基于SirT3探讨番泻苷Ａ抑制肠道线粒体过热治疗T2DM的作用机制

高脂高糖饮食、运动过少等不健康生活方式可导致能量过剩和代谢紊乱。营养过量供应通过“底物推动”效应造成线粒体功能紊乱，产生过量ATP及ROS，即称之为线粒体过热，由其造成的病理变化是T2DM重要诱因，这和中医认为内热逐渐成为T2DM重要病因相契合。大黄是从内热论治T2DM的代表药物之一。申请者上一个国自然项目研究发现大黄有效成分番泻苷A能调节线粒体过热，保护肠道L细胞GLP-1分泌并改善胰岛素抵抗，而作用机制尚未涉及。已知线粒体沉默信息调节因子（SirT3）是改善线粒体过热的关键因子，但与番泻苷Ａ的关联研究未见报导。因此提出本研究假说：番泻苷Ａ可能通过调节SirT3抑制线粒体过热，保护肠道L细胞线粒体结构及功能，改善GLP-1分泌，治疗T2MD。创新点是：采用SirT3基因敲除小鼠建模，从改善线粒体过热的关键因子入手，探讨番泻苷A抑制线粒体过热，为番泻苷A治疗T2DM提供分子机制依据。

High fat & sugar diet, lack of exercise and other unhealthy lifestyles lead to energy surplus and metabolic disorders. Excessive supply of nutrients causes mitochondrial dysfunction through the "substrate-pushed" effect, resulting in excessive production of ATP and ROS. We describe this phenomenon as mitochondrial overheating. The pathological changes it caused are important inducements of T2DM, which are consistent to the "internal heat" pathogenesis of diabetes that traditional Chinese medicine has recognized increasingly. Rhubarb is one of the representative drugs to treat T2MD from "internal heat ". The applicant's previous NSFC project found that sennoside A, an active ingredient of rhubarb, regulates mitochondrial overheating, protects the GLP-1 secretion of intestinal L cells and improves insulin resistance, but the mechanism of these effects has not been involved. Mitochondrial silencing information regulator (SirT3) is a key factor to improve mitochondrial overheating, and its association with sennoside A has not been reported. We hypothesize that sennoside A inhibits mitochondrial overheating through regulation of SirT3, thus protects mitochondrial structure and function of L cells, improve GLP-1 secretion, thereby exerts its anti-diabetic effects. The innovation of this project is: We establish a SirT3 conditional knock out mice model, explore the way sennoside A inhibits mitochondrial overheating focusing on the key regulator of this phenomenon, thus provide molecular mechanism basis for the application of rhubarb and its active component sennoside A in the treatment of T2DM.