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Tytuł pozycji:

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

Tytuł :
The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model.
Autorzy :
Joubert M; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.; Endocrinologie, CHU Caen, Caen, France.; EA 4650, UNICAEN, GIP Cyceron, Caen, France.
Jagu B; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
Montaigne D; Universite Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
Marechal X; Universite Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
Tesse A; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
Ayer A; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
Dollet L; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
Le May C; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
Toumaniantz G; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
Manrique A; EA 4650, UNICAEN, GIP Cyceron, Caen, France.
Charpentier F; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
Staels B; Universite Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
Magré J; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
Cariou B; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, CHU Nantes, Nantes, France.
Prieur X; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France .
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Źródło :
Diabetes [Diabetes] 2017 Apr; Vol. 66 (4), pp. 1030-1040. Date of Electronic Publication: 2017 Jan 04.
Typ publikacji :
Journal Article
Język :
English
Imprint Name(s) :
Publication: Alexandria, VA : American Diabetes Association
Original Publication: [New York, American Diabetes Association]
MeSH Terms :
Diabetic Cardiomyopathies*
Lipodystrophy*/genetics
Benzhydryl Compounds/*pharmacology
Diabetes Mellitus, Type 2/*drug therapy
Glucosides/*pharmacology
Heart/*drug effects
Hypoglycemic Agents/*pharmacology
Thiazolidinediones/*pharmacology
Ventricular Function/*drug effects
Animals ; Benzhydryl Compounds/therapeutic use ; Blood Glucose/metabolism ; Cardiomyopathy, Hypertrophic ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Disease Models, Animal ; Echocardiography ; Fluorodeoxyglucose F18 ; GTP-Binding Protein gamma Subunits ; Glucosides/therapeutic use ; Heart/diagnostic imaging ; Heterotrimeric GTP-Binding Proteins/genetics ; Hyperglycemia ; Hypoglycemic Agents/therapeutic use ; Magnetic Resonance Imaging ; Mice ; Mice, Knockout ; Myocardium/metabolism ; Pioglitazone ; Positron-Emission Tomography ; Radiopharmaceuticals ; Sodium-Glucose Transporter 2 Inhibitors ; Ventricular Dysfunction, Left
Substance Nomenclature :
0 (Benzhydryl Compounds)
0 (Blood Glucose)
0 (Bscl2 protein, mouse)
0 (GTP-Binding Protein gamma Subunits)
0 (Glucosides)
0 (Hypoglycemic Agents)
0 (Radiopharmaceuticals)
0 (Sodium-Glucose Transporter 2 Inhibitors)
0 (Thiazolidinediones)
0Z5B2CJX4D (Fluorodeoxyglucose F18)
1ULL0QJ8UC (dapagliflozin)
EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
X4OV71U42S (Pioglitazone)
Entry Date(s) :
Date Created: 20170106 Date Completed: 20170613 Latest Revision: 20210504
Update Code :
20210506
DOI :
10.2337/db16-0733
PMID :
28052965
Czasopismo naukowe
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.
(© 2017 by the American Diabetes Association.)

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