title: The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model.
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: lipodystrophicBscl2-/-(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, theO-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 theO-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.
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.|Endocrinologie, CHU Caen, Caen, France.|EA 4650, UNICAEN, GIP Cyceron, Caen, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Joubert
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Jagu
authors.affiliation: Universite Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Montaigne
authors.affiliation: Universite Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Marechal
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
authors.forename: Angela
authors.initials: A
authors.lastname: Tesse
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Ayer
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Dollet
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Le May
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Toumaniantz
authors.affiliation: EA 4650, UNICAEN, GIP Cyceron, Caen, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Manrique
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
authors.forename: Flavien
authors.initials: F
authors.lastname: Charpentier
authors.affiliation: Universite Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Magré
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, CHU Nantes, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
authors.affiliation: L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France xavier.prieur@univ-nantes.fr.
authors.forename: Xavier
authors.initials: X
authors.lastname: Prieur
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D058065:Diabetic Cardiomyopathies; D004195:Disease Models, Animal; D004452:Echocardiography; D019788:Fluorodeoxyglucose F18; D044388:GTP-Binding Protein gamma Subunits; D005960:Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects*; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006943:Hyperglycemia; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008060:Lipodystrophy / Q000235:genetics; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D000077205:Pioglitazone; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D045162:Thiazolidinediones / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D005960:Glucosides; D007004:Hypoglycemic Agents; D019275:Radiopharmaceuticals; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D045162:Thiazolidinediones; D019788:Fluorodeoxyglucose F18; C529054:dapagliflozin; D020962:Heterotrimeric GTP-Binding Proteins; D000077205:Pioglitazone