are advised to start intensive therapy as early as possible following diagnosis.
Despite these gains, type 1 and type 2 diabetes together are the leading cause of new blindness in people 20-74 years old. To combat this devastating complication, NIH’s National Eye Institute (NEI) supports the Diabetic Retinopathy Clinical Research Network, which is conducting multiple protocols to identify new prevention and treatment strategies for diabetic eye disease. The NEI is also leading an effort to involve small businesses in Innovative Patient Outreach Programs and Ocular Screening Technologies to Improve Detection of Diabetic Retinopathy. This funding opportunity is intended to help detect retinopathy in its early stages, when it is still possible to prevent blindness.
To better understand why diabetes leads to devastating complications like retinopathy and kidney disease, researchers from the Family Investigation of Nephropathy and Diabetes (FIND) consortium have compared the genomes of thousands of people with diabetes who either do or do not have kidney disease. The study identified four genetic regions where subtle differences correlate with increased risk of diabetic kidney disease. Other scientists looked carefully at specific genes they thought might contribute to the development of complications and found that a genetic region that controls production of the hormone erythropoietin leads to too much of the protein in people who develop proliferative diabetic retinopathy (the abnormal growth of blood vessels in the eye) and diabetic nephropathy. These results may one day help clinicians head off complications before they happen, and suggest novel therapeutic approaches for treating and preventing the devastating complications of both type 1 and type 2 diabetes.
Attracting New Talent and Applying New Technologies to Research on Type 1 Diabetes
A critical goal of the Special Statutory Funding Program for Type 1 Diabetes Research is to draw talented young investigators into the field, and help establish them as productive members of the scientific community. Many young investigators have innovative research ideas, but they lack the preliminary data required to compete in the traditional NIH peer review system. Therefore, the NIDDK established the Type 1 Diabetes Pathfinder Awards to help overcome this impediment. By providing multi-year support to new researchers with highly innovative projects, we hope to attract and retain high-caliber investigators to research careers in type 1 diabetes.
In October 2008, ten scientists won Pathfinder Awards for highly innovative research studies that offer exceptional promise for improving the understanding, prevention, and treatment of type 1 diabetes and its complications. The recipients, all new researchers who have never been principal investigators on an NIH-funded grant, will receive about $1.5 million each over a 5-year period to pursue their work. Their studies span a wide range of topics, from the development of a vaccine to prevent autoimmune diabetes to methods that speed wound healing and prevent recurrent injury.
Because type 1 diabetes research spans a broad range of scientific disciplines, a cadre of exceptionally talented and dedicated researchers is needed to bring expertise to bear on scientific challenges. As more and more exciting discoveries are made in the laboratory – at the “bench” – there is a need to rapidly move those results to the clinic – to the “bedside” – to benefit patients directly. Thus, the NIH is sponsoring “bench-to-bedside” initiatives, in which teams of basic scientists and clinical researchers work together on translational research projects focused on type 1 diabetes.
New technologies are driving many of these efforts. Genome-wide association studies have yielded powerful new findings that I previously mentioned in the contexts of both Goal I and Goal V. Closing the loop for the artificial pancreas and developing new cell-based therapies will help prevent hypoglycemia, while also improving glucose control and preventing long-term complications from hyperglycemia (elevated blood sugar). New technologies for imaging islets and beta cells have the potential to transform not only research but also care, as a clearer picture of what is happening in the pancreas may be possible. Another important translational research effort is the Type 1 Diabetes-Rapid Access to Intervention Development (T1D-RAID) program. T1D-RAID has provided resources for preclinical development of therapeutic agents to move them along the pipeline to clinical trials. For example, a drug produced under the T1D-RAID program is currently being tested in clinical trials of islet transplantation. Efforts in these diverse scientific disciplines combine to help move the field forward, and bring life-extending and improved health care to people with diabetes.
Looking to the future, in order to inform the program development process for NIH-supported type 1 diabetes research in the years ahead, the NIDDK is spearheading development of a Diabetes Research Strategic Plan, with extensive input from external scientific and lay experts. The Plan will help to synergize diabetes research, and bring benefit to all people with diabetes by identifying gaps, and finding solutions to help fill them.
For now, I am grateful for the opportunity to share with you these few examples of recent advances and ongoing research efforts. We continue to be inspired by the dedicated efforts of individuals affected by type 1 diabetes, and by organizations that represent them. We look forward to continuing to partner with these organizations on research efforts to combat type 1 diabetes and its complications. We are grateful for the full range of support that NIH has received for type 1 diabetes research. We continue to be diligent in our fight against diabetes so that we can help all the children at this hearing and the many other Americans whom they represent here today. Improving their quality of life—with the ultimate goal of curing their disease—is the driving force behind our efforts.
Thank you Mr. Chairman, Senator Collins, and Members of the Committee for your attention. I will be pleased to answer any questions you may have.
Last revised: June 18, 2013