Ricort J M, Tanti J F, Van Obberghen E, Le Marchand-Brustel Y
Institut National de la Santé et de la Recherche Médicale, INSERM U145, Faculté de Médecine, Nice, France.
Diabetologia. 1995 Oct;38(10):1148-56. doi: 10.1007/BF00422363.
Insulin-induced glucose transport stimulation, which results from the translocation of glucose transporter 4 (GLUT 4)-containing vesicles, is completely blocked after prolonged insulin treatment of 3T3-L1 adipocytes. Since GLUT 4 expression was reduced by only 30%, we looked at the insulin signaling pathway in this insulin-resistant model. Insulin-induced tyrosine phosphorylation of the major insulin receptor substrate IRS 1 was reduced by 50 +/- 7%, while its expression was decreased by 70 +/- 4%. When cells were treated with worthmannin (a PI3-kinase inhibitor) together with insulin, the expression of IRS 1 diminished to a much lower extent. Associated with the decrease in IRS 1 expression and phosphorylation, the activation by insulin of anti-phosphotyrosine immunoprecipitable PI3-kinase activity and of p44mapk activities was altered. However, the expression of these proteins was normal and p44mapk activity remained responsive to the tumour promoter TPA. Those results indicate that prolonged insulin treatment of 3T3-L1 adipocytes induces an insulin-resistant state with a reduced ability of insulin to stimulate the PI3-kinase and the MAP-kinases and a blockade of glucose transporter translocation.
胰岛素诱导的葡萄糖转运刺激是由含葡萄糖转运蛋白4（GLUT 4）的囊泡转位引起的，在对3T3-L1脂肪细胞进行长时间胰岛素处理后，这种刺激被完全阻断。由于GLUT 4表达仅降低了30%，我们研究了这个胰岛素抵抗模型中的胰岛素信号通路。胰岛素诱导的主要胰岛素受体底物IRS 1的酪氨酸磷酸化降低了50±7%，而其表达降低了70±4%。当细胞用渥曼青霉素（一种PI3激酶抑制剂）和胰岛素共同处理时，IRS 1的表达降低程度要低得多。与IRS 1表达和磷酸化的降低相关，胰岛素对抗磷酸酪氨酸免疫沉淀的PI3激酶活性和p44mapk活性的激活发生了改变。然而，这些蛋白质的表达正常，并且p44mapk活性仍然对肿瘤启动子TPA有反应。这些结果表明，对3T3-L1脂肪细胞进行长时间胰岛素处理会诱导胰岛素抵抗状态，胰岛素刺激PI3激酶和MAP激酶的能力降低，并且葡萄糖转运蛋白转位被阻断。
