The lack of caveolin-3, muscle-specific subtype of caveolin, leeds to the development of insulin resistance

2型糖尿病发病前会出现胰岛素抵抗，胰岛素的作用受损，主要是在骨骼肌中。小窝蛋白-3是小窝蛋白的一种肌肉特异性亚型，是细胞膜内发现的支架蛋白的一个主要成分。在这项研究中，我们发现，缺乏小窝蛋白-3导致胰岛素抵抗的发展，例如骨骼肌葡萄糖摄取减少，葡萄糖耐量试验表现受损，血脂升高。这种损伤在链脲佐菌素（一种胰腺β细胞毒素）的存在下明显增强，表明在存在额外风险因素的情况下，小鼠易患严重的糖尿病。胰岛素刺激的受体和下游分子（如IRS-1和Akt）的激活在caveolin-3缺失小鼠的骨骼肌中减弱，但在肝脏中没有，不影响蛋白质表达或亚细胞定位。通过针注射更多的小室蛋白-3恢复骨骼肌胰岛素信号传导。我们的研究结果表明，小窝蛋白-3是骨骼肌中胰岛素信号的增强剂，但不作为胰岛素受体的支架分子。此外，我们通过腺病毒介导的基因转移，在糖尿病动物模型中检测了小窝蛋白3在肝脏中过表达的影响，小窝蛋白在肝脏中内源性表达很少。基因转移显著改善了体内胰岛素敏感性，如注射胰岛素后血糖水平的下降，从而改善了糖尿病小鼠的葡萄糖代谢，如葡萄糖耐量试验表现更好，糖原合成增加。体外肝细胞中caveolin-3的过度表达导致胰岛素受体以及IRS-1和Akt在生理胰岛素浓度下的活化增加。我们的研究结果表明，小窝蛋白基因转移到肝脏可以增强胰岛素受体信号并模拟胰岛素的作用。少

Type 2 diabetes is preceded by the development of insulin resistance, in which the action of insulin is impaired, largely in skeletal muscles. Caveolin-3 is a muscle-specific subtype of caveolin, which is a major component of an example of a scaffolding protein, found within cellular membranes. In this study, we found that the lack of caveolin-3 led to the development of insulin resistance, as exemplified by decrease glucose uptake in skeletal muscles, impaired glucose tolerance test performance, and increases in serum lipids. Such impairments were markedly augmented in the presence of streptozotocin, a pancreatic β cell toxin, suggesting that the mice were susceptible to severe diabetes in the presence of an additional risk factor. Insulin-stimulated activation of receptors and downstream molecules, such as IRS-1 and Akt, was attenuated in the skeletal muscles of caveolin-3 null mice, but not in the liver, without affecting protein expression or sub cellular localization. Genetic tran … More sfer of caveolin-3 by needle injection restored insulin signaling in skeletal muscles. Our findings suggest that caveolin-3 is an enhancer of insulin signaling in skeletal muscles but does not act as a scaffolding molecule for insulin receptors. Moreover, We examined the effect of overexpressing caveolin-3 in the liver, which expresses little endogenous caveolin, by adenovirus-mediated gene transfer in diabetic animal models. Gene transfer significantly improved insulin sensitivity in vivo, as shown by an enhanced decline in blood glucose levels upon insulin injection, and thus improved glucose metabolism in diabetic mice, exemplified by greater glucose tolerance test performance and increased glycogen synthesis. Overexpression of caveolin-3 in hepatic cells in vitro led to increased activation of insulin receptors, as well as IRS-1 and Akt, at physiological concentrations of insulin. Our findings suggest that caveolin gene transfer to the liver enhances insulin receptor signal and mimics insulin action. Less