Abnormal glucagon secretion contributes to a longitudinal decline in glucose tolerance.

Abstract

Context: Defects in insulin secretion and action contribute to the progression of prediabetes to diabetes. However, the contribution of α-cell dysfunction to this process has been unclear.

Objective: Understand the relative contributions of α-cell and β-cell dysfunction to declining glucose tolerance.

Design: Longitudinal, community-based observational study.

Setting: Clinical Research Unit at an Academic Medical Center.

Patients/participants: We studied 96 subjects without diabetes (55 ± 1 years; BMI 27.7 ± 0.4 Kg/M2) on 2 occasions, 3 years apart using an oral 75g glucose challenge. Indices for insulin secretion and action were estimated using the oral minimal model. Glucagon secretion rate (GSR) was estimated by deconvolution from peripheral glucagon concentrations.

Intervention: This was an observational study.

Main outcome measure: Glucose tolerance status (categorical variable) and then symmetrical percent change in peak and 120-minute glucose (post-OGTT) concentrations (continuous variables).

Results: 32 subjects progressed from normal to Impaired Glucose Tolerance (IGT) or from IGT to type 2 diabetes. Disposition Index (DI) declined in the progressors (568±98 vs. 403±65 10-4 dl/kg/min per μU/ml, baseline vs. 3-years p=0.04). α-cell suppression by glucose (δGSR/δglucose) did not change in the non-progressors (1.5±0.1 vs. 1.3±0.1 nmol/min/L, p=0.37) but decreased (1.0±0.2 vs. 0.8±0.2 nmol/min/L, p<0.01) in those who progressed. Analysis of the entire cohort showed that DI and δGSR/δglucose were independently and inversely correlated with an increase in glycemic excursion.

Conclusions: These data show that α-cell dysfunction accompanies a decline in β-cell function as IGT or overt type 2 diabetes develops.