215-LB: The Role of GLP-1 in Glycemic Response to Protein Ingestion after Gastric Bypass Surgery or Sleeve Gastrectomy

Abstract

Protein ingestion increases the plasma insulin and glucagon responses, but the enteral factors involved are entirely unknown. We hypothesized that glucagon-like peptide 1 (GLP-1) signaling regulates glucose metabolism after protein ingestion, and that this effect may be amplified after Roux-en Y gastric bypass (GB) and sleeve gastrectomy (SG). We examined the glucose and islet-cell secretory responses to 50 g protein ingestion with and without GLP-1 receptor antagonist, exendin-(9-39) [Ex-9], in 4 GB-treated subjects, 4 SG-treated, and 4 non-operated controls (CN). The groups were matched for age, BMI, fat-free mass, fasting glucose and insulin, and HbA1c. The surgical groups also were matched for weight loss and time post-surgery; none had diabetes. Protein ingestion resulted in an early rise in glycemia (AUCGlucose 1hr) in GB and SG compared to CN (p<0.05), whose glucose values remained at basal concentrations. Both β- and α-cell hormonal responses were enhanced by protein ingestion in all 3 groups. GLP-1 receptor blockade increased fasting and prandial glycemia in all 3 groups, but to a greater extent in GB (p<0.05, interaction). This glycemic effect of Ex-9 was associated with a ~25% reduction in prandial insulin secretion in GB and SG and ~25% increase in prandial insulin response in CN (p<0.05, interaction). The prandial glucagon responses were larger during studies with Ex-9 compared to those without (p<0.05). Blocking the GLP-1R increased prandial insulin clearance (p<0.05) in all groups, but to a much larger extent in surgical subjects (p=0.1, interaction). Our findings indicate that glucose metabolism after protein ingestion is altered after GB and SG. To our knowledge, this is the first report demonstrating that endogenous GLP-1 contributes to glucose and islet-cell secretory response to protein ingestion, and that GB and SG exaggerate GLP-1 contribution to insulin secretion and clearance after protein ingestion. Disclosure M. S. Rayas: Research Support; Self; National Center for Advancing Translational Sciences. H. Honka: None. R. A. Defronzo: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. A. Gastaldelli: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Consultant; Self; Eli Lilly and Company, Inventiva Pharma, Research Support; Self; Gilead Sciences, Inc., Speaker’s Bureau; Self; Novo Nordisk. M. Salehi: None. Funding National Institutes of Health (DK105379)