Visfatin经PI3K-AKT信号途径调控骨骼肌胰岛素敏感性

Diabetes mellitus has been a disease which threatens humans'health severely, while the pathogenesis has been unknown completely. It is important of clinical values to investigate the pathogenesis and quest for new strategies to effective pharmacotherapy. The previous reports indicated that visfatin is shown to have insulin-mimetic effects. However, the influence and the related molecular mechanisms between visfatin and glycometabolism、insulin resistance in skeletal muscle is not completely clear. Our research group has found that the expressions of visfatin and PI3K in diabetic rats muscle were elevated，therefore we presume that visfatin is associated with pathogenetic mechanism of diabetic metabolic disorder，also plays an important role in improving glucolipid metabolism and insulin resistance through PI3K/AKT signal pathway.To extend the study, L6 skeletal muscle cells in vitro and sketel muscle issue of KKAy diabetic mice which induced with high fat and sugar diet were treated with special signaling pathway inhibitors and molecular biology methods to investigate the effect of visfatin on improving the glucolipid metabolism and insulin resistance through PI3K/AKT signal pathway, to find the possible mechanism of visfatin in glucose metabolism in sketel muscle and insulin resistance which may provide new targets for the prevention and therapy of diabetes and other linked metabolic diseases.

糖尿病已成为严重威胁人类健康的疾病，然而其发病机制尚未完全解析，因此，进一步探讨其发病机制并寻找有效的治疗策略具有重要临床意义。近来研究报道内脂素(Visfatin)具有类胰岛素作用，然而，关于Visfatin对骨骼肌糖代谢及胰岛素抵抗的影响及其相关分子机制尚未完全明了。本课题组前期研究发现糖尿病大鼠骨骼肌内脂素及PI3K均呈高表达状态，我们推测内脂素可能通过对PI3K/AKT信号通路的调控参与了糖尿病及胰岛素抵抗的发生发展。本实验拟通过体内外实验，采用高糖高脂诱导的L6骨骼肌细胞及KKAy糖尿病小鼠，利用特异性信号通路抑制剂及分子生物学方法，证实Visfatin通过PI3K/AKT途径调节骨骼肌糖代谢及胰岛素抵抗，探讨Visfatin 在骨骼肌糖代谢及 IR 的可能机制，并为糖尿病及其代谢相关疾病的防治提供新靶点。

糖尿病已成为严重威胁人类健康的疾病，然而其发病机制尚未完全解析，因此，进一步探讨其发病机制并寻找有效的治疗策略具有重要临床意义。近来研究报道内脂素(visfatin)具有类胰岛素作用，然而，关于Visfatin 对骨骼肌糖代谢及胰岛素抵抗的影响及其相关分子机制尚未完全明了。本课题组前期研究发现糖尿病大鼠骨骼肌内脂素及PI3K均呈高表达状态，我们推测内脂素可能通过对PI3K/AKT信号通路的调控参与了糖尿病及胰岛素抵抗的发生发展。本实验拟通过体内外实验，采用高糖高脂诱导的L6骨骼肌细胞及KKAy 糖尿病小鼠，利用特异性信号通路抑制剂及分子生物学方法，探讨Visfatin在骨骼肌糖代谢及胰岛素抵抗的可能机制，证实Visfatin可通过PI3K/AKT途径调节骨骼肌糖代谢及胰岛素抵抗，为糖尿病及其代谢相关疾病的防治提供新靶点。.研究内容：①分析Visfatin表达变化对骨骼肌胰岛素抵抗的影响；②分析Visfatin表达变化对骨骼肌PI3K/AKT 信号途径的影响；③分析PI3K/AKT途径抑制对Visfatin调节的骨骼肌胰岛素抵抗的影响，.研究结果：①visfatin过表达可显著降低L6骨骼肌细胞及KKAy糖尿病小鼠血糖水平及胰岛素抵抗；②过表达visfatin能够显著激活L6骨骼肌细胞及KKAy糖尿病小鼠骨骼肌PI3K/Akt通路，上调PI3K/Akt下游GSK3β、GLUT-4 、AS160和mTORC1蛋白表达，下调FoxO1蛋白表达；③Akt抑制剂可显著逆转visfatin过表达对L6骨骼肌细胞及KKAy糖尿病小鼠血糖水平及胰岛素抵抗的影响，并且下调PI3K/AKT通路下游GSK3β、GLUT-4 、AS160及mTORC1蛋白表达，上调FoxO1蛋白表达。.结论：visfatin可通过PI3K/AKT信号转导通路调节骨骼肌糖代谢及胰岛素抵抗。