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