Effect of GLP-1 Receptor Antagonism or Incretin Enhancer on Ad-Libitum Energy Intake in Subjects with and without Bariatric Surgery

Introduction and Objective: Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG) promote a significant and durable weight loss. Rerouted gut after these procedures exaggerates prandial glucagon-like peptide-1 (GLP-1) secretion. Whether an augmented GLP-1 response to meal ingestion following GB or SG would change the food behavior remains unknown. We compared the acute effects of increased incretin concentrations or GLP-1R blockade on ad-libitum energy intake (AdLibEI) among 3 BMI- and age-matched non-diabetic obese cohorts of GB (n=7), SG (n=9), and non-operated controls (CN, n=7). Methods: Participants were studied with 3-h meal test on 4 separate days: (A) 50-gram glucose ingestion with (OGT+S) and without (OGT) 200 mg sitagliptin (S) taken orally 2-h prior to OGT; (B) 50-gram whey protein ingestion with (OPT+Ex9) and without intravenous infusion of GLP-1R antagonist (exendin-(9-39) [Ex9], 750 pm/kg/min). After the 3-h meal studies, AdLibEI of a mixed-meal lunch (1736 kcal, 52% carbohydrate, 13% protein, 35% fat) and perception of appetite were measured. Results: As expected, AdLibEI was significantly lower in GB or SG compared to CN (p=0.001). Among 3 groups, post-OGT AdLibEI was reduced only in CN by sitagliptin (p=0.05 for interaction, ANOVA), due to a reduction in AdLib protein. Similarly, post-OPT AdLibEI tended to be lower in CN by prior Ex9 infusion but not in GB or SG (p=0.06), due to a diminished AdLib carbohydrate intake. While sitagliptin administration did not change the appetite scores among 3 cohorts, Ex9 infusion reduced desire to eat in CN but not in surgical subjects (p=0.014). Conclusion: These data indicate that, in the current model, enhancing or blocking endogenous GLP-1R signal has an acute affect on food intake in humans with intact gastrointestinal system. Unaffected energy intake by GLP-1R manipulation in GB and SG subjects, however, undermines a significant role for GLP-1 in mediating surgical-induced weight loss. Disclosure: G. Della Pepa: None. S. Sabatini: None. A. Alamdari: None. A. Gastaldelli: Advisory Panel; Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim, Novo Nordisk, Merck Sharp & Dohme Corp, Regeneron Pharmaceuticals. Other Relationship; Pfizer Inc, Madrigal Pharmaceuticals, Inc, Echosens, Eli Lilly and Company. Speaker's Bureau; Merck Sharp & Dohme Corp, Eli Lilly and Company, Novo Nordisk. M. Salehi: Advisory Panel; Vognex, Amylyx.