A Glucose Fraction Independent of Insulin Secretion: Implications for Type 1 Diabetes Progression in Autoantibody-Positive Cohorts

Objective: We assessed whether there is an impactful glucose fraction independent of insulin secretion in autoantibody-positive individuals. Research Design and Methods: Baseline 2-h oral glucose tolerance test data from the TrialNet Pathway to Prevention (TNPTP; n = 6190) and Diabetes Prevention Trial-Type 1 (DPT-1; n = 705) studies were used. Linear regression of area under the curve (AUC) glucose versus Index60 was performed to identify two fractions: dependent (dAUCGLU) or independent (iAUCGLU) of insulin secretion. Results: The lack of correlation (r = 0.06) of iAUCGLU and the inverse correlation of dAUCGLU (r = −0.59) with the first-phase insulin response from DPT-1 were consistent with the independent and dependent designations of the glucose fractions. Correlations of AUC C-peptide were inverse with dAUCGLU and positive with iAUCGLU (TNPTP: r = −0.72, r = 0.57; DPT-1: r = −0.56, r = 0.60). The explained variance of AUC C-peptide increased markedly after separating AUC glucose into its fractions (from 4% to 85% in TNPTP; from 1% to 67% in DPT-1). The independent fraction contributed more to the increased glycemia of impaired glucose tolerance (IGT) than did the dependent fraction. Both dAUCGLU and iAUCGLU predicted IGT and type 1 diabetes (T1D) (P < 0.0001 for all). However, whereas dAUCGLU was more predictive of T1D (chi-square: 849 vs. 249), iAUCGLU was more predictive of IGT (chi-square: 451 vs. 176). Conclusions: A glucose fraction independent of insulin secretion was identified that was appreciable in autoantibody-positive individuals. It provides insight into the relation between glucose and C-peptide, contributes substantially to the glycemia of IGT, and predicts both T1D and IGT, particularly the latter.