| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
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.
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