Metformin（二甲双胍）是使用最为广泛的治疗II型糖尿病的药物，并可以降低病人的肿瘤发病风险。Metformin能够激活AMPK，后者是其发挥药效的关键因子。然而，该过程的机制还不明确。我们之前发现，Ragulator（由LAMTOR1-5组成）和AXIN是能量胁迫条件下AMPK激活的必需因子；Ragulator-AXIN/LKB1-AMPK复合体在溶酶体上的组装的过程是该条件下AMPK激活的必要条件。我们前期的研究发现，Metformin不能在缺失了AXIN或者LAMTOR1的MEFs和小鼠肝脏中激活AMPK。同时，Metformin能引起Ragulator-AXIN/LKB1-AMPK复合体的形成。在此基础上，我们将继续研究Ragulator和AXIN在Metformin-AMPK信号通路中的作用和生理意义，从而加深我们对该药物药理作用的理解，为其更加深入而广泛的应用作出贡献。

Metformin is the most widely used drug for treating type 2 diabetes. Cancer incidence is reported to be much reduced among diabetic patients using the drug. The master energy sensor AMPK is activated during metformin treatment and is critical for pharmaceutical effects of the drug. However, how AMPK is activated by metformin remains elusive. We have reported that Ragulator (a pentamer of LAMTOR1-5) and AXIN are required for AMPK activation under energy stress. In this process, Ragulator triggers the formation of Ragulator-AXIN/LKB1-AMPK complex on lysosome and the complex formation is a prerequisite of AMPK activation. Our unpublished results further show that in AXIN- or LAMTOR1-deficient MEFs or mice livers, metformin fails to activate AMPK. In addition, metformin elicits lysosomal translocation of AXIN, leading to the accumulation of the Ragulator-AXIN/LKB1-AMPK complex on the surface of lysosome. These results indicate that metformin relies on the Ragulator-AXIN/LKB1-AMPK axis. Based on the preliminary data, we propose to investigate the roles of Ragulator and AXIN played in AMPK activation upon metformin treatment, and to explore the physiological significance of deficiency of AXIN or Ragulator with relation to metformin treatment. The proposed work will depict the panoramic and detailed pathway of metformin-AMPK, and make a major contribution to the understanding of the mechanisms for the pharmacological action of metformin, ultimately providing new therapeutic avenues for the prevention and treatment of type 2 diabetes.