脂毒性是肥胖导致2型糖尿病的主要病理生理机制。我们近期发现促进脂质合成的转录因子固醇调节元件结合蛋白1 c（SREBP-1c）可直接抑制胰岛素受体底物-1的基因启动子转录而导致骨骼肌胰岛素抵抗。既往研究表明胰岛素增强SREBP-1c转录活性，而我们体内体外实验均发现胰岛素可抑制SREBP-1c活化所导致的骨骼肌胰岛素抵抗，但机制不明确。我们进一步研究发现通过显性失活慢病毒抑制腺苷酸活化蛋白激酶（AMPK）活性则可拮抗胰岛素上述作用，同时胰岛素激活AMPK，升高AMP/ATP比值，表明胰岛素可能通过激活AMPK而拮抗SREBP-1c活化，但机制尚不明确。本项目通过建立基因敲除的小鼠模型和细胞模型等方法，进一步阐明AMPK在胰岛素抑制骨骼肌SREBP-1c活化而改善脂毒性胰岛素抵抗中的作用及其分子机制。研究结果将有助于推进对脂毒性机制的认识，并为早期胰岛素治疗2型糖尿病的靶点研究奠定理论基础。

Lipotoxicity plays an important role in the association between obesity and type 2 diabetes mellitus. Our recent study indicated for the first time that sterol regulatory element binding protein 1c (SREBP-1c), a transcription factor that controls cellular lipogenesis, participates in fatty acid-induced insulin resistance through a direct effect of suppressing the transcription of insulin receptor substrate-1 in skeletal muscle cells, addressing its potential importance in metabolic disease. Earlier studies suggested that insulin promotes SREBP-1c activation, whereas we found that insulin reduced SREBP-1c nuclear translocation and improved insulin resistance in vivo and in vitro, and little is known about the mechanism. AMP-activated protein kinase (AMPK) is known as an intracellular energy sensor. We found that the inhibition of SREBP-1c activity by insulin was significantly attenuated with AMPK dominant negative lentivirus. Meanwhile, we found that insulin increased AMPK phosphorylation and increased the AMP/ATP ratio in palmitate-pretreated L6 myotubes. These studies suggested that the activation of AMPK is necessary for insulin suppression of SREBP-1c activity in lipid nutrient excess. Based on these results, further studies will be performed to provide the molecular insight into the mechanism by which insulin activates AMPK to inhibit SREBP-1c activity and regulates mitochondrial function to increase AMP/ATP ratio. This study will extend the understanding of lipotoxicity and provide clues into the specific therapeutic target for improving insulin resistance and timing for insulin treatment in type 2 diabetes mellitus.