Seki N, Yagi S, Suzuki Y, Shimada F, Taira M, Makino H, Amano K, Yagui K, Saito Y, Hashimoto N
Clinical Research Center, National Hospital Organization, Chiba-East National Hospital, Chiba, Japan.
Horm Metab Res. 2008 Dec;40(12):833-7. doi: 10.1055/s-0028-1082082. Epub 2008 Oct 16.
Tyrosine phosphorylation of the insulin receptor is the initial event following receptor binding to insulin, and it induces further tyrosine phosphorylation of various intracellular molecules. This signaling is countered by protein tyrosine phosphatases (PTPases), which reportedly are associated with insulin resistance that can be reduced by regulation of PTPases. Protein tyrosine phosphatase 1B (PTP1B) and leukocyte antigen-related PTPase (LAR) are the PTPases implicated most frequently in insulin resistance and diabetes mellitus. Here, we show that PTP1B and LAR are expressed in human fibroblasts, and we examine the regulation of PTPase activity in fibroblasts from patients with an insulin receptor gene mutation as an in vitro model of insulin resistance. Total PTPase activity was significantly lower in the cytosolic and membrane fractions of fibroblasts with mutations compared with controls (p<0.05). Insulin stimulation of fibroblasts with mutations resulted in a significantly smaller increase in PTP1B activity compared with stimulation of wild-type fibroblasts (p<0.05). This indicates that insulin receptor gene mutations blunt increases in PTPase activity in response to insulin, possibly via a negative feedback mechanism. Our data suggest that the PTPase activity in patients with insulin receptor gene mutation and severe insulin resistance may differ from that in ordinary type 2 diabetes.
胰岛素受体的酪氨酸磷酸化是受体与胰岛素结合后的初始事件，它会诱导各种细胞内分子发生进一步的酪氨酸磷酸化。这种信号传导会被蛋白酪氨酸磷酸酶（PTPases）抵消，据报道，PTPases与胰岛素抵抗有关，通过调节PTPases可以降低胰岛素抵抗。蛋白酪氨酸磷酸酶1B（PTP1B）和白细胞抗原相关磷酸酶（LAR）是最常与胰岛素抵抗和糖尿病相关的PTPases。在此，我们表明PTP1B和LAR在人成纤维细胞中表达，并且我们将胰岛素受体基因突变患者的成纤维细胞中PTPase活性的调节作为胰岛素抵抗的体外模型进行研究。与对照组相比，突变型成纤维细胞的胞质和膜部分中的总PTPase活性显著降低（p<0.05）。与野生型成纤维细胞相比，胰岛素刺激突变型成纤维细胞导致PTP1B活性的增加明显较小（p<0.05）。这表明胰岛素受体基因突变可能通过负反馈机制减弱胰岛素刺激引起的PTPase活性增加。我们的数据表明，胰岛素受体基因突变和严重胰岛素抵抗患者的PTPase活性可能与普通2型糖尿病患者不同。
