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

Caveolin-3（肌肉特异性的 Caveolin 亚型）的缺乏会导致胰岛素抵抗的发生

• 批准号: 15590951
• 负责人: TOYA Yoshiyuki
• 金额: $ 2.05万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590951/
• 关键词: insulin resistance; insulin signal; caveolin; skeletal muscle; glycogen; type 2 diabetes; knockout mouse; gene transfer; インスリン

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

2型糖尿病之前是胰岛素抵抗的发展，其中胰岛素的作用受损，主要是在骨骼肌中。小窝蛋白-3是小窝蛋白的肌肉特异性亚型，其是在细胞膜内发现的支架蛋白的实例的主要组分。在这项研究中，我们发现小窝蛋白-3的缺乏导致胰岛素抵抗的发展，例如骨骼肌中葡萄糖摄取减少，葡萄糖耐量试验性能受损和血脂增加。在存在链脲佐菌素（一种胰腺β细胞毒素）的情况下，这种损伤显著增强，表明小鼠在存在额外风险因素的情况下易患严重糖尿病。胰岛素刺激的受体和下游分子（如IRS-1和Akt）的激活在小窝蛋白-3缺失小鼠的骨骼肌中减弱，但在肝脏中不减弱，而不影响蛋白表达或亚细胞定位。遗传转化 ...更多信息 通过针注射小窝蛋白-3的SFER恢复了骨骼肌中的胰岛素信号传导。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，我们研究了在糖尿病动物模型中，通过腺病毒介导的基因转移，在表达很少内源性小窝蛋白的肝脏中过表达小窝蛋白-3的效果。基因转移显著改善了体内胰岛素敏感性，如胰岛素注射后血糖水平的增强下降所示，并因此改善了糖尿病小鼠的葡萄糖代谢，例如更大的葡萄糖耐量试验表现和增加的糖原合成。小窝蛋白-3在体外肝细胞中的过表达导致在生理浓度的胰岛素下胰岛素受体以及IRS-1和Akt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增强胰岛素受体信号和模仿胰岛素的作用。少

项目成果

Insulin resistance in skeletal muscles of caveolin-3-null mice

• DOI: 10.1073/pnas.0402053101
• 发表时间: 2004-08-24
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Oshikawa, J;Otsu, K;Ishikawa, Y
• 通讯作者: Ishikawa, Y

Insulin resistance in 5keletal muscles of caveolin-3-null mice

Caveolin-3缺失小鼠5个骨骼肌的胰岛素抵抗

• 发表时间: 2004
• 期刊: Proc Natl Acad Sci USA 101・34
• 作者: Oshikawa;Jin;Otsu;Koji;Toya;Yoshiyuki;Tsunematsu;Takashi;Hankins;Raleigh;Kawabe;Jun-ichi;Minamisawa;Susumu;Umemura;Satoshi;Hagiwara Yasuko;Ishikawa;Yoshihiro;Oshikawa J
• 通讯作者: Oshikawa J