MECHANISMS FOR INSULIN RESISTANCE BY SERINE KINASE ACTIVATION

丝氨酸激酶激活引起胰岛素抵抗的机制

• 批准号: 17590918
• 负责人: KOBAYASHI Masashi
• 金额: $ 2.24万
• 依托单位: University of Toyama
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590918/
• 关键词: insulin resistance; IRS-1; serine phosphorylation; serine kinase; JNK; mTOR

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.

我们研究了胰岛素抵抗的机制与几种丝氨酸激酶的激活有关。第一个项目是对新的丝氨酸激酶进行分析。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，它以PI3依赖的方式在胰岛素刺激后泛素化IRS-1。这些数据在日本糖尿病协会年会上被驱逐出境。第二个项目是关于刺激IRS-1丝氨酸磷酸化的新配体。我们发现IL-1a激活了几种丝氨酸激酶，其中JNK和mTOR对IRS-1丝氨酸磷酸化起重要作用。这些数据发表在《分子内分泌学》杂志上。在此基础上，研究了苯甲酸和胰岛素对IRS-1丝氨酸磷酸化的不同作用机制。JNK对前者很重要，而mTOR对后者很重要。这些数据发表在BBRC上。第三个项目是在体内胰岛素抵抗模型中评估IRS-1丝氨酸磷酸化和SOCS的表达，这两者都被认为对IRS-1的降解很重要。在高脂喂养的小鼠和db/db/小鼠中，IRS-1丝氨酸磷酸化和SOCS的表达增强。胰岛素增敏药物吡格列酮降低IRS-1丝氨酸磷酸化和SOCS表达，导致IRS-1水平的胰岛素信号转导增强。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，在IRS-1丝氨酸磷酸化和SOCS表达的同时，胰岛素信号转导受到抑制，其中之一不会诱导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。

项目成果

Roles of mTOR and JNK in serine phosphorylation, translocation, and degradation of IRS-1

• DOI: 10.1016/j.bbrc.2005.07.152
• 发表时间: 2005-09-30
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Hiratani, K;Haruta, T;Kobayashi, M
• 通讯作者: Kobayashi, M

Effects of Pioglitazone on SOCS3 Expression : Potential Mechanisms for Its Effects on Insulin Sensitivity and Adiponectin Expression.

吡格列酮对 SOCS3 表达的影响：其对胰岛素敏感性和脂联素表达影响的潜在机制。

• 发表时间: 2007
• 期刊: Diabetes 56(3)
• 作者: Kanatani Y.;Usui I.;Ishizuka K.;Bukhari A.;Fujisaka S.;Urakaze M.;Haruta T.;Kishimoto T.;Naka T.;Kobayashi M.
• 通讯作者: Kobayashi M.

Interleukin-1alpha inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes.

• 发表时间: 2006
• 期刊: Molecular endocrinology
• 作者: Jianying He;I. Usui;K. Ishizuka;Yukiko Kanatani;K. Hiratani;M. Iwata;A. Bukhari;T. Haruta;T. Sasaoka;Masashi Kobayashi