Exenatide Sensitizes Insulin-Mediated Whole-Body Glucose Disposal and Promotes Uptake of Exogenous Glucose by the Liver

OBJECTIVE— Recent progress suggests that exenatide, a mimetic of glucagon-like peptide-1 (GLP-1), might lower glycemia independent of increased β-cell response or reduced gastrointestinal motility. We aimed to investigate whether exenatide stimulates glucose turnover directly in insulin-responsive tissues dependent or independent of insulinemia. RESEARCH DESIGN AND METHODS— An intraportal glucose infusion clamp was used in dogs to measure glucose turnover to encompass potent activation of the putative glucose/GLP-1 sensor in the porto-hepatic circulation with exenatide. The modified glucose clamp was performed in the presence of postprandial hyperinsulinemia and hyperglycemia with exenatide (20 μg) or saline injected at 0 min. Furthermore, the role of hyperglycemia versus hyperinsulinemia in exenatide-mediated glucose disposal was studied. RESULTS— With hyperinsulinemia and hyperglycemia, exenatide produced a significant increase in total glucose turnover by ∼30%, as indicated by portal glucose infusion rate (saline 15.9 ± 1.6 vs. exenatide 20.4 ± 2.1 mg · kg(−1) · min(−1), P < 0.001), resulting from increased whole-body glucose disposal (R(d), ∼20%) and increased net hepatic uptake of exogenous glucose (∼80%). Reducing systemic hyperglycemia to euglycemia, exenatide still increased total glucose turnover by ∼20% (saline 13.2 ± 1.9 vs. exenatide 15.6 ± 2.1 mg · kg(−1) · min(−1), P < 0.05) in the presence of hyperinsulinemia, accompanied by smaller increments in R(d) (12%) and net hepatic uptake of exogenous glucose (45%). In contrast, reducing hyperinsulinemia to basal levels, exenatide-increased total glucose turnover was completely abolished despite hyperglycemia (saline 2.9 ± 0.6 vs. exenatide 2.3 ± 0.3 mg · kg(−1) · min(−1), P = 0.29). CONCLUSIONS— Exenatide directly stimulates glucose turnover by enhancing insulin-mediated whole-body glucose disposal and increasing hepatic uptake of exogenous glucose, contributing to its overall action to lower postprandial glucose excursions.