99-OR: An Inflection Point (IP) of C-Peptide (C-P) Decline during Progression to Type 1 Diabetes (T1D)

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Evidence suggests the presence of an IP for accelerated β-cell loss during progression to T1D. Importantly, identification of an IP could guide subject selection for prevention trials. We used a 2-dimensional grid of area under the curve (AUC) glucose vs. AUC C-P to detect a C-P IP among Diabetes Prevention Trial-Type 1 (DPT-1; n=54) and TrialNet (TN; n=59) autoantibody positive (Ab+) participants. All analyzed were required to have OGTTs at baseline and every 6 months, then 2.0, 1.5, 1.0 and 0.5 yrs before diagnosis. In DPT-1, an IP was evident 1.5 yrs from diagnosis (Figure) (AUC C-P change from baseline to 1.5 yrs: 0.22±0.60 ng/ml, p=0.006; from 1.5 to 0.5 yrs: -0.42±1.23 ng/ml, p=0.026). In TN, a 1.5 yr IP was also evident (from baseline to 1.5 yrs: 0.18±0.95 ng/ml, p=0.184; from 1.5 to 0.5 yrs: -0.53±1.57 ng/ml, p=0.015), despite an older TN cohort (14.9±12.1 vs. 10.5±6.8 yrs, p=0.023) with higher AUC C-P (5.0±1.9 vs. 3.3±1.6 ng/ml, p<0.001). There was no IP in non-progressors. In summary, an IP occurred 1.5 yrs before diagnosis when C-P began to decline as glucose continued to increase in DPT-1 and TN, suggesting that a 1.5 yr IP of C-P decline is consistent among Ab+ populations. These findings emphasize the importance of identifying at risk individuals as potential participants in prevention trials prior to the IP, when the loss of insulin secretion becomes more severe. Disclosure H.M. Ismail: None. J.S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Avotres, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings, Inc., Immunomolecular Therapeutics, Intrexon, Oramed Pharmaceuticals, Orgenesis Inc., Sanofi, Tolerion, Inc., Viacyte, Inc. Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Tolerion, Inc. Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. J. Sosenko: None. J.P. Palmer: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. L. DiMeglio: None. M.J. Redondo: None. A. Steck: None. M.A. Atkinson: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. B.M. Nathan: None. Funding National Institutes of Health