Inhibition of carbohydrate-mediated glucagon-like peptide-l (7-36)amide secretion by circulating non-esterified fatty acids

Two studies were performed to assess the entero-insular axis in simple obes ity and the possible effect of variations in the level of circulating non-e sterified fatty acids (NEFA) on one of the components of the entero-insular axis, glucagon-like peptide-1 [(7-36) amide]. In the fi rst study, we comp ared the entero-pancreatic hormone response to oral carbohydrate in obese a nd lean women. Obese subjects demonstrated hyperinsulinaemia and impaired g lucose tolerance but this was not associated with an increased secretion of either glucose-dependent insulinotropic polypeptide or glucagon-like pepti de-1 (GLP-1). These findings therefore provide no support for the hypothesi s that overactivity of the entero-insular axis contributes to the hyperinsu linaemia seen in obesity. Indeed, the plasma GLP-1 response to carbohydrate was markedly attenuated in obese subjects, confirming previous observation s. In the second study, in which carbohydrate-stimulated CLP-1 responses we re again evaluated in obese and lean women, circulating NEFA levels were mo dulated using either heparin (to increase serum NEFA) or acipimox (to reduc e serum NEFA). Treatment with acipimox resulted in complete suppression of NEFA levels and in a markedly higher GLP-1 response than the response to ca rbohydrate alone or to carbohydrate plus heparin. We suggest that higher fa sting and postprandial NEFA levels in obesity may tonically inhibit nutrien t-mediated GLP-1 secretion, and that this results in attenuation of the CLP -1 response to carbohydrate. However, although serum NEFA levels post-acipi mox were similarly suppressed in both lean and obese subjects, the GLP-1 re sponse was again significantly lower in obese subjects, suggesting the poss ibility of an intrinsic defect of GLP-1 secretion in obesity. The reduction of GLP-1 levels in obesity may be important both in relation to its insuli notropic effect and to its postulated role as a satiety factor.