title: Exenatide Protects Against Glucose- and Lipid-Induced Endothelial Dysfunction: Evidence for Direct Vasodilation Effect of GLP-1 Receptor Agonists in Humans.
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 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.
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ juraj.koska@va.gov.
authors.forename: Juraj
authors.initials: J
authors.lastname: Koska
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sands
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: Camelia
authors.initials: C
authors.lastname: Burciu
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: Karen M
authors.initials: KM
authors.lastname: D'Souza
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Raravikar
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: James
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: Seth
authors.initials: S
authors.lastname: Truran
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Franco
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schwartz
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Schwenke
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Duke University, Durham, NC.
authors.forename: David
authors.initials: D
authors.lastname: D'Alessio
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: Raymond Q
authors.initials: RQ
authors.lastname: Migrino
authors.affiliation: Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Reaven
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D000077270:Exenatide; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000502:physiology; D014280:Triglycerides / Q000097:blood; D014664:Vasodilation / Q000187:drug effects*; D014688:Venoms / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014280:Triglycerides; D014688:Venoms; D000077270:Exenatide; D055372:AMP-Activated Protein Kinases