The Special Diabetes Program: 25 Years of Advancing Type 1 Diabetes Research

In 2023, the Special Statutory Funding Program for Type 1 Diabetes Research (Special Diabetes Program) celebrated 25 years of research progress. Since its inception in 1998, the Special Diabetes Program has demonstrated the value of consistent, long-term research support, enabling NIDDK to expand type 1 diabetes research beyond what was possible with regular appropriations and allowing researchers to conduct clinical trials unlikely to be performed in the private sector. As a result, Special Diabetes Program-funded research has led to life-changing improvements for people with the disease and ushered in a new era of type 1 diabetes management.

Congress established the Special Diabetes Program to support scientific research on the prevention and cure of type 1 diabetes and its complications. This Program has provided a total of about $3.39 billion for Fiscal Year (FY) 1998 through FY 2023. The Program is administered by NIDDK on behalf of the Secretary of the U.S. Department of Health and Human Services, in collaboration with multiple NIH Institutes and Centers and the Centers for Disease Control and Prevention, and with input from the statutory Diabetes Mellitus Interagency Coordinating Committee chaired by NIDDK.

A Multifaceted Approach to Type 1 Diabetes Research

NIDDK is pursuing a multipronged approach to type 1 diabetes research, focusing on key questions such as: how can we prevent this disease, how can we improve treatment, and how can we develop a cure? Listed below are major goals pursued by the Special Diabetes Program, accompanied by examples of the extensive progress enabled by Program funding.

Goal: Identify the genetic and environmental causes of type 1 diabetes

A person’s risk for developing type 1 diabetes is dependent on both genetic and environmental factors. Due to work funded by the Special Diabetes Program and others, over 90 percent of the genetic contributions to type 1 diabetes risk are known in those of European ancestry (who have the highest prevalence of type 1 diabetes), and researchers continue to enhance understanding of risk factors in other backgrounds. To identify environmental factors of type 1 diabetes risk, the long-term clinical research study The Environmental Determinants of Diabetes in the Young (TEDDY) screened over 425,000 newborns, enrolling 8,000 who were at high genetic risk of type 1 diabetes. These children will be followed until they are 15 years old, and they and their families have donated over 4 million biological study samples to date. TEDDY researchers are studying the children’s genes, proteins, and metabolites, as well as the microbes they carry and their environmental exposures.

TEDDY analyses have yielded new insights into childhood development, including how the microbes in a child’s gut change as they age and how those changes are affected by breastfeeding. TEDDY findings have also increased understanding of how to predict type 1 diabetes, allowing researchers to construct a risk score assessment tool that uses both genetic and immune factors to predict an individual’s risk of the disease. New research from TEDDY and other studies has also illustrated how type 1 diabetes is not a single disease but a “heterogeneous” one that progresses differently for different people. These and other TEDDY findings could lead to more personalized preventive strategies in the future as we move toward the goal of precision medicine.

Goal: Prevent or reverse type 1 diabetes

Long-term research supported by NIH and the Special Diabetes Program recently culminated in the November 2022 U.S. Food and Drug Administration (FDA) approval of teplizumab, the first early, preventive treatment that can delay clinical diagnosis of type 1 diabetes in those at high risk of developing the disease. Key research underlying this FDA approval stemmed from a trial conducted by the Special Diabetes Program-funded Type 1 Diabetes TrialNet, a large international consortium designed to perform clinical trials of therapies to delay or prevent type 1 diabetes progression. TrialNet’s clinical trial of teplizumab found that the drug delayed type 1 diabetes onset by nearly 3 years. (See the type 1 diabetes Personal Perspective in this chapter for more information and for the story of a volunteer who participated in this research.) The landmark FDA approval of teplizumab has ushered in a new era of type 1 diabetes prevention and underscored the value of TrialNet’s unique clinical trial infrastructure.

Teplizumab’s approval was made possible by decades of research—much of it NIH- and Special Diabetes Program-supported—into understanding type 1 diabetes progression and identifying potential therapies. For example, research conducted by the Immune Tolerance Network, led by the National Institute of Allergy and Infectious Diseases (NIAID) with Special Diabetes Program support, showed that teplizumab delayed the loss of insulin production in people with newly diagnosed type 1 diabetes. Additionally, data from TrialNet, TEDDY, and other studies were critical to the discovery that several distinct stages of type 1 diabetes occur before symptoms appear. Being able to identify people in the early stages of disease prior to clinical diagnosis has made type 1 diabetes prevention trials possible.

Goal: Develop cell replacement therapy

In type 1 diabetes, the immune system attacks and destroys the insulin-producing β (beta) cells in clusters called islets in the pancreas. Replacing these β cells could be a biological cure for the disease. The Clinical Islet Transplantation Consortium (CIT)—co- led by NIDDK and NIAID—has demonstrated that transplanting donated islets into a person with type 1 diabetes can eliminate severe episodes of low blood glucose (sugar), with some trial participants achieving near-normal average blood glucose levels and an improved quality of life. CIT trial data led to the July 2023 FDA approval of the first cellular therapy made from deceased donor pancreatic cells for the treatment of adults with type 1 diabetes and recurrent severe low blood glucose. This therapy provides an additional treatment option and, in some people, it can result in no longer needing to take insulin. However, islet transplantation’s current limitations—including the need for lifelong immunosuppression and the low availability of donated islets—make it suitable for only a small number of people, and cell replacement strategies that can benefit a wider range of individuals are needed.

Studies through the Beta Cell Biology Consortium and its successor, the Human Islet Research Network (HIRN), are advancing knowledge of how β cells are lost in type 1 diabetes and how they can be protected or replaced in people. HIRN investigations into how β cells develop and mature are allowing scientists to make new β-cell replacements and islet-like mini- organs or “organoids” in the lab. In addition to HIRN activities, other Special Diabetes Program-supported advances have been made in improving transplantation procedures and developing specialized encapsulation technologies to protect β-cell replacements from immune attack. Early Special Diabetes Program investments are providing the technical know-how required for future advances.

Goal: Improve type 1 diabetes management and care

The Special Diabetes Program has provided key support for the development of glucose management technologies, from continuous glucose monitors to artificial pancreas systems that automate insulin delivery. As a result, these devices have moved out of the lab and into people’s daily lives. In the last 8 years, 6 artificial pancreas devices have become commercially available, including devices for children as young as 2 years old. Five of these devices had NIDDK and Special Diabetes Program support during development and/or testing, demonstrating the value of long-term research funding.

The Special Diabetes Program has also played a unique role in expanding research on how new glucose management technologies can benefit everyone with type 1 diabetes, with the goal of having multiple artificial pancreas technologies available to fit diverse needs. Several Program-supported trials have sought to study the use of these devices in groups understudied by industry, such as during pregnancy, in people of certain racial or ethnic groups, and in those for whom managing blood glucose levels is particularly challenging.

Goal: Prevent or reduce the complications of type 1 diabetes

Persistent high blood glucose levels can damage nearly every part of the body, leading to life-threatening complications. The Special Diabetes Program has supported a robust portfolio of programs to improve prevention and treatment of these conditions. One particularly successful example is the National Eye Institute-led DRCR Retina Network (previously the Diabetic Retinopathy Clinical Research Network or DRCR.net), which has been transforming diabetic eye care for two decades. One of the DRCR Retina Network’s pivotal findings was that the anti-vascular endothelial growth factor (VEGF) drug, ranibizumab, was more effective than laser treatment at improving visual acuity for the most severe form of diabetic eye disease, proliferative diabetic retinopathy. This result led to ranibizumab being the first new option for treating proliferative diabetic retinopathy in four decades. The Network has also performed comparative effectiveness studies unlikely to be done by industry, confirming that three medications for diabetic macular edema were equally effective, a finding with significant cost implications.

Goal: Attract new talent and apply new technologies to research on type 1 diabetes

Tomorrow’s cutting-edge research requires fostering a talented, diverse biomedical workforce today. To this end, the Special Diabetes Program has supported creative new and early-stage investigators pursuing highly innovative new approaches in type 1 diabetes research. It has also helped expand the type 1 diabetes research community through career development and funding opportunities for researchers with specialized skillsets—such as bioengineers, behavioral scientists, and pediatric endocrinologists. Additionally, the Special Diabetes Program supports academic and small business investigators at all stages to help develop ground-breaking technologies. One such partnership resulted in an improved glucagon formulation that does not require refrigeration and thus is suitable for a ready- to-use rescue pen. This device is now commercially available to treat low blood glucose, a daily concern for people with type 1 diabetes.

Building on the Past, Looking to the Future

Through these and many other efforts, the Special Diabetes Program has catalyzed remarkable progress and fostered unique collaborations that have accelerated the pace of type 1 diabetes research.

Research funded by the Program has also yielded benefits beyond type 1 diabetes, for example by developing glucose management tools to help those with type 2 diabetes and by offering insights into other autoimmune diseases. Finally, the Special Diabetes Program has supported a pipeline of knowledge that has ushered in a new era of improved health, longevity, and quality of life for people with type 1 diabetes.

With continued research, NIDDK looks forward to a future when all people can be free from the burden of type 1 diabetes and its complications.