Lv Qiuyue, Le Liang, Xiang Jiamei, Jiang Baoping, Chen Sibao, Xiao Peigen
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Front Endocrinol (Lausanne). 2020 Mar 17;11:111. doi: 10.3389/fendo.2020.00111. eCollection 2020.
The hypoglycaemic target of empagliflozin (EMP), as a novel inhibitor of sodium-glucose cotransporter (SGLT2), is clear. However, recent studies have shown that EMP also has an important role in lipid metabolism and cardiovascular diseases. The liver plays an important role in the development of type 2 diabetes (T2D), although whether EMP affects liver glucose metabolism is currently not reported. This study was designed to evaluate the effect of EMP on hepatic glucose metabolism in T2D and the underlying mechanism. A model of T2D was established by a high-fat and glucose diet (HFD) combined with streptozotocin (30 mg/kg) in male Wistar rats. Serum samples were collected to measure biochemical indicators, and liver samples were extracted for RNA-seq assay. Quantitative real-time PCR (qPCR) was used to further verify the gene expression levels detected by the RNA-seq assay. The EMP group showed significantly decreased blood glucose, triglyceride, cholesterol, non-esterified fatty acid and low-density lipoprotein cholesterol levels, and increased high-density lipoprotein cholesterol levels in serum compared with the type 2 diabetes model (MOD) group. Furthermore, EMP decreased the levels of inflammatory factors IL-1β, IL-6, and IL-8 in the serum compared to the MOD. Liver transcriptome analysis showed EMP affects a large number of upregulated and downregulated genes. Some of these genes are novel and involve in the metal ion binding pathway and the negative regulation of transcription from the RNA polymerase II promoter pathway, which are also closely related to glucolipid metabolism and insulin signaling. Our study provides new knowledge about the mechanism through which SGLT inhibitor can offer beneficial effects in T2D and especially in the hepatic metabolism. These genes found in this study also laid a solid foundation for further research on the new roles and mechanisms of EMP.
恩格列净（EMP）作为一种新型钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂，其降糖靶点明确。然而，近期研究表明，EMP在脂质代谢和心血管疾病方面也具有重要作用。肝脏在2型糖尿病（T2D）的发生发展中起着重要作用，尽管目前尚无关于EMP是否影响肝脏葡萄糖代谢的报道。本研究旨在评估EMP对T2D肝脏葡萄糖代谢的影响及其潜在机制。通过高脂高糖饮食（HFD）联合链脲佐菌素（30 mg/kg）建立雄性Wistar大鼠T2D模型。采集血清样本检测生化指标，提取肝脏样本进行RNA测序分析。采用定量实时聚合酶链反应（qPCR）进一步验证RNA测序分析检测到的基因表达水平。与2型糖尿病模型（MOD）组相比，EMP组血清中的血糖、甘油三酯、胆固醇、非酯化脂肪酸和低密度脂蛋白胆固醇水平显著降低，高密度脂蛋白胆固醇水平升高。此外，与MOD组相比，EMP降低了血清中炎症因子IL-1β、IL-6和IL-8的水平。肝脏转录组分析显示，EMP影响大量上调和下调基因。其中一些基因是新发现的，涉及金属离子结合途径以及RNA聚合酶II启动子途径转录的负调控，这也与糖脂代谢和胰岛素信号密切相关。我们的研究为SGLT抑制剂在T2D尤其是肝脏代谢中发挥有益作用的机制提供了新知识。本研究中发现的这些基因也为进一步研究EMP的新作用和机制奠定了坚实基础。
