Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Biochim Biophys Acta Mol Basis Dis. 2020 Aug 1;1866(8):165807. doi: 10.1016/j.bbadis.2020.165807. Epub 2020 Apr 28.
Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy.
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.
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.
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.
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.
研究恩格列净对糖尿病心肌病模型左心室功能的 SGLT2 抑制作用。
SGLT2 抑制是治疗糖尿病的一种新策略。在 EMPA-REG 结局试验中，恩格列净治疗降低了糖尿病患者的心血管和全因死亡率，推测这可能是由于心脏有益作用，导致心力衰竭住院减少。相关机制目前仍不清楚，但可能是通过改变心脏底物利用，从而改善心脏的能量供应。
我们使用高脂肪西方饮食喂养的 db/db 小鼠，并用或不用恩格列净进行治疗，作为严重糖尿病的模型。通过压力导管评估左心室功能，并用或不用多巴酚丁胺进行压力负荷。
恩格列净治疗显著增加了糖尿，改善了葡萄糖代谢，改善了左心室舒张功能，并降低了小鼠的死亡率。这与心脏葡萄糖浓度降低和钙/钙调蛋白依赖性蛋白激酶（CaMKII）激活减少有关，随后肌浆网（SR）ryanodine 受体（RyR）的磷酸化减少。未检测到血清中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。
在严重糖尿病的小鼠模型中，恩格列净依赖的 SGLT2 抑制改善了舒张功能并降低了死亡率。舒张功能的改善可能是通过减少自发性舒张期 SR 钙释放介导的，但与心脏酮体和 BCAA 代谢的变化无关。
