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

糖尿病GLUT4易位及其异常的分子机制

• 批准号: 12470224
• 负责人: ASANO Tomoichiro
• 金额: $ 10.43万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470224/
• 关键词: Insulin; diabetes mellitus; Akt; PI 3 - Kinase; Insulin resistance; 糖輸送担体; AMPキナーゼ; インスリン作用; PI3-キナーゼ

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.

我们证明，PI 3-激酶的激活对于 GLUT4 易位至质膜是必要的，并表明位于 PI 3-激酶下游的 Akt 活性突变体的过度表达会诱导葡萄糖摄取增加，与观察到的情况类似。胰岛素刺激。由于Akt参与胰岛素诱导的葡萄糖代谢，我们利用酵母-二杂交系统筛选了与Akt相关的蛋白质，并鉴定了一个新的200kDa蛋白质。此外，我们构建了可以观察IRS-关联的系统。完整细胞系统中的蛋白质和 PI 3-激酶。另一方面，我们使用各种啮齿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，但在高血压大鼠模型中，胰岛素诱导的 PI 3 激酶激活显着增强。

项目成果

Asano,T.,Kanda,A., et al.: "P110β is upregulated during differentiation of 373-L cclls cells and contributes to highly insulin-responsive glucose transport activity"J.Biol.Chem.. 275(23). 17671-17676 (2000)

Asano, T.、Kanda, A. 等人：“P110β 在 373-L clls 细胞分化过程中上调，并有助于高度胰岛素响应的葡萄糖转运活性”J.Biol.Chem.. 275(23)。 -17676 (2000)

Yamada, T., et al.: "3-phosphoinositide-dependent protein kinase 1, an Akt1 kinase, is involved in dephosphorylation of Thr308 of Akt1 in Chinese hamster ovary cells"J. Biol. Chem.. 276. 5339-5345 (2001)

Yamada, T., et al.：“3-磷酸肌醇依赖性蛋白激酶 1，一种 Akt1 激酶，参与中国仓鼠卵巢细胞中 Akt1 Thr308 的去磷酸化”J.

Fanaki,M.,Katagir,H., et al.: "Structure and function of phophatidylinsitol-3,4 kinase"Cell.Sigual.. 12(3). 135-142 (2000)

Fanaki,M.,Katagir,H.等人：“磷脂酰肌醇-3,4激酶的结构和功能”Cell.Sigual.. 12(3)。

Ogihara, T., et al.: "Insulin resistance with enhanced insulin-signaling iu high-salt-Diet-Fed rats"Diabetes. 50. 573-583 (2001)

Ogihara, T. 等人：“高盐饮食喂养大鼠中胰岛素信号增强导致胰岛素抵抗”糖尿病。

Sakoda, H., et al.: "Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction"Diabetes. 49. 1700-1708 (2000)

Sakoda, H. 等人：“3T3-L1 脂肪细胞中地塞米松诱导的胰岛素抵抗是由于葡萄糖转运的抑制而不是胰岛素信号转导所致”糖尿病。