The inability of phosphatidylinositol 3-kinase activation to stimulate GLUT4 translocation indicates additional signaling pathways are required for insulin-stimulated glucose uptake.

Recent experimental evidence has focused attention to the role of two molecules, insulin receptor substrate 1 (IRS-1) and phosphatidylinositol 3-kinase (PI3-kinase), in linking the insulin receptor to glucose uptake; IRS-1 knockout mice are insulin resistant, and pharmacological inhibitors of PI3-kinase block insulin-stimulated glucose uptake. To investigate the role of PI3-kinase and IRS-1 in insulin-stimulated glucose uptake we examined whether stimulation of insulin-sensitive cells with platelet-derived growth factor (PDGF) or with interleukin 4 (IL-4) stimulates glucose uptake; the activated PDGF receptor (PDGFR) directly binds and activates PI3-kinase, whereas the IL-4 receptor (IL-4R) activates PI3-kinase via IRS-1 or the IRS-1-related molecule 4PS. We found that stimulation of 3T3-L1 adipocytes with PDGF resulted in tyrosine phosphorylation of the PDGFR and activation of PI3-kinase in these cells. To examine whether IL-4 stimulates glucose uptake, L6 myoblasts were engineered to overexpress GLUT4 as well as both chains of the IL-4R (L6/IL-4R/GLUT4); when these L6/IL-4R/GLUT4 myoblasts were stimulated with IL-4, IRS-1 became tyrosine phosphorylated and associated with PI3-kinase. Although PDGF and IL-4 can activate PI3-kinase in the respective cell lines, they do not possess insulin's ability to stimulate glucose uptake and GLUT4 translocation to the plasma membrane. These findings indicate that activation of PI3-kinase is not sufficient to stimulate GLUT4 translocation to the plasma membrane. We postulate that activation of a second signaling pathway by insulin, distinct from PI3-kinase, is necessary for the stimulation of glucose uptake in insulin-sensitive cells. IMAGES:

近期的实验证据将研究焦点投向了两种分子——胰岛素受体底物1（insulin receptor substrate 1，IRS-1）与磷脂酰肌醇3-激酶（phosphatidylinositol 3-kinase，PI3-kinase）——在连接胰岛素受体与葡萄糖摄取过程中所发挥的作用：敲除IRS-1的小鼠会表现出胰岛素抵抗，而PI3-激酶的药理学抑制剂能够阻断胰岛素刺激的葡萄糖摄取。为探究PI3-激酶与IRS-1在胰岛素刺激的葡萄糖摄取过程中的作用，本研究考察了用血小板衍生生长因子（platelet-derived growth factor，PDGF）或白细胞介素4（interleukin 4，IL-4）刺激胰岛素敏感细胞是否能够促进葡萄糖摄取。活化的血小板衍生生长因子受体（PDGF receptor，PDGFR）可直接结合并激活PI3-激酶，而白细胞介素4受体（IL-4 receptor，IL-4R）则通过IRS-1或IRS-1相关分子4PS激活PI3-激酶。本研究发现，用PDGF刺激3T3-L1脂肪细胞，可使该细胞中的PDGFR发生酪氨酸磷酸化，并激活PI3-激酶。为验证IL-4是否能够促进葡萄糖摄取，研究人员对L6成肌细胞进行基因工程改造，使其过表达葡萄糖转运蛋白4（glucose transporter type 4，GLUT4）以及IL-4R的两条链，构建得到L6/IL-4R/GLUT4细胞株；当用IL-4刺激这些L6/IL-4R/GLUT4成肌细胞时，IRS-1会发生酪氨酸磷酸化，并与PI3-激酶结合。尽管PDGF与IL-4均可在各自的细胞系中激活PI3-激酶，但二者均不具备胰岛素的固有能力，无法刺激葡萄糖摄取以及GLUT4转位至细胞膜。上述研究结果表明，仅激活PI3-激酶并不足以促进GLUT4转位至细胞膜。本研究推测，胰岛素除激活PI3-激酶通路外，还需启动另一类截然不同的信号通路，方可实现胰岛素敏感细胞的葡萄糖摄取刺激效应。图像：