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

Am J Physiol Heart Circ Physiol. 2013 Aug 1;305(3):H295-304. doi: 10.1152/ajpheart.00990.2012. Epub 2013 May 24.

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.

Keywords: diabetes mellitus; glucagon-like peptide-1; insulin resistance; mitochondria; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetic Cardiomyopathies / blood
  • Diabetic Cardiomyopathies / diagnostic imaging
  • Diabetic Cardiomyopathies / drug therapy*
  • Diabetic Cardiomyopathies / physiopathology
  • Diet, High-Fat
  • Disease Models, Animal
  • Dyslipidemias / blood
  • Dyslipidemias / drug therapy
  • Echocardiography, Doppler
  • Exenatide
  • Fibrosis
  • Glucagon-Like Peptide-1 Receptor
  • Glutathione Peroxidase / metabolism
  • Hypertrophy, Left Ventricular / blood
  • Hypertrophy, Left Ventricular / drug therapy
  • Hypertrophy, Left Ventricular / physiopathology
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacology*
  • Inflammation Mediators / metabolism
  • Infusions, Subcutaneous
  • Insulin Resistance
  • Intercellular Adhesion Molecule-1 / metabolism
  • Lipid Metabolism / drug effects*
  • Macrophage Colony-Stimulating Factor / metabolism
  • Male
  • Mice
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / pathology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • NADPH Oxidase 4
  • NADPH Oxidases / metabolism
  • Oxidative Stress / drug effects*
  • Peptides / administration & dosage
  • Peptides / pharmacology*
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / metabolism
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Time Factors
  • Venoms / administration & dosage
  • Venoms / pharmacology*
  • Ventricular Dysfunction, Left / blood
  • Ventricular Dysfunction, Left / drug therapy
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Function, Left / drug effects
  • Ventricular Remodeling / drug effects*

Substances

  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Icam1 protein, mouse
  • Inflammation Mediators
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Intercellular Adhesion Molecule-1
  • Macrophage Colony-Stimulating Factor
  • Exenatide
  • Glutathione Peroxidase
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse