Increased prandial GLP-1-induced insulin secretion after gastric bypass (GB), especially in those with late-complication of hypoglycemia, is well characterized. We previously reported that meal ingestion increases insulin and GLP-1 secretion during a sub-basal glycemic clamp in individuals after GB. Here, we investigated whether altered meal-stimulated β-cell output in this setting is due to the enhanced glucose-independent actions of GLP-1 using a potent GLP-1 receptor (GLP-1R) antagonist, exendin-(9-39) (Ex-9). Nine subjects with history of GB, 6 with prior sleeve gastrectomy (SG), and 4 non-operated healthy subjects were studied twice with and without Ex-9 infusion during a 5-hr hyperinsulinemic (120mU/m2/min) hypoglycemic (55mg/dl) clamp. The GB, SG, and CN groups were matched for BMI, FFM, A1c, and age; and the GB and SG for weight loss and time postsurgery; none had diabetes. Islet and gut hormones were measured before and after a liquid meal (280kcal, 20% glucose) at 2 hr of clamp studies. Fasting levels of glucose, islet and GI hormones were similar between 2 studies and among 3 groups. Insulin sensitivity (M/I) didn’t differ among the groups but insulin clearance was larger in surgical patients (P=0.08). Blocking GLP-1R did not affect β-cell secretory response before or after meal ingestion whereas α-cell responses to hypoglycemia alone or to meal ingestion were increased during Ex-9 infusion (pre-meal: 18, 9, 47%, and post-meal: 42, 14, 13% in GB, SG, and CN, respectively, P<0.05). Prandial GIP was similar among 3 groups and not affected by Ex-9. GLP-1 response was larger in GB compared to SG and CN, and was further increased by Ex-9 (P<0.01). Our findings indicate that in nondiabetic subjects with prior history of GB and SG, endogenous GLP-1 contribution to prandial β-cell secretion is glucose-dependent. Glucagonostatic effect of endogenous GLP-1, on the other hand, is preserved during hypoglycemic condition after these surgeries.
H. Honka: None. A.M. Al Zubaidi: None. A. Gastaldelli: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk Inc. R.A. DeFronzo: None. M. Salehi: None.
Finnish Cultural Foundation (00180071); National Institutes of Health (DK105379)