PSUN299 GLP-1 Contribution to Insulin Secretory Response to Protein Ingestion and Insulin Kinetics Following Gastric Bypass and Sleeve Gastrectomy

Rapid passage of ingested nutrients to the gut after Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG) results in hyperinsulinemia after glucose ingestion, in part due to an enhanced glucagon-like peptide-1 (GLP-1)-induced insulin secretory response (ISR) and reduced metabolic clearance rate of insulin (MCRI). The effect of endogenous GLP-1 on insulin kinetics is unknown, and so is GLP-1 contribution to insulin secretory response to non-glucose nutrient ingestion. In non-surgical subjects, protein ingestion enhances insulin secretion and reduces MCRI. We hypothesized that protein ingestion enhances GLP-1-induced ISR and alters MCRI in proportion to changes in nutrient influx after GB and SG. To test this hypothesis ISR, β-cell sensitivity to glucose (BGS), MCRI, and oral glucose insulin sensitivity (OGIS) were measured on 3 days during 50 g glucose ingestion as well as 50 g protein ingestion with and without GLP-1R antagonist, exendin (9-39) [Ex-9] infusion. Ten GB-treated subjects, 9 SG-treated, and 7 non-operated controls (CN) were enrolled. The 3 non-diabetic groups were matched for age, BMI, fat-free mass, HbA1c; surgical groups were matched for weight loss and time post-surgery. Fasting glucose, insulin, and ISR were similar among the 3 groups and among the 3 studies but fasting MCRI was greater in surgical groups than CN (p<0.05). Compared to glucose, protein ingestion led to larger BGS in 3 groups despite smaller overall ISR response (AUCISR3h) (p<0.05). Blocking GLP-1R during protein ingestion decreased AUCISR3h only in surgical subjects (p<0.05 for interaction), whereas BGS was reduced similarly in 3 groups during Ex-9 infusion (p<0.05). OGIS was smaller during protein than glucose ingestion in 3 groups (p<0.05). GLP-1R blockade did not affect insulin sensitivity. Following nutrient ingestion in parallel with increase in insulin secretion MCRI was reduced to nadir values at 40 minutes, but then gradually increased approaching premeal values at different pace among surgical and non-surgical subjects (p<0.05). The slope of MCRI: Insulin (0-40 min) was smaller after protein ingestion than glucose, and after protein with Ex-9 infusion than without in 3 groups (p<0.05). Blocking GLP-1R had no effect on MCRI values in the latter phase of protein ingestion when insulin secretion reduced approaching premeal values. There was no association between parameters of insulin sensitivity and insulin clearance during glucose or protein ingestion. Our findings indicate that the regulation of insulin secretion and clearance during protein ingestion is altered after GB and SG. Further, endogenous GLP-1 contribution to insulin secretory response to protein ingestion after GB and SG is enhanced, but GLP-1 effect on insulin kinetics is trivial. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.