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 ␤-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.

Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus

“…However, these data should be confirmed in patients well-matched for BMI because high BMI (present in these patients with NAFLD) is one of the strongest predictors of deficient GLP-1 secretion [78] . Finally, in another study, improved glucose control correlated with liver fat reduction in obese T2DM patients given GLP-1 receptor agonists exenatide or liraglutide for 6 months [60] .…”

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

“…This is in accordance with insulin resistance induced by dexamethasone in the present study. The insulin resistance, therefore, seems indirectly to be part of the explanation for the reduced incretin effect in the present study [6,7,10].…”

“…It is markedly reduced in type 2 diabetes [4,5], and is diminished in individuals with impaired glucose tolerance (IGT) [6] and obesity [7]. The reduced incretin effect found in type 2 diabetes is associated with a reduced insulinotropic effect of GLP-1 [8,9] and GIP [9].…”

Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion

“…Because of such interdependence, it is difficult to discriminate between the separate roles of obesity and glucose tolerance in the effect of incretins on beta cell function. Recently, however, some light has been shed on this topic, showing that obesity and glucose tolerance each attenuate the effect of incretin and the GLP1 response independently of one another [7].…”