Insulin resistance in skeletal muscles of caveolin-3-null mice
Insulin resistance in skeletal muscles of caveolin-3-null mice
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DOI：
10.1073/pnas.0402053101
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发表时间：
2004-08-24
影响因子：
11.1
通讯作者：
Ishikawa, Y
中科院分区：
文献类型：
--
作者：
Oshikawa, J;Otsu, K;Ishikawa, Y
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 （Cav3）是小窝蛋白的肌肉特异性亚型，是在膜内发现的支架蛋白的一个例子。Cav也被称为生长信号抑制剂，尽管最近证明Cav3的遗传破坏不会增加小鼠的生长。然而，我们发现Cav3的缺乏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（一种胰腺细胞毒素）的存在下明显增强，这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。胰岛素刺激的胰岛素受体和下游分子（如IRS-1和Akt）的激活在Cav3缺失小鼠的骨骼肌中减弱，但在肝脏中没有减弱，不影响蛋白质表达或亚细胞定位。针注射Cav3基因转移恢复骨骼肌胰岛素信号传导。我们的研究结果表明，Cav3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。
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 (Cav3) is a muscle-specific subtype of caveolin, an example of a scaffolding protein found within membranes. Cav is also known as growth signal inhibitor, although it was recently demonstrated that the genetic disruption of Cav3 did not augment growth in mice. We found, however, that the lack of Cav3 led to the clevelopment of insulin resistance, as exemplified by decreased 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 13 cell toxin, suggesting that the mice were susceptible to severe diabetes in the presence of an additional risk factor. Insulin-stimulated activation of insulin receptors and downstream molecules, such as IRS-1 and Akt, was attenuated in the skeletal muscles of Cav3 null mice, but not in the liver, without affecting protein expression or subcellular localization. Genetic transfer of Cav3 by needle injection restored insulin signaling in skeletal muscles. Our findings suggest that Cav3 is an enhancer of insulin signaling in skeletal muscles but does not act as a scaffolding molecule for insulin receptors.