Insulinotropic effect of endogenous incretins is greater after gastric bypass than sleeve gastrectomy despite diminished beta-cell sensitivity to plasma incretins
Authors: Salehi Marzieh , Peterson Richard , Tripathy Devjit , Pezzica Samantha , DeFronzo Ralph , Gastaldelli Amalia 
Published: March 2023

AbstractBackground/AimsPrandial hyperinsulinemia after Roux-en Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, β-cell sensitivity toexogenousincretin is markedly reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and β-cell response to increasing concentrations ofendogenousincretins.MethodsGlucose kinetics, insulin secretion rate (ISR), and incretin responses to 50-gram oral glucose ingestion were compared between 10 non-diabetic subjects with GB versus 9 matched individuals with SG and 7 non-operated normal glucose tolerant controls (CN) on two days with and without administration of 200 mg sitagliptin.ResultsFasting glucose and hormonal levels were similar among 3 groups. Increasing plasma concentrations of endogenous incretins by 2-3-fold diminished post-OGTT glycemia and increased β-cell secretion in all 3 groups (p<0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p<0.05 for interaction). As a result, sitagliptin administration led to hypoglycemia in 3 of 10 GB. Yet, plot of the slope of ISR versus the increase in endogenous incretin concentration was smaller after GB compared to both SG and CN.ConclusionAugmented glycemic-induced β-cell response caused by enhanced incretin activity is unique to GB and not shared with SG. However, the β-cell sensitivity to increasing concentrations ofendogenousincretin is smaller after bariatric surgery, particularly after GB, compared to non-operated controls, indicating a long-term adaptation of gut-pancreas axis after these procedures.HIGHLIGHTSWhat is known?Glycemic effects of gastric bypass (GB) and sleeve gastrectomy (SG) is attributed to rapid nutrient flux and enhanced insulinotropic effects of gut hormones but β-cell sensitivity toexogenousGLP-1 or GIP is diminished after GB.What the present findings add?Post-OGTT β-cell sensitivity to enhancedendogenousincretins by DPP4i is markedly reduced in bariatric subjects versus non-operated controls, and yet insulin secretory response (disposition index) is increased leading to hypoglycemia in GB and not SG.Significance?Blunted sensitivity to GLP-1 may represent β-cell adaptation to massive elevation in GLP-1 secretion following bariatric surgery to protect against hypoglycemia.The differential effect of enhanced concentrations of incretins on post-OGTT insulin response (disposition index) among GB versus SG highlights a distinct adaptive process among the two procedures.Augmented insulinotropic effects of gut hormones on postprandial insulin secretory response after GB despite a reduced beta-cell sensitivity to plasma concentrations of GLP-1 makes a case for non-hormonal mechanisms of GLP-1 action after GB.Better understanding of long-term effects of bariatric surgery on gut-pancreas axis activity is critical in development of GLP-1-based strategies to address glucose abnormalities (both hyperglycemia and hypoglycemia) in these settings.