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

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

Author information

1
L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
2
Endocrinologie, CHU Caen, Caen, France.
3
EA 4650, UNICAEN, GIP Cyceron, Caen, France.
4
Universite Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
5
L'Institut du Thorax, INSERM, CNRS, Université de Nantes, CHU Nantes, Nantes, France.
6
L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France xavier.prieur@univ-nantes.fr.

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.

PMID:
28052965
DOI:
10.2337/db16-0733
[Indexed for MEDLINE]
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