通过调控糖异生途径抑制肝糖异生过程以降低血糖是治疗2型糖尿病（T2DM）的重要策略。肝糖异生调控通路复杂，尽管研究发现法尼醇X受体（FXR）可通过SHP或GR等通路抑制糖异生，但FXR调控糖异生机制依然不十分清楚。2008-2011年，我们在实施基金委重大研究计划重点项目“基于天然活性分子LX0278为探针的胰岛素增敏新信号通路的发现”（90713046）研究中，发现FXR作用GLUT4启动子调节GLUT4表达，同时还发现与FXR激动剂相同，设计获得的FXR选择性小分子拮抗剂NDB也能有效抑制肝糖异生。随后解析的FXR-LBD/NDB复合物晶体结构首次揭示了NDB对FXR的拮抗机制，并提出NDB可能诱导FXR采用新的通路调控糖异生途径。因此，以NDB为探针开展“FXR调控肝糖异生新信号通路的发现”研究，并在此基础上发现具有新作用机制的抗T2DM药物先导化合物，具有重要的科学和实用价值。

It is a promising therapeutic strategy against type 2 diabetes (T2DM) to improve hyperglycaemia by inhibition of gluconeogenesis in the liver through regulating the relevant pathways. The regulation pathways for hepatic gluconeogenesis are complex. Despite the discovery that farnesoid X receptor (FXR) can suppress hepatic gluconeogenesis through several SHP or GR related signal pathways, FXR-involved regulation mechanism against gluconeogenesis is still unclear. From 2008 to 2011, we implemented the key project of the NSFC major research plan, entitled "Exploration of new insulin sensitization signal pathways based on the active natural product LX0278 as a probe” (90713046), and found that FXR regulates GLUT4 expression by direct interaction with GLUT4 gene promoter. At the same time, we also determined that similar to the case for FXR agonist, the discovered selective small molecule antagonist NDB of FXR can also effectively restrain hepatic gluconeogenesis. Moreover, the analyzed crystal structure of FXR-LBD/NDB complex firstly revealed the antagonistic mechanism of NDB against FXR, and implied that NDB may induce FXR to regulate hepatic gluconeogenesis via new signal pathways. Therefore, the study on the new signaling pathways for the regulation of FXR against hepatic gluconeogenesis and the discovery of new anti-T2DM drug lead compound based on these new determined pathways will exhibit potent scientific and practical values.