| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Research Abstract |
We have reported that chronic GH pretreatment inhibited insulin-induced glucose uptake without affecting insulin-induced GLUT4 translocation. This study was undertaken to identify Akt substrates and GLUT4 postranslational modification that regulate GLUT4 transport activity. In addition, in order to rescue insulin resistance we searched for the small molecular chemicals and antibodies that modulate GLUT4 transport activity.At first, we succeeded to isolate the Akt substrates, AS47, whose insulin-inducedphosphorylation was suppressed by GH pretreatment. Knockdown of AS47 inhibited insulin-induced glucose uptake without affecting GLUT4 translocation, suggesting that AS47 plays important roles in GLUT4 transport activity.Next, we searched for posttranslational modification motif in a GLUT4 molecule. GLUT4 was site-directed mutagenized in some modification sites and these mutants were transfected into HEK293 cell. And then glucose uptake was measured. Mutation at the phosphorylation site of GLUT4 (GLUT4-P) significantly enhanced glucose transport activity, suggesting that phosphorylation impaired GLUT4 transport activity. Moreover, we have already succeeded to isolate antibodies, which recognize GLUT4 extracellular domain.In this study we succeeded to identify the Akt substrate and GLUT4 posttranslational modification, which play important roles in GLUT4 transport activity. Chemicals or antibodies, which interact with the Akt substrate and GLUT4 could be candidates tocure insulin resistance.
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