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

Research output: Contribution to journalArticle

60 Citations (Scopus)

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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Vasodilation
Lipids
Arterioles
Type 2 Diabetes Mellitus
Glucose
AMP-Activated Protein Kinases
Endothelial Cells
Lunch
Glucose Intolerance
Breakfast
Subcutaneous Fat
exenatide
Cross-Over Studies
Blood Vessels
Glucagon-Like Peptide-1 Receptor
Fasting
Triglycerides
Placebos

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Exenatide protects against glucoseand lipid-induced endothelial dysfunction : Evidence for direct vasodilation effect of glp-1 receptor agonists in humans. / Koska, Juraj; Sands, Michelle; Burciu, Camelia; D'Souza, Karen M.; Raravikar, Kalyani; Liu, James; Truran, Seth; Franco, Daniel A.; Schwartz, Eric A.; Schwenke, Dawn C.; D'Alessio, David; Migrino, Raymond Q.; Reaven, Peter D.

In: Diabetes, Vol. 64, No. 7, 07.2015, p. 2624-2635.

Research output: Contribution to journalArticle

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 2015, 'Exenatide protects against glucoseand lipid-induced endothelial dysfunction: Evidence for direct vasodilation effect of glp-1 receptor agonists in humans', Diabetes, vol. 64, no. 7, pp. 2624-2635. https://doi.org/10.2337/db14-0976
Koska, Juraj ; Sands, Michelle ; Burciu, Camelia ; D'Souza, Karen M. ; Raravikar, Kalyani ; Liu, James ; Truran, Seth ; Franco, Daniel A. ; Schwartz, Eric A. ; Schwenke, Dawn C. ; D'Alessio, David ; Migrino, Raymond Q. ; Reaven, Peter D. / Exenatide protects against glucoseand lipid-induced endothelial dysfunction : Evidence for direct vasodilation effect of glp-1 receptor agonists in humans. In: Diabetes. 2015 ; Vol. 64, No. 7. pp. 2624-2635.
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AU - D'Souza, Karen M.

AU - Raravikar, Kalyani

AU - Liu, James

AU - Truran, Seth

AU - Franco, Daniel A.

AU - Schwartz, Eric A.

AU - Schwenke, Dawn C.

AU - D'Alessio, David

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