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      Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes.

      American Journal of Physiology - Heart and Circulatory Physiology

      Animals, Diabetes Mellitus, Type 2, blood, drug therapy, genetics, Diabetic Cardiomyopathies, physiopathology, ultrasonography, Diet, High-Fat, Disease Models, Animal, Dyslipidemias, Echocardiography, Doppler, Fibrosis, Glutathione Peroxidase, metabolism, Hypertrophy, Left Ventricular, Hypoglycemic Agents, administration & dosage, pharmacology, Inflammation Mediators, Infusions, Subcutaneous, Insulin Resistance, Intercellular Adhesion Molecule-1, Lipid Metabolism, drug effects, Macrophage Colony-Stimulating Factor, Male, Mice, Mitochondria, Heart, pathology, Myocardium, NADPH Oxidase, Oxidative Stress, Peptides, Receptors, Glucagon, agonists, Superoxide Dismutase, Time Factors, Venoms, Ventricular Dysfunction, Left, Ventricular Function, Left, Ventricular Remodeling

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          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.

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