Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs

Abstract

IntroductionThe insulinotropic capacity of exogenous glucagon like peptide-1 (GLP-1) is reduced in type 2 diabetes and the insulin-resistant obese. We have tested the hypothesis that this response is the consequence of a reduced pancreatic GLP-1 receptor (GLP-1r) density in insulin-resistant obese animals.Research design and methodsGLP-1r density was measured in lean and insulin-resistant adult miniature pigs after the administration of a 68Ga-labeled GLP-1r agonist. The effect of hyperinsulinemia on GLP-1r was assessed using sequential positron emission tomography (PET), both in the fasted state and during a clamp. The impact of tissue perfusion, which could account for changes in GLP-1r agonist uptake, was also investigated using 68Ga-DOTA imaging.ResultsGLP-1r binding potential in the obese pancreas was reduced by 75% compared with lean animals. Similar reductions were evident for fat tissue, but not for the duodenum. In the lean group, induced hyperinsulinemia reduced pancreatic GLP-1r density to a level comparable with that of the obese group. The reduction in blood to tissue transfer of the GLP-1r ligand paralleled that of tissue perfusion estimated using 68Ga-DOTA.ConclusionsThese observations establish that a reduction in abdominal tissue perfusion and a lower GLP-1r density account for the diminished insulinotropic effect of GLP-1 agonists in type 2 diabetes.

Vagally Mediated Gut-Brain Relationships in Appetite Control-Insights from Porcine Studies

“…Accordingly, in the pig, obesity-induced insulin resistance leads to functional portal denervation with marked suppression of vagal sensitivity to portal glucose. The latter appears to be the consequence of a reduction in the density of GLP-1r, as indicated by diminished GLP-1r binding potential in obese insulin-resistant animals [ 79 ]. The concept of a functional denervation at the portal level suggests that it might be possible to restore pharmacologically the portal glucose sensor in obese insulin-resistant patient through the expression of GLP-1r.…”