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

Objective

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. 

Results

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.