石胆酸介导TGR5/GLP-1轴在中远段小肠切除术后调节肝脏糖异生的机制研究

胆汁酸（BA）信号和2型糖尿病（T2DM）的缓解密切相关，但其详细机制尚不清楚。申请者前期自主研发了一种新的研究BA信号与糖耐量改善机制的手术模型──中远段小肠切除术（DBRPI）。DBRPI升高了胆汁酸池，并激活依赖胰高血糖素样肽-1（GLP-1）的“后肠机制”改善机体葡萄糖代谢。近期预实验发现DBRPI术后石胆酸（LCA）明显升高，末端回肠组织中G蛋白偶联受体（TGR5）及胰高血糖素样肽-1（GLP-1）基因表达明显上调，肝脏中糖异生关键酶基因表达下调。由此推测：DBRPI术后LCA可能介导TGR5/GLP-1轴调节肝脏糖异生。本项目拟以细胞结合动物实验，借助DBRPI模型和LCA等干预措施，采用PCR、ELISA以及靶向代谢组学等实验方法探究：1）LCA在DBRPI术后如何调节肠道GLP-1分泌；2）GLP-1在DBRPI术后调节肝脏糖异生具体机制，为T2DM的治疗提供新的靶点。

Bile acid (BA) signal is closely related to the remission of type 2 diabetes mellitus (T2DM), but the detailed mechanism is not clear. In the early stage, the applicant independently developed a new surgical model of mid to distal small bowel resection ((DBRPI)) to study the mechanism of BA signal and glucose tolerance improvement. DBRPI increases the bile acid pool and activates the "hindgut mechanism" dependent on glucagon-like peptide-1 (GLP-1) to improve glucose metabolism. Recent preliminary experiments showed that lithocholic acid (LCA) was significantly increased after DBRPI, the expression of G protein coupled receptor (TGR5) and glucagon-like peptide-1 (GLP-1) genes expression in terminal ileum was significantly up-regulated, and the expression of key gluconeogenesis enzymes in liver was down-regulated. It is speculated that LCA may mediate the regulation of hepatic gluconeogenesis by TGR5/GLP-1 axis after DBRPI. This project intends to use cell and animal experiment, with the help of DBRPI model and LCA intervention measures, using PCR, ELISA and targeted metabolomics and other experimental methods to explore: 1) how LCA regulates intestinal GLP-1 secretion after DBRPI; 2) the specific mechanism of GLP-1 regulating liver gluconeogenesis after DBRPI, which provides a new target for the treatment of T2DM.