Analysis of negative-feed back mechanism through mTOR pathway in insulin action.

在3T3-L1脂肪细胞中，胰岛素诱导的胰岛素样生长因子受体1在Ser307、Ser612和Ser636/639上的磷酸化可被雷帕霉素降低，并被JNK抑制剂SP 600125进一步抑制。雷帕霉素和SP 600125均可抑制山奈酚诱导的相同残基上的磷酸化。与胰岛素不同，茴香霉素不能引起IRS-1的易位或降解。2)IL-1α和IRS-1丝氨酸磷酸化。在IL-1刺激后15min左右，IRS-1在一些丝氨酸残基上被短暂磷酸化，激活了一些丝氨酸激酶、IKK、JNK、ERK和p70S6K。IRS-1的酪氨酸磷酸化仅被IKK抑制剂或JNK抑制剂所恢复，提示这两种信号转导通路的特异性参与。IL-1不抑制胰岛素刺激的Akt磷酸化和2-脱氧葡萄糖摄取。IL-1对AKT的磷酸化有协同抑制作用。因此，短期的IL-1治疗会在IRS-1的丝氨酸磷酸化水平上引起短暂的胰岛素抵抗。在其他细胞因子如IL-6存在的情况下，IL1可能抑制IRS-1下游的胰岛素信号。

1)Roles of mTOR and INK in insulin or anisomycin-induced IRS-1 serine phosphorylation.In 3T3-L1 adipocytes, insulin-induced phosphorylation of IRS-1 on Ser 307, ser 612, and Ser 636/639 was reduced by rapamycin, and was further inhibited by the combination with JNK inhibitor, SP 600125. Anisomycin-induced phosphorylation on the same residues was inhibited both rapamycin and SP 600125. Unlike insulin, anisomycin failed to elicit translocation or degradation of IRS-1. Therefore, mTOR and JNK pathways play the same IRS-1 serine phosphorylation, but are different in IRS-1 translocation and degradation.2)IL-1α and IRS-1 serine phosphorylation.IRS-1 was transiently phosphorylated on some serine residues around 15min after IL-1 stimulation, when several serine kinases, IKK, JNK, ERK, and p70S6K were activated. Tyrosine phosphorylation of IRS-1 was recovered only by IKK inhibitor or JNK inhibotor, suggesting the specific involvement of these two kinases. Insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake were not inhibited by IL-1. Akt phosphorylation was synergistically inhibited by IL-1 in the presence IL-6. Thus, short term IL-1 treatment transiently causes insulin resistance at the level of IRS-1 with its serine phosphorylation. IL1 may suppress insulin signaling downstream of IRS-1 in the presence of other cytokines, such as IL-6.