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In recognition of NIDDK\u2019s 75th anniversary, this review will summarize the major findings, accomplishments, and future opportunities of its long-running program TrialNet. More than 20 intervention, observational, and mechanism-directed clinical studies have been conducted in collaboration with thousands of people living with type 1 diabetes and their families. New and repurposed immunotherapies have been successful in stages 2 and 3 of type 1 diabetes, contributing to the U.S. Food and Drug Administration approval of the first disease-modifying therapy to delay the onset of type 1 diabetes. Mechanistic findings continue to drive ongoing and future trial designs including novel combination therapies. TrialNet has several ongoing trials, with several for early stages of type 1 diabetes in development. There are new initiatives within TrialNet for community engagement, increasing clinical trial representation, personalizing treatments, and training the next generation of translational investigators.<\/jats:p>","DOI":"10.2337\/dc24-2908","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T13:05:01Z","timestamp":1746623101000},"page":"1112-1124","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":22,"title":["Type 1 Diabetes TrialNet: Leading the Charge in Disease Prediction, Prevention, and Immunotherapeutic Mechanistic Understanding"],"prefix":"10.2337","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5144-7836","authenticated-orcid":false,"given":"Laura M.","family":"Jacobsen","sequence":"first","affiliation":[{"name":"Departments of Pediatrics and Pathology, University of Florida Diabetes Institute 1 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie L.","family":"Felton","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B. 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