运动/肌肉收缩以不同于胰岛素的信号通路促进骨骼肌摄取葡萄糖（glucose uptake, GU），文献和我们报道AMPK和Rac1介导此作用，但详细机制不明。近来报道Axin1介导胰岛素促进的脂肪细胞GU，在肝细胞低能量时参与激活AMPK，我们预实验发现收缩上调Axin1，参与激活AMPK。此外，预实验提示AMPK通过Tiam1激活Rac1，推测AMPK/Axin1-Tiam1-Rac1通路介导收缩促进骨骼肌GU的作用。另一方面，运动还增加胰岛素敏感性，但尚未发现被运动放大的胰岛素信号。申请人报道收缩和胰岛素共用Rac1和几个Rab蛋白，预实验发现肥胖下调它们和Tiam1的表达，运动逆转此作用，推测它们参与运动增加胰岛素敏感性的作用。本研究拟应用我们建立的细胞株和敲除小鼠等动物模型验证我们的推测。本课题的完成将进一步阐明运动调节血糖的机制，发现新的药物靶点，有助于2型糖尿病的预防和治疗。

Exercise/muscle contraction stimulates skeletal muscle glucose uptake through different signaling pathways compared to insulin action. Researchers and our group have previously reported that AMP-activated protein kinase (AMPK) and Rac1 mediate contraction-stimulated glucose uptake, however, the detailed mechanisms are not clear yet. A recent study illustrated that Axin1 regulated insulin-stimulated glucose uptake in adipocytes. An Axin1-AMPK complex is also involved in the activation of liver AMPK during low-energy conditions. Our preliminary data demonstrate that contraction up-regulates Axin1 protein levels in skeletal muscle. In addition, our findings also implicate AMPK activation of Rac1 via the Rac1-GEF, Tiam1. Therefore, we hypothesize that an AMPK/Axin1-Tiam1-Rac1 signaling pathway mediates contraction-promoted skeletal muscle glucose uptake. Interestingly, exercise/muscle contraction can also enhance muscle insulin sensitivity. But the insulin signaling molecules that are amplified by exercise are not known. We previously reported that both contraction and insulin shared Rac1and Rabs 8a, 13 and 14 to stimulate skeletal muscle glucose uptake. Our preliminary data illustrate that some of these Rabs, Rac1 and Tiam1 are down-regulated in skeletal muscle of high-fat diet-induced obesity in mice, and these changes are reversed by exercise. We hypothesize that some of these molecules are involved in the mechanism of exercise-improved insulin sensitivity. In this study, we will utilize muscle cells stably expressing epitope-tagged GLUT4, mice with skeletal muscle-specific knockout of Axin1 and other mouse models to interrogate our hypotheses. The completion of this project will further illustrate the mechanisms of exercise-regulated whole-body glucose homeostasis and insulin sensitivity. It could also provide new drug targets to prevent and treat type 2 diabetes.