American Diabetes Association
2 files

The Transition from a Compensatory Increase to a Decrease in C-peptide During the Progression to Type 1 Diabetes and Its Relation to Risk

posted on 2022-08-19, 12:04 authored by Heba M Ismail, David Cuthbertson, Stephen E. Gitelman, Jay S. Skyler, Andrea K. Steck, Henry Rodriguez, Mark Atkinson, Brandon M. Nathan, Maria J. Redondo, Kevan C Herold, Carmella Evans-Molina, Linda A DiMeglio, Jay Sosenko, DPT-1 and TrialNet Study Groups



To define the relationship between glucose and C-peptide during the progression to type 1 diabetes.

Research Design and Methods

We longitudinally studied glucose and C-peptide response curves (GCRCs), area under curve (AUC) 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 (TNPTP; n=82) participants who had OGTTs at baseline and follow-up timepoints before diagnosis. 


Similar evolutions of GCRC configurations were evident between DPT-1 and TNPTP from baseline to 0.5 years pre-diagnosis. Whereas AUC glucose increased throughout from baseline to 0.5 years pre-diagnosis, AUC C-peptide increased from baseline until 1.5 years pre-diagnosis (DPT-1: p=0.004; TNPTP: p=0.012) and then decreased from 1.5 years to 0.5 years pre-diagnosis (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-minute AUC C-peptide). Median Index60 values of  DPT-1 (1.44) and TNPTP (1.05) progressors to type 1 diabetes 1.5 years pre-diagnosis (time of transition from increasing to decreasing AUC C-peptide) were used as thresholds to identify individuals at high risk for type 1 diabetes 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 approximately 1.5 years pre-diagnosis was validated in two independent cohorts. The median Index60 value at that timepoint can be used as a pathophysiologic-based threshold for identifying individuals at high risk for type 1 diabetes.


We acknowledge the support of the Type 1 Diabetes TrialNet Study Group, which identified study participants and provided samples and follow-up data for this study. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, through the cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085453, U01 DK085461, U01 DK085465, U01 DK085466, U01 DK085476, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK106993, UC4 DK11700901, U01 DK 106693-02, and the JDRF. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the JDRF. This work was also made possible with support from Grant Numbers, KL2TR002530 (A Carroll, PI), and UL1TR002529 (A. Shekhar, PI) from the National Institutes of Health (NIH), National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award; and NIH R01 DK121843 (MJR) and R01 DK124395 (MJR).


Usage metrics

    Diabetes Care


    Ref. manager