Meng Zhuo-Xian, Gong Jianke, Chen Zhimin, Sun Jingxia, Xiao Yuanyuan, Wang Lin, Li Yaqiang, Liu Jianfeng, Xu X Z Shawn, Lin Jiandie D
Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Chronic Disease Research Institute of School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; College of Life Science and Technology and Collaborative Innovation Center for Brain Science, Key Laboratory of Molecular Biophysics of MOE, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
Mol Cell. 2017 May 4;66(3):332-344.e4. doi: 10.1016/j.molcel.2017.04.007.
Skeletal muscle is a major site of postprandial glucose disposal. Inadequate insulin action in skeletal myocytes contributes to hyperglycemia in diabetes. Although glucose is known to stimulate insulin secretion by β cells, whether it directly engages nutrient signaling pathways in skeletal muscle to maintain systemic glucose homeostasis remains largely unexplored. Here we identified the Baf60c-Deptor-AKT pathway as a target of muscle glucose sensing that augments insulin action in skeletal myocytes. Genetic activation of this pathway improved postprandial glucose disposal in mice, whereas its muscle-specific ablation impaired insulin action and led to postprandial glucose intolerance. Mechanistically, glucose triggers K channel-dependent calcium signaling, which promotes HDAC5 phosphorylation and nuclear exclusion, leading to Baf60c induction and insulin-independent AKT activation. This pathway is engaged by the anti-diabetic sulfonylurea drugs to exert their full glucose-lowering effects. These findings uncover an unexpected mechanism of glucose sensing in skeletal myocytes that contributes to homeostasis and therapeutic action.
骨骼肌是餐后葡萄糖代谢的主要场所。骨骼肌细胞中胰岛素作用不足会导致糖尿病患者血糖升高。虽然已知葡萄糖可刺激β细胞分泌胰岛素，但葡萄糖是否直接参与骨骼肌中的营养信号通路以维持全身葡萄糖稳态在很大程度上仍未得到探索。在这里，我们确定了Baf60c-Deptor-AKT通路是肌肉葡萄糖感应的一个靶点，该靶点可增强骨骼肌细胞中的胰岛素作用。该通路的基因激活改善了小鼠餐后葡萄糖代谢，而其肌肉特异性缺失则损害了胰岛素作用并导致餐后葡萄糖不耐受。从机制上讲，葡萄糖触发钾通道依赖性钙信号传导，促进HDAC5磷酸化和核排除，导致Baf60c诱导和胰岛素非依赖性AKT激活。抗糖尿病磺脲类药物通过该通路发挥其完全的降糖作用。这些发现揭示了骨骼肌细胞中一种意想不到的葡萄糖感应机制，该机制有助于维持体内稳态和发挥治疗作用。
