Cardiovascular Research Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Sorbonne Universités, UPMC University Paris 06, Institut de Cardiologie (AP-HP), Centre Hospitalier Universitaire Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), INSERM UMRS 1166, Paris, France.
Cardiovasc Drugs Ther. 2017 Jun;31(3):233-246. doi: 10.1007/s10557-017-6734-1.
Cardiovascular (CV) diseases in type 2 diabetes (T2DM) represent an enormous burden with high mortality and morbidity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as a new antidiabetic class that improves glucose control, as well as body weight and blood pressure with no increased risk of hypoglycemia. The first CV outcome study terminated with empagliflozin, a specific SGLT2 inhibitor, has shown a reduction in CV mortality and in heart failure hospitalization, suggesting a beneficial impact on cardiac function which remains to be demonstrated. This study was designed to examine the chronic effect of empagliflozin on left ventricular (LV) systolic and diastolic functions in a genetic model of T2DM, ob/ob mice.
Cardiac phenotype was characterized by echocardiography, in vivo hemodynamics, histology, and molecular profiling. Our results demonstrate that empagliflozin significantly lowered HbA1c and slightly reduced body weight compared to vehicle treatment with no obvious changes in insulin levels. Empagliflozin also improved LV maximum pressure and in vivo indices of diastolic function. While systolic function was grossly not affected in both groups at steady state, response to dobutamine stimulation was significantly improved in the empagliflozin-treated group, suggesting amelioration of contractile reserve. This was paralleled by an increase in phospholamban (PLN) phosphorylation and increased SERCA2a/PLN ratio, indicative of enhanced SERCA2a function, further supporting improved cardiac relaxation and diastolic function. In addition, empagliflozin reconciled diabetes-associated increase in MAPKs and dysregulated phosphorylation of IRS1 and Akt, leading to improvement in myocardial insulin sensitivity and glucose utilization.
The data show that chronic treatment with empagliflozin improves diastolic function, preserves calcium handling and growth signaling pathways and attenuates myocardial insulin resistance in ob/ob mice, findings suggestive of a potential clinical utility for empagliflozin in the treatment of diastolic dysfunction.
2 型糖尿病（T2DM）患者的心血管（CV）疾病死亡率和发病率高，负担沉重。钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂作为一种新的抗糖尿病药物，可改善血糖控制，同时降低体重和血压，且不增加低血糖风险。首个 CV 结局研究因恩格列净（一种特异性 SGLT2 抑制剂）而终止，该研究显示 CV 死亡率和心力衰竭住院率降低，表明对心脏功能有有益影响，但这仍需进一步证实。本研究旨在研究恩格列净对 T2DM 遗传模型-ob/ob 小鼠左心室（LV）收缩和舒张功能的慢性影响。
通过超声心动图、体内血流动力学、组织学和分子谱分析来描述心脏表型。结果表明，与 vehicle 处理相比，恩格列净显著降低了 HbA1c 并略微减轻了体重，但胰岛素水平没有明显变化。恩格列净还改善了 LV 最大压力和体内舒张功能指标。虽然在稳态时两组的收缩功能均未受到明显影响，但恩格列净治疗组对多巴酚丁胺刺激的反应明显改善，提示收缩储备得到改善。这与 PLN 磷酸化增加和 SERCA2a/PLN 比值增加相一致，提示 SERCA2a 功能增强，进一步支持心脏舒张和舒张功能的改善。此外，恩格列净缓解了糖尿病相关的 MAPKs 增加和 IRS1 和 Akt 异常磷酸化，从而改善了心肌胰岛素敏感性和葡萄糖利用。
数据表明，恩格列净的慢性治疗可改善舒张功能，维持钙处理和生长信号通路，并减轻 ob/ob 小鼠的心肌胰岛素抵抗，这提示恩格列净在治疗舒张功能障碍方面可能具有临床应用价值。
