TGR5-GLP-1信号通路在石胆酸调控妊娠期胰岛素抵抗中的作用及机制

胆汁酸是一种重要内分泌调节因子，可通过激活G蛋白偶联受体-5（TGR5）提高胰岛素敏感性，改善糖代谢。我们的前期研究表明，妊娠糖尿病（GDM）孕妇孕早期总胆汁酸水平显著升高，进一步代谢组学分析显示：GDM患者石胆酸（已知最强的TGR5激动剂）水平升高幅度最大。给孕鼠喂养添加石胆酸的饲料，其胎盘和脂肪TGR5表达明显增加，脂肪GLUT-1和GLUT-4表达上调，血清TNF-α水平下降。但石胆酸如何改善孕期胰岛素抵抗？其分子机制仍不清楚。为回答此科学问题，本项目拟通过石胆酸或TGR5 激活或TGR5抑制治疗后孕鼠胰岛素抵抗及其受体后胰岛素信号传导、葡萄糖摄取等通路和TGR5-GLP-1通路变化的体内研究，及石胆酸对胰岛素靶组织和细胞的TGR5-GLP-1信号通路变化等体外研究，多层次阐明TGR5-GLP-1通路在石胆酸减轻妊娠期胰岛素抵抗的分子机制，为有效防治GDM提供全新的思路和分子靶点。

Bile acids were recently shown to be a new kind of endocrine regulators, and they improved insulin sensitivity and enhance glucose metabolism by activating G protein-coupled receptor (TGR5). Our preliminary data indicated that first-trimester total bile acid(TBA) levels were significantly elevated and independently associated with the incidence of gestational diabetes mellitus (GDM). Then our metabolomics analysis by a cohort study in pregnant women with or without GDM firstly revealed that the increase in the levels of lithocholic acid (LCA), known as the strongest agonist of TGR5, was greatest in GDM women. Furthermore, we found in the animal model that after treatment with LCA, the levels of TGR5 in placenta and adipose tissue from pregnant mice were significantly increased, at the same time, the expressions of GLUT-1 and GLUT-4 in adipose tissue were significantly increased, and the serum TNF-α levels decreased..However, how does LCA alleviate the insulin resistance in pregnancy? It is not clear till now. To answer this scientific question, we designed the present study to clarify the effect of TGR5-GLP-1 signaling in the mechanism of LCA to induce insulin resistance alleviation during pregnancy by:1) in vivo study with the systemic insulin sensitivity, glucose uptake, inflammation and TGR5-GLP-1 signaling after LCA and TGR5 activated or inhibited intervention; 2)in vitro study with the TGR5-GLP-1 signaling and inflammatory response in target cells of insulin and intestine L cells treated with LCA or its inhibitor. .This program will reveal the molecular mechanism of TGR5-GLP-1 signal activation in the improvement of insulin sensitivity induced by LCA. And these results will provide the scientific basis of exploring a novel molecular target and new potential stratgies for GDM prevention through improving insulin sensitivity.