Exenatide Protects Against Glucose- and Lipid-Induced Endothelial Dysfunction: Evidence for Direct Vasodilation Effect of GLP-1 Receptor Agonists in Humans.

Published

Journal Article

GLP-1 receptor (GLP-1R) agonists may improve endothelial function (EF) via metabolic improvement and direct vascular action. The current study determined the effect of GLP-1R agonist exenatide on postprandial EF in type 2 diabetes and the mechanisms underlying GLP-1R agonist-mediated vasodilation. Two crossover studies were conducted: 36 participants with type 2 diabetes received subcutaneous exenatide or placebo for 11 days and EF, and glucose and lipid responses to breakfast and lunch were determined; and 32 participants with impaired glucose tolerance (IGT) or diet-controlled type 2 diabetes had EF measured before and after intravenous exenatide, with or without the GLP-1R antagonist exendin-9. Mechanisms of GLP-1R agonist action were studied ex vivo on human subcutaneous adipose tissue arterioles and endothelial cells. Subcutaneous exenatide increased postprandial EF independent of reductions in plasma glucose and triglycerides. Intravenous exenatide increased fasting EF, and exendin-9 abolished this effect. Exenatide elicited eNOS activation and NO production in endothelial cells, and induced dose-dependent vasorelaxation and reduced high-glucose or lipid-induced endothelial dysfunction in arterioles ex vivo. These effects were reduced with AMPK inhibition. In conclusion, exenatide augmented postprandial EF in subjects with diabetes and prevented high-glucose and lipid-induced endothelial dysfunction in human arterioles. These effects were largely direct, via GLP-1R and AMPK activation.

Full Text

Duke Authors

Cited Authors

  • Koska, J; Sands, M; Burciu, C; D'Souza, KM; Raravikar, K; Liu, J; Truran, S; Franco, DA; Schwartz, EA; Schwenke, DC; D'Alessio, D; Migrino, RQ; Reaven, PD

Published Date

  • July 2015

Published In

Volume / Issue

  • 64 / 7

Start / End Page

  • 2624 - 2635

PubMed ID

  • 25720388

Pubmed Central ID

  • 25720388

Electronic International Standard Serial Number (EISSN)

  • 1939-327X

Digital Object Identifier (DOI)

  • 10.2337/db14-0976

Language

  • eng

Conference Location

  • United States