SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob-/- mice
SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob-/- mice
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DOI：
10.1186/s12933-019-0820-6
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发表时间：
2019-02-07
影响因子：
9.3
通讯作者：
Jonsson-Rylander, Ann-Cathrine
中科院分区：
文献类型：
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作者：
Adingupu, Damilola D.;Gopel, Sven O.;Jonsson-Rylander, Ann-Cathrine
钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）是一类抗糖尿病药物，可降低因心力衰竭而住院的死亡率和风险。临床研究表明，SGLT2i可促进机体向空腹状态代谢的转变，其特征是体重和血糖降低，胰高血糖素/胰岛素比值升高，血酮水平适度升高。因此，我们研究了ob/ob（-/-）小鼠代谢变化与心血管功能之间的关系；早期糖尿病的啮齿动物模型，特别关注冠状动脉微血管功能。由于瘦素缺乏，这些小鼠会出现代谢综合征/糖尿病和肝脂肪变性。它们也会引起心脏收缩和微血管功能障碍，因此是心脏代谢疾病转化研究的一个有希望的模型。我们研究了该小鼠模型在代谢参数方面是否以类似人类的方式对恩格列净治疗产生反应，并验证了它可能对冠状动脉微血管功能和收缩性能产生直接影响的假设。方法采用SGLT2i对小鼠、未治疗的ob/ob（-/-）和治疗的ob/ob（-/-）进行随访，随访时间为10周。采用无创多普勒超声显像监测冠状动脉血流速度储备（CFVR）和分数面积变化（FAC）。在整个研究过程中，通过HbA1c测量跟踪食物摄入、尿葡萄糖偏移和葡萄糖控制。通过组织学和研究结束时确定的代谢参数来评估肝脂肪变性。结果在临床研究中观察到，钠-葡萄糖共转运蛋白2抑制剂治疗ob/ob（-/-）动物导致转向更多的分解代谢状态：血胆固醇和HbA1c降低，而胰高血糖素/胰岛素比值和酮水平升高。SGLT2i治疗降低肝脏甘油三酯、脂肪变性和丙氨酸转氨酶，这是肝功能障碍的一个指标。内皮功能指标l-精氨酸/ADMA比值升高。SGLT2i治疗可改善心脏收缩功能和冠状动脉微血管功能，分别由FAC和CFVR改善所示。结论钠-葡萄糖共转运蛋白2抑制剂对ob/ob（-/-）小鼠的治疗模拟了代谢和心血管改善的主要临床发现，因此是一个有用的转化模型。我们证明SGLT2抑制可改善冠状动脉微血管功能和收缩性能，这两项指标在人类CV结果中具有很强的预测价值，同时在糖尿病前期和心力衰竭的临床前模型中也有已知的代谢变化。
BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2i) is the first class of anti-diabetes treatment that reduces mortality and risk for hospitalization due to heart failure. In clinical studies it has been shown that SGLT2i's promote a general shift to fasting state metabolism characterized by reduced body weight and blood glucose, increase in glucagon/insulin ratio and modest increase in blood ketone levels. Therefore, we investigated the connection between metabolic changes and cardiovascular function in the ob/ob(-/-) mice; a rodent model of early diabetes with specific focus on coronary microvascular function. Due to leptin deficiency these mice develop metabolic syndrome/diabetes and hepatic steatosis. They also develop cardiac contractile and microvascular dysfunction and are thus a promising model for translational studies of cardiometabolic diseases. We investigated whether this mouse model responded in a human-like manner to empagliflozin treatment in terms of metabolic parameters and tested the hypothesis that it could exert direct effects on coronary microvascular function and contractile performance.MethodsLean, ob/ob(-/-) untreated and ob/ob(-/-) treated with SGLT2i were followed for 10weeks. Coronary flow velocity reserve (CFVR) and fractional area change (FAC) were monitored with non-invasive Doppler ultrasound imaging. Food intake, urinary glucose excursion and glucose control via HbA1c measurements were followed throughout the study. Liver steatosis was assessed by histology and metabolic parameters determined at the end of the study.ResultsSodium-glucose cotransporter 2 inhibitors treatment of ob/ob(-/-) animals resulted in a switch to a more catabolic state as observed in clinical studies: blood cholesterol and HbA1c were decreased whereas glucagon/insulin ratio and ketone levels were increased. SGLT2i treatment reduced liver triglyceride, steatosis and alanine aminotransferase, an indicator for liver dysfunction. l-Arginine/ADMA ratio, a marker for endothelial function was increased. SGLT2i treatment improved both cardiac contractile function and coronary microvascular function as indicated by improvement of FAC and CFVR, respectively.ConclusionsSodium-glucose cotransporter 2 inhibitors treatment of ob/ob(-/-) mice mimics major clinical findings regarding metabolism and cardiovascular improvements and is thus a useful translational model. We demonstrate that SGLT2 inhibition improves coronary microvascular function and contractile performance, two measures with strong predictive values in humans for CV outcome, alongside with the known metabolic changes in a preclinical model for prediabetes and heart failure.