Molecular mechanism underlying the GLUT4 translocation and its abnormality in diabetes mellitus

我们证明了PI 3-激酶的激活对于GLUT4转运到质膜是必要的，并且表明PI 3-激酶下游Akt的活性突变体的过表达诱导了葡萄糖摄取的增加，与胰岛素刺激相似。由于Akt参与胰岛素诱导的葡萄糖代谢，我们使用酵母- 2杂交系统筛选了与Akt相关的蛋白，并鉴定了一个新的200kDa蛋白。此外，我们还构建了一个系统，通过该系统我们可以在完整的细胞系统中观察irs蛋白和PI 3-激酶的结合。另一方面，我们利用各种啮齿类动物模型研究了胰岛素抵抗的分子机制。一个有趣的发现是，尽管存在胰岛素抵抗，胰岛素诱导的PI 3-激酶激活在高血压大鼠模型中显着增强。

We demonstrated that the activation of PI 3-kinase is necessary for the translocation of GLUT4 to the plasma membrane, and showed that the overexpression of the active mutant of Akt located downstream of PI 3-kinase induced the increased glucose uptake, similarly as observed for insulin stimulation. Since Akt is involved in the insulin-induced glucose metabolisms, we screened the protein associated with Akt, using yeast-two hybrid system, and identified a novel 200kDa protein.Furthermore, we constructed the system by which we can observe the association of IRS-protein and PI 3-kinase in an intact cell system. On the other hand, we investigated the molecular mechanisms of insulin resistance using various rodent models. An interesting finding is that the insulin-induced PI 3-kinase activation was markedly enhanced in the hypertensive rat models, despite the presence of insulin resistance.