Visual Abstract

T1D staging is used for eligibility criteria in T1D prevention trials, but recent findings suggest that using glucose alone, without measures of insulin secretion, to define T1D progression may group together highly heterogeneous individuals. Thus, utilizing the large TrialNet Pathway to Prevention cohort, we aimed to examine heterogeneity for T1D-related characteristics, including risk for T1D, among 1,325 Ab+ individuals who upon OGTT screening were in the highest AUC glucose quintile (≥151 mg/dL) within the nondiabetic range. Within that highest AUC glucose quintile, we compared T1D characteristics of participants in the highest (≥8.03 ng/mL, n=378) vs. the lowest (<3.68 ng/mL, n=252) AUC C-peptide quintiles. Marked differences were evident in characteristics and T1D risk, though AUC glucose levels were similar (Table). Differences in Ab+ prevalence persisted after adjusting for age and BMI, and in obesity/overweight after adjusting for age.

In conclusion, despite similar AUC glucose values, C-peptide levels identified individuals with greatly different characteristics, including a near 3-fold difference in 5-yr T1D risk of those in lowest vs. highest C-peptide quintiles. Using glucose without C-peptide to define T1D stages results in pronounced heterogeneity, which can lower the ability to demonstrate efficacy in T1D prevention trials.


M. J. Redondo: Advisory Panel; Self; Provention Bio, Inc. J. Sosenko: None. D. D. Cuthbertson: None. B. M. Nathan: None. E. K. Sims: None. M. Tosur: Advisory Panel; Self; Provention Bio, Inc. I. Libman: Advisory Panel; Self; Novo Nordisk. J. S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Oramed Pharmaceuticals, Inc., Orgenesis Inc., Tolerion, Inc., Viacyte, Inc., Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics, Inc., Consultant; Self; AstraZeneca, Avotres Inc., Bayer AG, IM Therapeutics, Novo Nordisk, Precigen, Inc., Provention Bio, Inc., Sanofi, Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc. M. A. Atkinson: None.


National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF

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