Le Marchand-Brustel Y, Tanti J F, Cormont M, Ricort J M, Grémeaux T, Grillo S
INSERM U 145 Faculty of Medicine, Nice, France.
J Recept Signal Transduct Res. 1999 Jan-Jul;19(1-4):217-28. doi: 10.3109/10799899909036647.
Insulin resistance is commonly associated with obesity in rodents. Using mice made obese with goldthioglucose (GTG-obese mice), we have shown that insulin resistance results from defects at the level of the receptor and from intracellular alterations in insulin signalling pathway, without major alteration in the number of the Glut 4 glucose transporter. Activation of phosphatidylinositol 3-kinase (PI 3-kinase) was found to be profoundly affected in response to insulin. This defect appears very early in the development of obesity, together with a marked decrease in IRS 1 tyrosine phosphorylation. In order to better understand the abnormalities in glucose transport in insulin resistance, we have studied the pathway leading from the insulin receptor kinase stimulation to the translocation of the Glut 4 containing vesicles. This stimulation involves the activation of PI 3-kinase, which in turns activates protein kinase B. We have then focussed at the mechanism of vesicle exocytosis, and more specifically at the role of the small GTPase Rab4 in this process. We have shown that Rab4 participates, first in the intracellular retention of the Glut 4 containing vesicles, second in the insulin signalling pathway leading to glucose transporter translocation.
胰岛素抵抗在啮齿动物中通常与肥胖相关。利用用金硫葡萄糖诱导肥胖的小鼠（GTG肥胖小鼠），我们已经表明胰岛素抵抗是由受体水平的缺陷以及胰岛素信号通路中的细胞内改变引起的，而葡萄糖转运蛋白4（Glut 4）的数量没有重大改变。发现磷脂酰肌醇3激酶（PI 3激酶）的激活在对胰岛素的反应中受到深刻影响。这种缺陷在肥胖发展的早期就出现了，同时胰岛素受体底物1（IRS 1）酪氨酸磷酸化显著降低。为了更好地理解胰岛素抵抗中葡萄糖转运的异常，我们研究了从胰岛素受体激酶刺激到含Glut 4囊泡转位的途径。这种刺激涉及PI 3激酶的激活，PI 3激酶进而激活蛋白激酶B。然后我们专注于囊泡胞吐作用的机制，更具体地说是小GTP酶Rab4在这个过程中的作用。我们已经表明，Rab4首先参与含Glut 4囊泡的细胞内滞留，其次参与导致葡萄糖转运蛋白转位的胰岛素信号通路。
