Exenatide protects against glucoseand lipid-induced endothelial dysfunction: Evidence for direct vasodilation effect of glp-1 receptor agonists in humans

Juraj Koska, Michelle Sands, Camelia Burciu, Karen M. D'Souza, Kalyani Raravikar, James Liu, Seth Truran, Daniel A. Franco, Eric A. Schwartz, Dawn C. Schwenke, David D'Alessio, Raymond Q. Migrino, Peter D. Reaven

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60 Scopus citations

Abstract

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 dietcontrolled 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.

Original languageEnglish (US)
Pages (from-to)2624-2635
Number of pages12
JournalDiabetes
Volume64
Issue number7
DOIs
StatePublished - Jul 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Koska, J., Sands, M., Burciu, C., D'Souza, K. M., Raravikar, K., Liu, J., Truran, S., Franco, D. A., Schwartz, E. A., Schwenke, D. C., D'Alessio, D., Migrino, R. Q., & Reaven, P. D. (2015). Exenatide protects against glucoseand lipid-induced endothelial dysfunction: Evidence for direct vasodilation effect of glp-1 receptor agonists in humans. Diabetes, 64(7), 2624-2635. https://doi.org/10.2337/db14-0976