The Sodium–Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model
| Autor: | Benoît Jagu, Jocelyne Magré, L. Dollet, Bertrand Cariou, Xavier Prieur, Xavier Marechal, David Montaigne, Michael Joubert, Cédric Le May, Audrey Ayer, Gilles Toumaniantz, Flavien Charpentier, Angela Tesse, Alain Manrique, Bart Staels |
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| Přispěvatelé: | unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Blood Glucose
Lipodystrophy Diabetic Cardiomyopathies [SDV]Life Sciences [q-bio] Endocrinology Diabetes and Metabolism medicine.medical_treatment Glucose uptake Left Cardiomyopathy 030204 cardiovascular system & hematology Seipin chemistry.chemical_compound Mice Ventricular Dysfunction Left 0302 clinical medicine Glucosides Diabetic cardiomyopathy GTP-Binding Protein gamma Subunits Ventricular Dysfunction Medicine Ventricular Function Dapagliflozin ComputingMilieux_MISCELLANEOUS Mice Knockout Hypertrophic cardiomyopathy Heart [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Heterotrimeric GTP-Binding Proteins Magnetic Resonance Imaging 3. Good health Echocardiography Type 2 medicine.drug medicine.medical_specialty Knockout 030209 endocrinology & metabolism 03 medical and health sciences Sodium-Glucose Transporter 2 [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system Fluorodeoxyglucose F18 Internal medicine Diabetes Mellitus Internal Medicine [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] Animals Hypoglycemic Agents Benzhydryl Compounds Sodium-Glucose Transporter 2 Inhibitors Pioglitazone Animal business.industry Insulin Myocardium [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology Cardiomyopathy Hypertrophic medicine.disease Disease Models Animal Endocrinology chemistry Diabetes Mellitus Type 2 Hypertrophic Hyperglycemia Positron-Emission Tomography Disease Models Thiazolidinediones Radiopharmaceuticals business |
| Zdroj: | Diabetes Diabetes, American Diabetes Association, 2017, 66 (4), pp.1030-1040. ⟨10.2337/db16-0733⟩ Diabetes, 2017, Equipe IIa Equipe III Equipe IV, 66 (4), pp.1030--1040. ⟨10.2337/db16-0733⟩ |
| ISSN: | 0012-1797 |
| DOI: | 10.2337/db16-0733⟩ |
| Popis: | International audience; 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. [(18)F]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. |
| Databáze: | OpenAIRE |
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