Abnormal glucagon secretion contributes to a longitudinal decline in glucose tolerance
Sneha Mohan, Hannah E Christie, Marcello C Laurenti, Aoife M Egan, Kent R Bailey, Claudio Cobelli, Chiara Dalla Man, Adrian VellaAbstract
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.