title: Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner.
abstract: Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9-39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9-39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Rui
authors.initials: R
authors.lastname: Wei
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Jing
authors.initials: J
authors.lastname: Ke
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Peking University Third Hospital, Beijing, China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Cardiology, Peking University Third Hospital, Beijing, China.
authors.forename: Xinheng
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Guang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism and tpho66@bjmu.edu.cn.
authors.forename: Tianpei
authors.initials: T
authors.lastname: Hong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000328:Adult; D002316:Cardiotonic Agents / Q000008:administration & dosage; D003925:Diabetic Angiopathies / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D000077270:Exenatide; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000097:blood*; D052250:Nitric Oxide Synthase Type III / Q000097:blood; D051058:Oncogene Protein v-akt / Q000097:blood; D010455:Peptides / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D014688:Venoms / Q000008:administration & dosage*
chemical_list: D002316:Cardiotonic Agents; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; coronary flow velocity reserve; endothelial nitric oxide synthase; exenatide; glucagon-like peptide-1; human umbilical vein endothelial cells; type 2 diabetes mellitus