OBJECTIVES Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy. BACKGROUND SGLT2 inhibition is a new strategy to treat diabetes. In the EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart. METHODS We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress. RESULTS Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected. CONCLUSIONS In a murine model of severe diabetes empagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism.

中文翻译：

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依帕列净改善db / db小鼠的左心室舒张功能。

目的研究依帕格列净抑制SGLT2对糖尿病性心肌病模型左心室功能的影响。背景技术SGLT2抑制是治疗糖尿病的新策略。在EMPA-REG结果试验中，依帕列净治疗降低了糖尿病患者的心血管和整体死亡率，这可能是由于有益的心脏作用，从而减少了心衰住院率。目前尚不清楚相关的机制，但可能是由于心脏底物利用率的变化而介导的，从而改善了心脏的能量供应。方法我们将db / db小鼠用于高脂西方饮食，无论是否接受依帕列净治疗，均作为严重糖尿病的模型。通过有或没有多巴酚丁胺负荷的压力导管评估左心室功能。结果使用依格列净治疗可显着增加糖尿，改善糖代谢，改善左心室舒张功能并降低小鼠死亡率。这与降低的心脏葡萄糖浓度和降低的钙/钙调蛋白依赖性蛋白激酶（CaMKII）活化有关，随后使瑞丹碱受体（RyR）的磷酸化程度降低。血清中未检测到心脏酮体或支链氨基酸（BCAA）代谢物的变化，也未影响这些底物的相关分解代谢酶的心脏表达。结论在严重糖尿病小鼠模型中，依帕格列净依赖的SGLT2抑制作用可改善舒张功能并降低死亡率。