The role of phosphatidylinositol turnover on insulin-induced GLUT4 translocation and glucose uptake.

磷脂酰肌醇周转对胰岛素诱导的 GLUT4 易位和葡萄糖摄取的作用。

• 批准号: 11671119
• 负责人: OKUYA Shigeru
• 金额: $ 1.92万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671119/
• 关键词: insulin-induced glucose uptake; phosphatidylinositol; GLUT4 translocation; phosphatidylinositol 3-kinase; PI 3, 4, 5-P_3; PI 3, 4-P_2; SHIP(SH2-containing inositol 5'-phosphatase); PI 3,4,5-P_3; SHIP (SH2-containing inositol 5'-phosphatase); GLUT

Insulin stimulation leads to rapid activation of phosphatidylinositol 3-kinase(PI3-kinase)and the subsequent formation of phosphatidylinositol(PI)3, 4-P_2 and PI 3, 4, 5-P_3, which are thought to be involved in signaling for insulin-dependent glucose transporter GLUT4 translocation and glucose uptake. However, the specific role of each of these PIs in insulin signaling is still controversial. Therefore, we assessed the effects of wild type SH2-containing inositol 5'-phosphatase(wt-SHIP)expression, which is expected to decrease the cellular levels of PI 3, 4, 5-P_3, on these biological effects. Moreover, we compared the effects of myristoylated SHIP(myr-SHIP), which has a membrane targeting moiety, to those of wt-SHIP, because PI turnover is thought to occur at plasma membrane.LacZ(as control), wild-SHIP or myr-SHIP is overexpressed into 3T3-L1 adipocytes using recombinant adenovirus system. Overexpression of each protein was confirmed with immunoblotting, and 5'-phosphatase activity of … More the expressed SHIP was verified by dephosphorylation of[3'-^<32>P]PI 3, 4, 5-P_3 to[3'-^<32>P]PI 3, 4-P_2 in vitro. At 10^<-7> M insulin concentration overexpression of wt-SHIP and myr-SHIP did not inhibit but rather stimulated insulin-induced glucose uptake by 1.7-fold and 2.7-fold above the value obtained with overexpression of LacZ, respectively, in 3T3-L1 adipocytes. Overexpression of wt-SHIP and myr-SHIP did not have any significant effect on total GLUT4 expression, but did potentiate insulin-induced GLUT4 translocation.In summary, our results demonstrated that expression of wt-SHIP and myr-SHIP potentiated insulin-induced GLUT4 translocation and glucose uptake, suggesting that PI 3, 4-P_2, rather than PI 3, 4, 5-P_3, is the major phospholipid product mediating these biological actions.In addition, we also repored that dominant negative mutant hepatocyte nuclear factor(HNF)-1α influenced insulin secretion, and that troglitazone increased plasma vascular endothelial growth factor levels, which might cause edema and vascular complications. Less

胰岛素刺激导致磷脂酰肌醇3-激酶（PI 3-kinase）的快速激活，并随后形成磷脂酰肌醇（PI）3，4-P_2和PI 3，4，5-P_3，它们被认为参与胰岛素依赖性葡萄糖转运蛋白GLUT 4转位和葡萄糖摄取的信号传导。然而，这些PI中的每一个在胰岛素信号传导中的具体作用仍然存在争议。因此，我们评估了野生型含SH 2的肌醇5 '-磷酸酶（wt-SHIP）表达对这些生物学效应的影响，预期其降低PI 3，4，5-P_3的细胞水平。此外，我们比较了具有膜靶向部分的肉豆蔻酰化SHIP（myr-SHIP）与wt-SHIP的作用，因为PI被认为发生在质膜上。每种蛋白质的过表达用免疫印迹法确认，并且5 '-磷酸酶活性测定表明， ...更多信息 体外脱磷酸化[3 '-^<32>P]PI 3，4，5-P_3为[3'-^<32>P]PI 3，4-P_2，证实了表达的SHIP。在<-7>3 T3-L1脂肪细胞中，在10 μ M胰岛素浓度下，过表达wt-SHIP和myr-SHIP并不抑制而是刺激胰岛素诱导的葡萄糖摄取，分别比过表达LacZ获得的值高1.7倍和2.7倍。总之，我们的结果表明，wt-SHIP和myr-SHIP的表达增强了胰岛素诱导的GLUT 4易位和葡萄糖摄取，表明PI 3，4-P_2，而不是PI 3，4，5-P_3，此外，我们还报道了显性负突变型肝细胞核因子（HNF）-1α影响胰岛素分泌，曲格列酮增加血浆血管内皮生长因子水平，可能引起水肿和血管并发症。少

项目成果

Y.Tanizawa, et al.: "Overexpression of dominant negative mutant hepatocyte nuclear factor(HNF)-1α inhibits arginine-induced insulin secretion in MIN6"Diabetologia. 42. 887-891 (1999)

Y. Tanizawa 等人：“显性失活突变型肝细胞核因子 (HNF)-1α 的过度表达抑制 MIN6 中精氨酸诱导的胰岛素分泌”《糖尿病学》42. 887-891 (1999)。

Y.Tanizawa, et al.: "Overexpression of dominant negative mutant hepatocyte nuclear factor (HNF)-1 α inhibits arginine-induced insulin secretion in MIN6"Diabetologia. 42. 887-891 (1999)

Y. Tanizawa 等人：“显性失活突变型肝细胞核因子 (HNF)-1 α 的过度表达抑制 MIN6 中精氨酸诱导的胰岛素分泌”Diabetologia。 42. 887-891 (1999)

M.Emoto, et al.: "Toroglitazone Treatment Increases Plasma Vascular Endothelial Growth Factor in Diabetic Patients and Its mRNA in 3T3-L1 Adipocytes"Diabetes. (in press). (2000)

M.Emoto 等人：“Toroglitazone 治疗可增加糖尿病患者血浆血管内皮生长因子及其在 3T3-L1 脂肪细胞中的 mRNA”糖尿病。

M.Emoto, et al.: "Toroglitazone Treatment Increases Plasma Vascular Endothelial Growth Factor in Diabetic Patients and Its mRNA in 3T3-L1 Adipocytes"Diabetes. (in press).

M.Emoto 等人：“Toroglitazone 治疗可增加糖尿病患者血浆血管内皮生长因子及其在 3T3-L1 脂肪细胞中的 mRNA”糖尿病。