title: Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes.
abstract: Glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) is a remedy for type 2 diabetes mellitus (T2DM). Ex-4 ameliorates cardiac dysfunction induced by myocardial infarction in preclinical and clinical settings. However, it remains unclear whether Ex-4 may modulate diabetic cardiomyopathy. We tested the impact of Ex-4 on two types of diabetic cardiomyopathy models, genetic (KK) and acquired T2DM induced by high-fat diet [diet-induced obesity (DIO)], to clarify whether Ex-4 may combat independently of etiology. Each type of mice was divided into Ex-4 (24 nmol·kg(-1)·day(-1) for 40 days; KK-ex4 and DIO-ex4) and vehicle (KK-v and DIO-v) groups. Ex-4 ameliorated systemic and cardiac insulin resistance and dyslipidemia in both T2DM models. T2DM mice exhibited systolic (DIO-v) and diastolic (DIO-v and KK-v) left ventricular dysfunctions, which were restored by Ex-4 with reduction in left ventricular hypertrophy. DIO-v and KK-v exhibited increased myocardial fibrosis and steatosis (lipid accumulation), in which were observed cardiac mitochondrial remodeling and enhanced mitochondrial oxidative damage. Ex-4 treatment reversed these cardiac remodeling and oxidative stress. Cytokine array revealed that Ex-4-sensitive inflammatory cytokines were ICAM-1 and macrophage colony-stimulating factor. Ex-4 ameliorated myocardial oxidative stress via suppression of NADPH oxidase 4 with concomitant elevation of antioxidants (SOD-1 and glutathione peroxidase). In conclusion, GLP-1R agonism reverses cardiac remodeling and dysfunction observed in T2DM via normalizing imbalance of lipid metabolism and related inflammation/oxidative stress.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Monji
authors.forename: Toko
authors.initials: T
authors.lastname: Mitsui
authors.forename: Yasuko K
authors.initials: YK
authors.lastname: Bando
authors.forename: Morihiko
authors.initials: M
authors.lastname: Aoyama
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Shigeta
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy; D015150:Echocardiography, Doppler; D000077270:Exenatide; D005355:Fibrosis; D000067757:Glucagon-Like Peptide-1 Receptor; D005979:Glutathione Peroxidase / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D055104:Infusions, Subcutaneous; D007333:Insulin Resistance; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013997:Time Factors; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; C090509:Icam1 protein, mouse; D018836:Inflammation Mediators; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D018799:Intercellular Adhesion Molecule-1; D016173:Macrophage Colony-Stimulating Factor; D000077270:Exenatide; D005979:Glutathione Peroxidase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: diabetes mellitus; glucagon-like peptide-1; insulin resistance; mitochondria; oxidative stress