GLP-1 enhances beta-cell response to protein ingestion and bariatric surgery amplifies it

BackgroundThe glycemic-independent actions of glucagon-like peptide 1 (GLP-1) in the prandial state in humans are largely unknown. Protein ingestion stimulates beta-cell secretion without changing plasma glucose concentration. We examined the contribution of endogenous GLP-1 to glucose metabolism and beta-cell response to protein ingestion under basal glucose concentrations, and whether these responses are affected by rerouted gut after gastric bypass (GB) or sleeve gastrectomy (SG). MethodsInsulin secretion rate (ISR) and glucose fluxes during a 50-gram oral protein load were compared between 10 non-diabetic individuals with GB, 9 matched subjects with SG and 7 non-operated controls (CN) with and without intravenous infusion of exendin-(9-39) [Ex-9], a specific GLP-1 receptor (GLP-1R) antagonist. ResultsBlocking GLP-1R increased plasma glucose concentration before and after protein ingestion and decreased beta-cell sensitivity to glucose in the first 30 minutes of protein ingestion (p<0.05) in all 3 groups. However, reduction in the premeal ISR by Ex-9 infusion only was observed in CN (p<0.05 for interaction), whereas diminished prandial ISR3h by GLP-1R blockade was observed in GB and SG and not in controls (p<0.05 for interaction). Also, GLP-1R blockade enhanced post-protein insulin action in GB and SG, but not in CN. Endogenous glucose production (EGP) during the first hour after protein ingestion was increased in all 3 groups but EGP3h was accentuated by Ex-9 infusion only in GB (p<0.05 for interaction). ConclusionThese findings are consistent with both a glucose-independent pancreatic and extra-pancreatic role for GLP-1 during protein ingestion in humans that are exaggerated by bariatric surgery. Trial registrationThis study was registered at Clinical Trials.Gov: NCT02823665