The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model

Diabetes. 2017 Apr;66(4):1030-1040. doi: 10.2337/db16-0733. Epub 2017 Jan 4.

Abstract

Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for heart failure. T2DM is associated with altered cardiac energy metabolism, leading to ectopic lipid accumulation and glucose overload, the exact contribution of these two parameters remaining unclear. To provide new insight into the mechanism driving the development of diabetic cardiomyopathy, we studied a unique model of T2DM: lipodystrophic Bscl2-/- (seipin knockout [SKO]) mice. Echocardiography and cardiac magnetic resonance imaging revealed hypertrophic cardiomyopathy with left ventricular dysfunction in SKO mice, and these two abnormalities were strongly correlated with hyperglycemia. Surprisingly, neither intramyocardial lipid accumulation nor lipotoxic hallmarks were detected in SKO mice. [18F]Fludeoxyglucose positron emission tomography showed increased myocardial glucose uptake. Consistently, the O-GlcNAcylated protein levels were markedly increased in an SKO heart, suggesting a glucose overload. To test this hypothesis, we treated SKO mice with the hypoglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin and the insulin sensitizer pioglitazone. Both treatments reduced the O-GlcNAcylated protein levels in SKO mice, and dapagliflozin successfully prevented the development of hypertrophic cardiomyopathy. Our data demonstrate that glucotoxicity by itself can trigger cardiac dysfunction and that a glucose-lowering agent can correct it. This result will contribute to better understanding of the potential cardiovascular benefits of SGLT2 inhibitors.

MeSH terms

  • Animals
  • Benzhydryl Compounds / pharmacology*
  • Benzhydryl Compounds / therapeutic use
  • Blood Glucose / metabolism
  • Cardiomyopathy, Hypertrophic
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetic Cardiomyopathies*
  • Disease Models, Animal
  • Echocardiography
  • Fluorodeoxyglucose F18
  • GTP-Binding Protein gamma Subunits
  • Glucosides / pharmacology*
  • Glucosides / therapeutic use
  • Heart / diagnostic imaging
  • Heart / drug effects*
  • Heterotrimeric GTP-Binding Proteins / genetics
  • Hyperglycemia
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Lipodystrophy* / genetics
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Knockout
  • Myocardium / metabolism
  • Pioglitazone
  • Positron-Emission Tomography
  • Radiopharmaceuticals
  • Sodium-Glucose Transporter 2 Inhibitors
  • Thiazolidinediones / pharmacology*
  • Ventricular Dysfunction, Left
  • Ventricular Function / drug effects*

Substances

  • 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
  • Benzhydryl Compounds
  • Blood Glucose
  • Bscl2 protein, mouse
  • GTP-Binding Protein gamma Subunits
  • Glucosides
  • Hypoglycemic Agents
  • Radiopharmaceuticals
  • Sodium-Glucose Transporter 2 Inhibitors
  • Thiazolidinediones
  • Fluorodeoxyglucose F18
  • Heterotrimeric GTP-Binding Proteins
  • Pioglitazone