MECHANISMS FOR INSULIN RESISTANCE BY SERINE KINASE ACTIVATION

我们研究了与几种丝氨酸激酶激活相关的胰岛素抵抗机制。第一个项目是分析新的丝氨酸激酶。我们发现p70S6激酶参与了TNFa刺激后IRS-1的丝氨酸磷酸化。Mdm2是一种泛素连接酶，在胰岛素刺激后以pi3激酶依赖的方式使IRS-1泛素化。这些数据在日本糖尿病协会年会上发表。第二个项目是刺激IRS-1丝氨酸磷酸化的新配体。我们发现IL-la刺激了几种丝氨酸激酶，其中JNK和mTOR对IRS-1丝氨酸磷酸化很重要。这些数据发表在《分子内分泌学》上。然后，研究了大霉素和胰岛素对IRS-1丝氨酸磷酸化的不同机制。JNK对前者很重要，而mTOR对后者很重要。这些数据已在BBRC中报道。第三个项目是评估体内胰岛素抵抗模型中IRS-1丝氨酸磷酸化和SOCS表达，这两者对于IRS-1的降解都很重要。在高脂喂养小鼠和db/db/小鼠中，IRS-1丝氨酸磷酸化和SOCS表达增强。吡格列酮是一种胰岛素增敏药物，可降低IRS-1丝氨酸磷酸化和SOCS表达，导致IRS-1水平的胰岛素信号传导增强。这些数据发表在《糖尿病》杂志上。最后，研究了IRS-1丝氨酸磷酸化与SOCS表达的关系。我们发现胰岛素信号在IRS-1丝氨酸磷酸化和SOCS表达的情况下被抑制，其中一种不诱导3T3-L1脂肪细胞的胰岛素抵抗。这些数据发表在《内分泌学》杂志上。

We investigated the mechanisms for insulin resistance associated to the activation of several serine kinases. First project was the analysis of the new serine kinases. We found that p70S6 kinase was involved in the serine phosphorylation of IRS-1 after TNFa stimulation. Mdm2 was a ubiquitin ligase, which ubiquitinated IRS-1 after insulin stimulation in PI3-kinase dependent manner. These data were deported in the annual meeting of Japan Diabetes Association. Second project was about the new ligands, which stimulated IRS-1 serine phosphorylation. We found that IL-la stimulated several serine kinases, in which JNK and mTOR were important for IRS-1 serine phosphorylation. These data were reported in Molecular Endocrinology. Then, the different mechanisms for IRS-1 serine phosphorylation by either anisomycin or insulin were studied. JNK was important for the former, whereas mTOR was important for the latter. These data were reported in BBRC. The third project was the evaluation of IRS-1 serine phosphorylation and SOCS expression, both of which were known to be important for the degradation of IRS-1, in in vivo insulin resistant models. In high fat-fed mice and db/db/ mice, IRS-1 serine phosphorylation and SOCS expression was enhanced. Pioglitazone, a insulin sensitizing drug, decreased both IRS-1 serine phyosphorylation and SOCS expression, leading to the enhanced insulin signaling at IRS-1 level. These data were reported in Diabetes. Finally, the relationship between IRS-1 serine phosphorylation and SOCS expression was examined. We found that insulin signaling was inhibited in the presence of both IRS-1 serine phosphorylation and SOCS expression, one of which did not induce insulin resistance in 3T3-L1 adipocytes. These data were reported in Endocrinology.