NIDDK: Celebrating 75 Years of Advancing Diabetes Research Free

For over 40 years, the Diabetes Control and Complications Trial (DCCT) and its follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, have demonstrated the value of long-term cohort characterization and analysis to elucidate the natural history of type 1 diabetes and its complications and to inform clinical standards of care (3). Starting in 1983, DCCT showed that intensive blood glucose management for those with type 1 diabetes greatly lowered the chances of developing eye, kidney, and nerve disease compared with the conventional treatment at the time. The results from DCCT were paradigm changing, and the findings resulted in accepted clinical standards of care, which remain some of the most notable contributions to the diabetes field. EDIC continues to follow participants, conducting novel research on the long-term benefits of early, intensive blood glucose management. Insights from EDIC also inform new research into the incidence and pathology of type 1 diabetes complications. The collective findings from DCCT/EDIC have been transformational, demonstrating conclusively the value of intensive blood glucose management as part of standard diabetes care and prompting the development of improved insulin analogs and insulin delivery devices to mimic normal physiology. In addition to DCCT/EDIC, NIDDK has launched new initiatives to provide a deeper understanding of understudied complications such as cardiovascular disease in type 1 diabetes, like the ongoing Cardiovascular Repository for Type 1 Diabetes (CaRe-T1D), which provides resources and fosters collaborative efforts to better understand cardiovascular disease in those with type 1 diabetes (4).

Another result of DCCT/EDIC was to usher in a new era of research to develop better approaches to manage blood glucose levels, including glucose management technologies. This push achieved a major milestone in 2016 with the first U.S. Food and Drug Administration (FDA) approval of a commercial “hybrid” artificial pancreas device that revolutionized management of type 1 diabetes. Decades of NIDDK foundational research support contributed to this landmark technology through development of continuous glucose monitors, insulin pumps, dosing algorithms, and other components, as well as through clinical device testing (5,6). Today, multiple artificial pancreas devices—many developed and/or tested with NIDDK support—are FDA approved and are reducing the treatment burden of type 1 diabetes. Research continues to improve the components and testing of these technologies to ensure all people with type 1 diabetes can benefit from them.

In addition to efforts to ease the burden of type 1 diabetes management, NIDDK is pursuing strategies to ultimately cure the disease, including islet transplantation. Over 20 years of National Institutes of Health–supported research, including research conducted by the Clinical Islet Transplantation (CIT) Consortium, led to the 2023 FDA approval of the first cellular therapy for people with type 1 diabetes whose disease is complicated by frequent and severe hypoglycemic events, impaired awareness of hypoglycemia, or the inability of insulin-based management to prevent acute complications. This approval marked a critical step in the development of cell replacement therapies (7). Complementing this clinical effort, the Human Islet Research Network (HIRN)—founded in 2014 to build on the advances of the NIDDK-supported Beta Cell Biology Consortium (2001–2015)—continues to conduct innovative research to better understand how β-cells are lost in type 1 diabetes and how to protect or replenish them in people with the disease (8). These efforts and others have resulted in significant progress toward development of encapsulated human islets, animal models for studying their efficacy, and different approaches, such as immunotherapy, to improve islet transplantation. Such advances, in parallel with research toward generating and preserving sufficient numbers of islets for implantation, continue to lay the groundwork for cell replacement therapy as a cure for type 1 diabetes.

The Type 1 Diabetes TrialNet is another example of the benefits of sustained long-term research investment by NIDDK. Established in 2001, this international consortium offers risk screening for relatives of people with type 1 diabetes and is uniquely able to efficiently conduct trials of agents to delay and prevent clinical diagnosis of type 1 diabetes and to slow disease progression in the newly diagnosed (9). Furthermore, TrialNet is the only clinical study in the world that is following people with type 1 diabetes before, during, and after diagnosis. TrialNet research led to the breakthrough FDA approval in 2022 of teplizumab as the first early, preventive treatment that can delay clinical diagnosis of type 1 diabetes in people aged 8 years and older. Ongoing research by TrialNet continues to shed light on other possible prevention therapies, with one trial ongoing and several others planned.

NIDDK support of type 2 diabetes research also transformed type 2 diabetes prevention as a result of the Diabetes Prevention Program (DPP) and the ongoing Diabetes Prevention Program Outcomes Study (DPPOS) (10). The DPP showed that people who are at high risk for type 2 diabetes can prevent or delay the disease by losing a modest amount of weight through lifestyle changes (dietary changes and increased physical activity). Metformin was also used initially and was found to prevent the disease, though to a lesser degree. Both strategies were shown to have long-term benefits in delaying disease onset. DPPOS continues to provide valuable insight into not only type 2 diabetes complications but also the links between the disease and age-related morbidities.

In addition to advances in prevention, NIDDK has supported the development of new type 2 diabetes treatment options. Decades of NIDDK support for basic research to understand and characterize the hormones controlling blood glucose levels, including the discovery of the glucagon gene (11), ultimately led to important therapeutics such as the glucagon-like peptide 1 receptor agonists that have revolutionized treatment of obesity. In addition, foundational research by NIDDK also led to a new class of drugs, sodium–glucose cotransporter 2 inhibitors, that allow the kidneys to dispose of excess blood glucose in the urine, safely and effectively lowering blood glucose levels and improving glycemic control (12). Importantly, another major NIDDK study—Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)—compared different treatment strategies to give providers information and options for personalizing treatment (13).

To build on the success of these past advances and continue to drive progress in diabetes research, NIDDK is supporting efforts to understand the causes of diabetes heterogeneity (14). Identifying the molecular, cellular, clinical, and environmental factors contributing to variances in diabetes timing, course, and response to therapy is a key step to unlocking the underpinnings of heterogeneity of diabetes toward the goal of precision medicine. NIDDK is currently funding many initiatives to address heterogeneity of diabetes. For example, the Rare and Atypical Diabetes Network (RADIANT) study, launched in 2020, is targeting the causes of diabetes heterogeneity by seeking to identify and describe unusual forms of diabetes. It is hoped that efforts like RADIANT will not only improve diabetes diagnostic methods and increase understanding of the different ways diabetes can manifest but also pave the way for new treatments to improve patients’ quality of life. Additional efforts by NIDDK to understand heterogeneity of diabetes include the Diabetes Related to Acute Pancreatitis and Its Mechanisms (DREAM) study (15) from the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC), COVID and Diabetes Assessment (CODA) study (16), and DEFINE T2D (Definition, Etiology, Function: Integration to Enhance Type 2 Diabetes Treatment) (17).

Another high-priority focus for NIDDK is to support work elucidating the factors driving the epidemic of type 2 diabetes in American youth. SEARCH for Diabetes in Youth (SEARCH), funded by NIDDK and the Centers for Disease Control and Prevention, provided key epidemiological data on pediatric diabetes for over 20 years, laying the groundwork for further efforts such as the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study and the Restoring Insulin Secretion (RISE) consortium (18). These major studies, among their many insights, provided key evidence that youth-onset type 2 diabetes is more aggressive and more challenging to treat than adult-onset type 2 diabetes. These findings shaped pediatric diabetes care and helped identify critical knowledge gaps that informed the recently initiated DISCOVERY of Risk Factors for Type 2 Diabetes in Youth (DISCOVERY) study. DISCOVERY’s goal—to understand the biological, social, and environmental drivers of youth-onset type 2 diabetes—will be an essential step toward more targeted and effective diagnostic, preventive, and treatment approaches in young people.

Finally, we expect that basic research will continue to drive innovation in diabetes diagnosis, treatment, and prevention. Researchers have amassed an enormous amount of data on the genetic and molecular pathways underlying chronic metabolic diseases, and analyzing and extracting insights from this treasure trove will be a challenging but rewarding opportunity to understand the underpinnings of diabetes. NIDDK’s partnership with industry and nonprofit partners through the Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD) is already leveraging genomic association and functional data toward identifying promising new targets for type 1 diabetes therapeutic development (19). Additionally, as artificial intelligence and machine learning approaches provide new tools to analyze large research data sets, NIDDK is seeking to harness these advances by funding artificial intelligence–powered efforts to extract knowledge on type 2 diabetes heterogeneity from existing NIDDK research studies. The Environmental Determinants of Diabetes in the Young (TEDDY) study has also used innovative machine learning tools to identify new biomarkers that can predict the development of islet autoimmunity and type 1 diabetes diagnosis up to 6 months in advance (20). Such state-of-the-art techniques have the potential to unlock even more advances from the enormous amount of data TEDDY has collected on environmental factors and type 1 diabetes, advances that could identify factors that protect against or trigger disease onset or progression (21).

Even more than new technologies, the next generation of diabetes researchers is the key to tomorrow’s advances in diabetes care. NIDDK is committed to maintaining a steady pool of talented researchers, including through such efforts as the national Diabetes-Docs: Physician-Scientist DiabDocs-K12 Program and the New Investigator Gateway Awards for Collaborative Type 1 Diabetes Research. These programs aim to provide training, mentorship, and career opportunities to draw talented scientists into diabetes research and ensure that they can realize their potential to contribute to biomedical research.

As we celebrate NIDDK’s first 75 years, we also applaud the efforts of the investigators, staff, and volunteer research participants without whom all the achievements we have discussed would not have been possible. Research is a collaborative endeavor, best bolstered by collaboration, cooperation, and the shared desire to improve people’s health. We look forward to strengthening our partnerships, building on past successes, and continuing our meaningful research mission to improve quality of life and bring about a brighter future for those with and at risk for diabetes.

Acknowledgments. The authors thank Erica R. Hennes at NIDDK for her work on the figure.

Funding. The authors are employees of the NIDDK, National Institutes of Health.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Handling Editors. The journal editor responsible for overseeing the review of the manuscript was Steven E. Kahn.