The Pathological Evolution of Glucose Response Curves During the Progression to Type 1 Diabetes in the TrialNet Pathway to Prevention Study

Abstract

Objective: Glucose response curves (GRCs) during oral glucose tolerance tests (OGTTs) are predictive of type 1 diabetes. We performed a longitudinal analysis in pancreatic autoantibody-positive individuals to assess 1) characteristic GRC changes during progression to type 1 diabetes and 2) GRC changes in relation to β-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes.

Research design and methods: Among antibody-positive individuals with serial OGTTs in the TrialNet Pathway to Prevention study, GRC changes from first to last OGTTs were compared between progressors (n = 298) to type 1 diabetes and nonprogressors (n = 2,216). GRC changes from last OGTT before diagnosis to diagnostic OGTTs were studied in progressors.

Results: GRCs changed more frequently from biphasic (two peaks) to monophasic (one peak) GRCs between first and last OGTTs in progressors than in nonprogressors (75.4% vs. 51.0%, respectively; P < 0.001). In contrast, GRCs of progressors changed less frequently from monophasic to biphasic than those of nonprogressors (12.6% vs. 30.6%; P < 0.001). Monotonic (continuous increase) GRCs were present in 47.7% of progressors at diagnosis. The early (30-0 min) C-peptide response decreased in progressors with GRCs changing from biphasic to monophasic between first and last OGTTs (P < 0.001) and from monophasic to monotonic between last and diagnostic OGTTs (P < 0.001). Conversely, the early C-peptide response increased among nonprogressors with GRCs changing from monophasic to biphasic (P < 0.001). Changes in GRCs were related to changes in GCRCs.

Conclusions: Characteristic GRC changes, biphasic to monophasic to monotonic, occur during the progression to type 1 diabetes. These GRC changes correspond to decreasing β-cell function.

Figure 1

Change in GRC shape over time from first to last OGTT among progressors and nonprogressors. Progressors (change from first to last, n = 298): P = 0.043. Nonprogressors (change from first to last, n = 2,216): P < 0.001.

Figure 2

Change in GRC shapes, among progressors who had a diagnostic OGTT for comparison (n = 153), from first to last OGTT and from last OGTT prior to diagnosis to diagnostic OGTT (Dx OGTT). P value <0.001 for the difference in distribution of the GRC shape at each time point.

Figure 3

Two-dimensional grids (glucose on the y-axis and C-peptide on the x-axis) showing the GCRCs from 30 to 120 min and their centroid comparisons (comparison of the central location for each plot) for nonprogressors with GRCs that changed from monophasic to biphasic from first to last OGTT (A), progressors with GRCs that changed from monophasic to monotonic from last to diagnostic OGTTs (B), and progressors with GRCs that remained monophasic from last to diagnostic OGTTs (C). Arrows in each panel point to the change in location of the centroid locations on the grid. *Mean values for glucose and C-peptide at the different time points (30–120 min) during the OGTT.