OBJECTIVE-To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i.e., the gain in -cell function after oral glucose versus intravenous glucose). (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20 -61 kg/m 2 ). C-peptide deconvolution was used to reconstruct insulin secretion rates, and -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-tointravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique.
RESEARCH DESIGN AND METHODS-Isoglycemic oralRESULTS-The incretin effect on total insulin secretion and -cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P Յ 0.05). The results were similar when subjects were stratified by BMI tertile (P Յ 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r ϭ 0.27-0.59, P Յ 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r ϭ 0.53, P Ͻ 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients.CONCLUSIONS-Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another.