Early and Later C-Peptide Responses during Oral Glucose Tolerance Testing (OGTT) Are Independently and Oppositely Predictive of Type 1 Diabetes (T1D) in Autoantibody-Positive (Ab+) Individuals

A longitudinal study showed that early C-peptide (C-P) responsiveness during OGTTs declined during progression to T1D, whereas later C-P responsiveness increased until the diagnosis was imminent. Here we exmaine: 1) whether the baseline C-P response pattern predicts T1D as suggested by the findings from that longitudinal study, and 2) the basis for the higher later C-peptide response during progression. Baseline 2-hour OGTTs from 670 Diabetes Prevention Trial-type 1 participants (age: 13.8±9.6 years; BMI-z: 0.3±1.1; 56% male) were analyzed. In univariate regression models, the early C-P response (30-0 min) was inversely predictive of T1D (X²=28.8, p<0.001), whereas the later C-P response (120-60 min) was positively predictive (X²= 23.3, p<0.001). Each was at least as predictive as the AUC C-peptide (inverse association; X² = 20.4; p<0.001), a standard prediction measure. In a model including both early and late C-P responses, both remained oppositely predictive of T1D with a stronger overall association (X²=41.1; p<0.001 for both). To explain the positive association of greater T1D risk with a high later C-P, we examined the association between the sum of glucose levels from 60 to 120 min and the 120-60 min C-P; there was a strong positive association (r=0.44, p<0.001). All associations persisted after age and BMI-z adjustments.

In conclusion, the findings show that lower early and higher later C-P responses are both indicators of risk for progression to T1D. Moreover, the findings suggest that the increasing later C-P response reflects an attempt by the β-cell to compensate for higher glucose levels due to a deficient early C-P response. These findings are similar to the evolution of C-P responses during type 2 diabetes development. Partitioning C-peptide into early and later responses appears beneficial for T1D prediction and for studying β-cell deterioration during progression.