title: Exenatide sensitizes insulin-mediated whole-body glucose disposal and promotes uptake of exogenous glucose by the liver.
abstract: OBJECTIVE
  Recent progress suggests that exenatide, a mimetic of glucagon-like peptide-1 (GLP-1), might lower glycemia independent of increased beta-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.
  
  
  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 microg) 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 approximately 30%, as indicated by portal glucose infusion rate (saline 15.9 +/- 1.6 vs. exenatide 20.4 +/- 2.1 mg x kg(-1) x min(-1), P < 0.001), resulting from increased whole-body glucose disposal (R(d), approximately 20%) and increased net hepatic uptake of exogenous glucose ( approximately 80%). Reducing systemic hyperglycemia to euglycemia, exenatide still increased total glucose turnover by approximately 20% (saline 13.2 +/- 1.9 vs. exenatide 15.6 +/- 2.1 mg x kg(-1) x 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 x kg(-1) x 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.
authors.affiliation: Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Zheng
authors.forename: Viorica
authors.initials: V
authors.lastname: Ionut
authors.forename: Vahe
authors.initials: V
authors.lastname: Mooradian
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovski
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004285:Dogs; D000077270:Exenatide; D005947:Glucose / Q000378:metabolism* / Q000493:pharmacokinetics; D006943:Hyperglycemia / Q000378:metabolism / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010455:Peptides / Q000494:pharmacology*; D014688:Venoms / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D005947:Glucose