Maegawa H, Ide R, Hasegawa M, Ugi S, Egawa K, Iwanishi M, Kikkawa R, Shigeta Y, Kashiwagi A
Third Department of Medicine, Shiga University of Medical Science, Japan.
J Biol Chem. 1995 Mar 31;270(13):7724-30. doi: 10.1074/jbc.270.13.7724.
The mechanisms for the insulin resistance induced by hyperglycemia were investigated by studying the effect of high glucose concentration (HG) and its modulation by thiazolidine derivatives, on insulin signaling using Rat 1 fibroblasts expressing human insulin receptors (HIRc). Incubating HIRc cells in 27 mM D-glucose for 4 days impaired the insulin-stimulated phosphorylation of pp185 and receptor beta-subunits. Both protein kinase C activities and phorbol dibutyrate binding to intact cells were unchanged; however, cytosolic protein-tyrosine phosphatase (PTPase) activity increased within 1 h prior to the impairment of insulin receptor kinase in HG cells (Maegawa, H., Tachikawa-Ide, R., Ugi, S., Iwanishi, M., Egawa, K., Kikkawa, R., Shigeta, Y., and Kashiwagi, A. (1993) Biochem. Biophys. Res. Commun. 197, 1078-1082). Increased PTPase activity was consistent with a 2-fold increase in the amount of PTP1B, and anti-PTP1B antibody inhibited this increment of cytosolic PTPase activity in HG cells. Co-incubating cells with pioglitazone prevented these abnormalities in cytosolic PTPase, the PTP1B content and the impaired phosphorylation of pp185 and receptor beta subunits in HG cells. Finally, HG cells had impaired insulin-stimulated alpha-amino-isobutyric acid uptake, which was ameliorated by exposure to thiazolidine derivatives. In conclusion, exposing cells to high glucose levels desensitizes insulin receptor function, and thiazolidine derivatives can reverse the process via the normalization of cytosolic PTPase, but not of protein kinase C.
通过使用表达人胰岛素受体（HIRc）的大鼠1成纤维细胞，研究高葡萄糖浓度（HG）及其经噻唑烷衍生物调节对胰岛素信号传导的影响，以探究高血糖诱导胰岛素抵抗的机制。将HIRc细胞在27 mM D-葡萄糖中孵育4天，会损害胰岛素刺激的pp185和受体β亚基的磷酸化。蛋白激酶C活性和佛波醇二丁酸酯与完整细胞的结合均未改变；然而，在HG细胞中胰岛素受体激酶受损之前1小时内，胞质蛋白酪氨酸磷酸酶（PTPase）活性增加（前川浩、立川井手礼、宇木史、岩西真、江川启、岸川隆、重田洋、柏木昭（1993年）《生物化学与生物物理研究通讯》197，1078 - 1082）。PTPase活性增加与PTP1B量增加2倍一致，并且抗PTP1B抗体抑制了HG细胞中胞质PTPase活性的这种增加。使细胞与吡格列酮共同孵育可防止HG细胞中胞质PTPase、PTP1B含量以及pp185和受体β亚基磷酸化受损的这些异常情况。最后，HG细胞胰岛素刺激的α-氨基异丁酸摄取受损，而暴露于噻唑烷衍生物可改善这种情况。总之，使细胞暴露于高葡萄糖水平会使胰岛素受体功能脱敏，并且噻唑烷衍生物可通过使胞质PTPase正常化而非蛋白激酶C正常化来逆转这一过程。
