基于维生素K2循环VK2调节NAMPT/SIRT1信号通路改善骨骼肌IR作用机制研究

胰岛素抵抗（IR）是2型糖尿病（T2DM）的早期病理生理机制。骨骼肌是IR发病的主要部位，改善骨骼肌IR对防治T2DM意义重大。维生素K（VK）通过VK循环发挥凝血等功能。近年来，VK改善IR的作用备受关注。前期研究发现，VK2通过上调SIRT1信号通路，改善线粒体功能紊乱，减轻骨骼肌IR，而采用SIRT1 siRNA特异性抑制SIRT1蛋白表达后，VK2上述作用消失，表明SIRT1是VK2改善IR的关键作用靶点，但其具体分子机制尚未明确。预实验显示，VK2具有增加VK2循环关键酶和NAD+合成酶Nampt基因表达的作用，据此我们假设：基于VK2循环VK2通过NAMPT/SIRT1信号通路改善骨骼肌IR作用机制。本项目拟在细胞和动物层面，应用Nampt CKO基因敲除小鼠、NAMPT激动剂、慢病毒敲低或过表达等技术，探讨VK2改善IR的作用机制，为探索基于VK2防治IR的措施提供理论依据。

Insulin resistance (IR) plays a significant pathophysiologic role in T2DM. Skeletal muscle is the main organ of the prevalence of IR, understanding the mechanisms of IR is of critical importance. Vitamin K (VK) is an essential micronutrient known for its beneficial role in blood coagulation. Recently, however, coagulation-unrelated functions of VK have attracted scientific attention. VK cycle is required for the biological functions of VK. Our previous study revealed that VK2 improves mitochondrial dysfunction and inhibits IR in skeletal muscle through SIRT1/AMPK signal pathway. Interestingly, the benefits of VK2 were abrogated in C2C12 transfected with SIRT1 siRNA. However, the signaling mechanisms of VK2 in regulating SIRT1 signaling and IR remain unclear. Our research also shown VK2 significantly increased VK cycle enzymes and NAD+ biogenesis gene expression of Nampt. Based on previous research, our study focused on investigating alleviates insulin resistance in skeletal muscle via activating NAMPT/SIRT1 signaling pathway. Muscle skeletal-specific Nampt-conditional knockout (Nampt CKO) mice, NAMPT agonist and lentivirus NAMPT knockdown and overexpression used to explore the mechanism of VK2 cycle improving IR. The results of this study will provide a novel therapeutic strategy and target for the prevention of IR.