Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients.

Abstract

Objective: To quantitate the separate impact of obesity and hyperlycemia on the incretin effect, i.e. the gain in β-cell function after oral glucose vs intravenous glucose.

Research Design and Methods: Isoglycemic oral (75 g) and IV glucose administration was performed in 51 subjects (24 NGT, 17 IGT and 10 type 2 DM), with a wide range of BMI (20-61 kg^.m⁻²). C-peptide deconvolution was used to reconstruct insulin secretion rates, and β-cell glucose sensitivity (=slope of the insulin secretion/glucose concentration dose-response curve) was determined by mathematical modeling. The incretin effect was defined as the oral/IV ratio of responses. In 8 NGT and 10 DM, oral glucose appearance was measured by the double-tracer technique.

Results: The incretin effect on total insulin secretion and β-cell glucose sensitivity, and the GLP-1 response to oral glucose were significantly reduced in DM compared to NGT or IGT (p≤0.05). The results were similar when subjects were stratified by BMI tertile (p≤0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (=2-hour plasma glucose levels) and BMI (partial r =0.27-0.59, p≤0.05) in an independent, additive manner. Oral glucose appearance did not differ between DM and NGT, and was positively related to the GLP-1 response (r=0.53, p<0.01). Glucagon suppression during the OGTT was blunted in DM patients.

Conclusions: Potentiation of insulin secretion, glucose sensing, GLP-1 release, and glucagon suppression are physiological manifestations of the incretin effect. The incretin effect is impaired as an independent function of both glucose tolerance and obesity.