Abstract

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-glucose clamp” was utilized in dogs to measure glucose turnover so as 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 (EX, 20μg) or saline (SAL) injected at 0 min. Furthermore, the role of hyperglycemia vs. 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 (SAL 15.9±1.6 vs. EX 20.4±2.1 mg·kg⁻¹·min⁻¹, P<0.001), resulting from increased whole-body glucose disposal (Rd, ∼20%) and increased net hepatic uptake of exogenous glucose (∼80%). Reducing systemic hyperglycemia to euglycemia, exenatide still increased total glucose turnover by ∼20% (SAL 13.2±1.9 vs. EX 15.6±2.1 mg·kg⁻¹·min¹, P<0.05) in the presence of hyperinsulinemia, accompanied by smaller increments in Rd (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 (SAL 2.9±0.6 vs. EX 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.