二甲双胍通过调控溶酶体相关细胞器发生及功能发挥其降糖作用的机制研究

二甲双胍是当前治疗2型糖尿病（T2DM）的首选药物，也是全球使用频率最高的降糖药物，然而其降糖的作用机制却尚不清楚。我们先前的研究阐释了二甲双胍作用通路下游的关键元件：核孔复合物（NPC）和酰基辅酶A脱氢酶10(ACAD10)，很好地解释了该药物抗肿瘤抗衰老的作用机制，但它具体是如何作用于NPC-ACAD10元件的还不清楚。本项目的预实验结果提示，溶酶体相关细胞器（LRO）是二甲双胍作用通路中NPC的上游元件，参与了二甲双胍在小鼠中的降糖作用，但具体作用机制也还不清晰。本研究拟充分利用秀丽线虫、细胞和小鼠模型的各自优势，揭示二甲双胍通过LRO作用于其下游元件的分子机理，并深入探讨该药物通过调控LRO发生及功能发挥降糖作用的机制。完成本项目，不仅可以为二甲双胍的临床应用提供重要理论依据，还可以为人们理解T2DM发生发展的原因提供参考，并为T2DM新型治疗措施的研发提供新靶点。

Metformin, as the first line therapy for type 2 diabetes mellitus (T2DM), has been most prescribed for the antglycemic usage worldwide. However, the mechanism for which metformin exerts its antiglycemic effect remains largely unknown. In the previous work, we identified nuclear pore complex (NPC) and the acyl-CoA dehydrogenase 10 （ACAD10）as the essential downstream elements for metformin to inhibit cancer growth and C. elegans aging, although it is yet unclear how the drug works through the signal relay NPC-ACAD10. Our preliminary results for this proposal supported that lysosome related organelles (LRO) act as the upstream signal of NPC-ACAD10 in the metformin response pathway. Furthermore, we found that metformin improves glucose tolerance via an LRO dependent manner in mice. The central goal of this application is to reveal the underlying machinery how metformin lowers blood glucose by modulating the LRO biogenesis and function. To achieve the aim, the project will leverage facile genetic discovery across model systems, and ultimately validate our main hypothesis in cultured mammalian cells and animals. Successful completion of this project will provide basis for metformin application in clinic, promising clues for understanding the causes of T2DM and alternative targets paving the way for a new generation of antiglycemic reagents.