Exenatide Sensitizes Insulin-Mediated Whole-Body Glucose Disposal and Promotes Uptake of Exogenous Glucose by the Liver
Open Access
- 1 February 2009
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 58 (2), 352-359
- https://doi.org/10.2337/db08-0875
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 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 (Rd, ∼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 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 (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.Keywords
This publication has 53 references indexed in Scilit:
- Exenatide can reduce glucose independent of islet hormones or gastric emptyingAmerican Journal of Physiology-Endocrinology and Metabolism, 2008
- Marginal-Zone B-Cells of Nonobese Diabetic Mice Expand With Diabetes Onset, Invade the Pancreatic Lymph Nodes, and Present Autoantigen to Diabetogenic T-CellsDiabetes, 2008
- Intraportally delivered GLP-1, in the presence of hyperglycemia induced via peripheral glucose infusion, does not change whole body glucose utilizationAmerican Journal of Physiology-Endocrinology and Metabolism, 2008
- Intraportal GLP-1 infusion increases nonhepatic glucose utilization without changing pancreatic hormone levelsAmerican Journal of Physiology-Endocrinology and Metabolism, 2007
- Exogenously imposed postprandial-like rises in systemic glucose and GLP-1 do not produce an incretin effect, suggesting an indirect mechanism of GLP-1 actionAmerican Journal of Physiology-Endocrinology and Metabolism, 2006
- Rapid translocation of hepatic glucokinase in response to intraduodenal glucose infusion and changes in plasma glucose and insulin in conscious ratsAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
- Glucagon-Like Peptide-1 Augments Insulin-Mediated Glucose Uptake in the Obese StateJournal of Clinical Endocrinology & Metabolism, 2002
- Insulinotropic Hormone Glucagon-Like Peptide-1-(7-37) Appears Not to Augment Insulin-Mediated Glucose Uptake in Young Men during EuglycemiaJournal of Clinical Endocrinology & Metabolism, 1998
- Evidence for decreased splanchnic glucose uptake after oral glucose administration in non-insulin-dependent diabetes mellitus.JCI Insight, 1997
- Transendothelial insulin transport is not saturable in vivo. No evidence for a receptor-mediated process.JCI Insight, 1996