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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^sup -1^ . min^sup -1^, P < 0.001), resulting from increased whole-body glucose disposal (R^sub 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^sup -1^ . min^sup -1^, P < 0.05) in the presence of hyperinsulinemia, accompanied by smaller increments in R^sub 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^sup -1^ . min^sup -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. Diabetes 58:352-359, 2009
Exenatide is the synthetic form of exendin-4 and a long-acting mimetic of the incretin hormone glucagon-like peptide-1 (GLP-1) (1). Originally isolated from salivary secretions of the lizard Gila monster, exendin-4 shows a 53% amino acid sequence identity to GLP-1 (2) and shares many actions with GLP-1 via pancreatic GLP-1 receptor (3). Exenatide stimulates glucose-dependent insulin response (4-6), suppresses glucagon secretion (5), and inhibits gastrointestinal motility (7). Exenatide has also been implicated in regulating food intake (8) and ß-cell proliferation (9). Exenatide is resistant to digestion by dipeptidyl...