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

Abstract

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 <i>1</i>) characteristic GRC changes during progression to type 1 diabetes and <i>2</i>) GRC changes in relation to β-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes. 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 (<i>n</i> = 298) to type 1 diabetes and nonprogressors (<i>n</i> = 2,216). GRC changes from last OGTT before diagnosis to diagnostic OGTTs were studied in progressors. 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; <i>P</i> < 0.001). In contrast, GRCs of progressors changed less frequently from monophasic to biphasic than those of nonprogressors (12.6% vs. 30.6%; <i>P</i> < 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 (<i>P</i> < 0.001) and from monophasic to monotonic between last and diagnostic OGTTs (<i>P</i> < 0.001). Conversely, the early C-peptide response increased among nonprogressors with GRCs changing from monophasic to biphasic (<i>P</i> < 0.001). Changes in GRCs were related to changes in GCRCs. 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.