Michael Joubert, 1,2,3 Benoît Jagu, 1 David Montaigne, 4 Xavier Marechal, 4 Angela Tesse, 1 Audrey Ayer, 1 Lucile Dollet, 1 Cédric Le May, 1 Gilles Toumaniantz, 1 Alain Manrique, 3 Flavien Charpentier, 1 Bart Staels, 4 Jocelyne Magré, 1 Bertrand Cariou, 5 and Xavier Prieur 1 The Sodium–Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model Diabetes 2017;66:1030–1040 | DOI: 10.2337/db16-0733 Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for heart failure. T2DM is asso- ciated 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 2/2 (seipin knockout [SKO]) mice. Echocardiography and car- diac magnetic resonance imaging revealed hypertrophic cardiomyopathy with left ventricular dysfunction in SKO mice, and these two abnormalities were strongly corre- lated with hyperglycemia. Surprisingly, neither intramyo- cardial lipid accumulation nor lipotoxic hallmarks were detected in SKO mice. [ 18 F]Fludeoxyglucose positron emission tomography showed increased myocardial glu- cose uptake. Consistently, the O-GlcNAcylated protein levels were markedly increased in an SKO heart, suggest- ing a glucose overload. To test this hypothesis, we treated SKO mice with the hypoglycemic sodium–glucose co- transporter 2 (SGLT2) inhibitor dapagliflozin and the insu- lin sensitizer pioglitazone. Both treatments reduced the O-GlcNAcylated protein levels in SKO mice, and dapagli- flozin successfully prevented the development of hy- pertrophic 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 car- diovascular benefits of SGLT2 inhibitors. Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for heart failure (HF) (1,2). Whereas the prevalence of HF in the general population is 1–4%, it reaches ;12% in patients with T2DM (3). In 1972, Rubler et al. (4) reported a specific diabetes-associated cardiac in- jury called diabetic cardiomyopathy. This cardiomyopathy is defined by ventricular dysfunction occurring without coro- nary disease or hypertension (1,5). Diabetic cardiomyopathy is also characterized by left ventricular (LV) hypertrophy, diastolic dysfunction, and myocardial fibrosis (1,5). A large body of work indicates that diabetic cardiomy- opathy is associated with altered cardiac energy metabo- lism (6). Indeed, in obese patients with T2DM, heart lipid uptake is increased (7). Several studies support that free fatty acid (FFA) accumulation leads to the increased pro- duction of diacylglycerol (DAG), ceramides, and reactive oxygen species (ROS), affecting cardiac insulin sensitivity (8,9) and cardiac contractility (6,10,11). On the other hand, hyperglycemia and glucose overload have been involved in cardiac hypertrophy and dysfunction in the context of T2DM and obesity (12). The diabetic heart is simultaneously characterized by impaired insulin- stimulated glucose uptake (13) and obvious signs of glucose overload, such as ROS and advanced glycation end product (AGE) production as well as hexosamine pathway chronic activation (12,14). Interestingly, when comparing obese patients with and without diabetes, we previously demon- strated that hyperglycemia per se plays a central role in the 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 Corresponding author: Xavier Prieur, xavier.prieur@univ-nantes.fr. Received 14 June 2016 and accepted 16 December 2016. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0733/-/DC1. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. 1030 Diabetes Volume 66, April 2017 COMPLICATIONS