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: lipodystrophic (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. [F]Fludeoxyglucose positron emission tomography showed increased myocardial glucose uptake. Consistently, the -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-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.

The collaborative work of droplet assembly

“…Many patients have metabolic syndrome and diabetes. A subset of patients suffer from cardiomyopathy, which may be related more to hyperglycemia and mitochondrial defects than to fat storage [26]. Patients also display deficiencies in other systems, including nervous and reproductive.…”

Seipin deficiency leads to defective parturition in mice†

“…glucose and insulin. This speculation was supported by a recent study demonstrating that the development of hypertrophic cardiomyopathy in Bscl2 −/− mice was prevented by the treatment with dapagliflozin, a hypoglycemic sodium-glucose cotransporter 2 inhibitor [16]. We have been studying the functions of seipin in reproductive systems using seipin-deficient Bscl2 −/− mice and identified roles of seipin in mammary gland development, vaginal opening, and spermatogenesis [11,12].…”

“…This study revealed that seipin deficiency led to uterine smooth muscle hypertrophy in middle-aged mice but not in the prepubertal mice. Since Bscl2 mRNA had relatively low expression levels in the myometrium from prepubertal to adult and throughout the pregnancy, it was possible that uterine smooth muscle hypertrophy might be the result of a systemic effect similar as hypertrophy of other muscles in the seipin-deficient mice [11,12,16]. A previous study demonstrated that Bscl2 −/− mice had elevated glucose and insulin levels with insulin resistance [10].…”

“…It is very likely that uterine hypertrophy in the adult Bscl2 −/− mice is the consequence of elevated glucose levels and insulin resistance. Since the development of hypertrophic cardiomyopathy in Bscl2 −/− mice could be prevented by the treatment with a hypoglycemic sodium-glucose cotransporter 2 inhibitor [16], indicative of a systemic effect, pharmacological approaches to treat diabetes could be tested in Bscl2 −/− mice to determine their effects on preventing uterine hypertrophy in Bscl2 −/− mice. In order to differentiate seipin uterine local effect or seipin global effect on uterine hypertrophy, uterine-specific Bscl2 −/− mice could be generated and studied.…”

Sodium-Glucose Cotransporter 2 Inhibitors for Heart Failure

“…Dapagliflozin successfully prevented the development of hypertrophic cardiomyopathy in a diabetic lipodystrophic mouse model [4]. Left ventricular hypertrophy and cardiac diastolic function in a female rodent model of diabetes were improved by empagliflozin [5].…”