The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model
The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model
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DOI：
10.2337/db16-0733
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发表时间：
2017-04-01
期刊：
影响因子：
7.7
通讯作者：
Prieur, Xavier
中科院分区：
文献类型：
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作者：
Joubert, Michael;Jagu, Benoit;Prieur, Xavier
2型糖尿病（T2 DM）是公认的心力衰竭的独立危险因素。T2 DM与心脏能量代谢改变相关，导致异位脂质蓄积和葡萄糖超负荷，这两个参数的确切作用尚不清楚。为了提供对糖尿病性心肌病发展机制的新见解，我们研究了一种独特的T2 DM模型：脂肪营养不良Bscl（-/-）（seipin敲除[SKO]）小鼠。超声心动图和心脏磁共振成像显示，在SKO小鼠肥厚型心肌病左心室功能不全，这两个异常与高血糖强烈相关。令人惊讶的是，在SKO小鼠中既没有检测到心肌内脂质积聚，也没有检测到脂毒性标志。[F-18]氟脱氧葡萄糖正电子发射断层扫描显示心肌葡萄糖摄取增加。一致地，在SKO心脏中O-GlcNAc酰化蛋白水平显著增加，表明葡萄糖超负荷。为了验证这一假设，我们用降糖钠-葡萄糖协同转运蛋白2（SGLT 2）抑制剂达格列净和胰岛素增敏剂吡格列酮治疗SKO小鼠。两种治疗均降低了SKO小鼠的O-GlcNAc酰化蛋白水平，达格列净成功预防了肥厚性心肌病的发生。我们的数据表明，葡萄糖毒性本身可引发心功能不全，降糖药物可纠正它。这一结果将有助于更好地了解SGLT 2抑制剂的潜在心血管益处。
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 Bscl(-/-) (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-18] 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.