Ismail, Heba M.Cuthbertson, DavidGitelman, Stephen E.Skyler, Jay S.Steck, Andrea K.Rodriguez, HenryAtkinson, MarkNathan, Brandon M.Redondo, Maria J.Herold, Kevan C.Evans-Molina, CarmellaDiMeglio, Linda A.Sosenko, JayDPT-1 and TrialNet Study Groups2024-06-062024-06-062022-10Ismail, H. M., Cuthbertson, D., Gitelman, S. E., Skyler, J. S., Steck, A. K., Rodriguez, H., Atkinson, M., Nathan, B. M., Redondo, M. J., Herold, K. C., Evans-Molina, C., DiMeglio, L. A., Sosenko, J., & on behalf of DPT-1 and TrialNet Study Groups. (2022). The Transition From a Compensatory Increase to a Decrease in C-peptide During the Progression to Type 1 Diabetes and Its Relation to Risk. Diabetes Care, 45(10), 2264–2270. https://doi.org/10.2337/dc22-0167https://hdl.handle.net/1805/41276OBJECTIVE To define the relationship between glucose and C-peptide during the progression to type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS We longitudinally studied glucose and C-peptide response curves (GCRCs), area under curve (AUC) for glucose, and AUC C-peptide from oral glucose tolerance tests (OGTTs), and Index60 (which integrates OGTT glucose and C-peptide values) in Diabetes Prevention Trial–Type 1 (DPT-1) (n = 72) and TrialNet Pathway to Prevention Study (TNPTP) (n = 82) participants who had OGTTs at baseline and follow-up time points before diagnosis. RESULTS Similar evolutions of GCRC configurations were evident between DPT-1 and TNPTP from baseline to 0.5 years prediagnosis. Whereas AUC glucose increased throughout from baseline to 0.5 years prediagnosis, AUC C-peptide increased from baseline until 1.5 years prediagnosis (DPT-1, P = 0.004; TNPTP, P = 0.012) and then decreased from 1.5 to 0.5 years prediagnosis (DPT-1, P = 0.017; TNPTP, P = 0.093). This change was mostly attributable to change in the late AUC C-peptide response (i.e., 60- to 120-min AUC C-peptide). Median Index60 values of DPT-1 (1.44) and TNPTP (1.05) progressors to T1D 1.5 years prediagnosis (time of transition from increasing to decreasing AUC C-peptide) were used as thresholds to identify individuals at high risk for T1D in the full cohort at baseline (5-year risk of 0.75–0.88 for those above thresholds). CONCLUSIONS A transition from an increase to a decrease in AUC C-peptide ∼1.5 years prediagnosis was validated in two independent cohorts. The median Index60 value at that time point can be used as a pathophysiologic-based threshold for identifying individuals at high risk for T1D.en-USPublisher Policyglucose and C-peptide response curves (GCRCs)oral glucose tolerance tests (OGTTs)Type I Diabetesrisk factorsArticle