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Regulation of insulin-induced metabolic action in whole body by lipid phosphatase

脂质磷酸酶调节胰岛素诱导的全身代谢作用

基本信息

批准号：
13671179
负责人：
SASAOKA Toshiyasu
金额：
$ 0.83万
依托单位：
TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671179/
关键词：
Inuslin Insulin resistance Lipid phosphatese SHIP2 PI3-kinase Akt Atypical PKC Atypical PKC リポッドホスファターゼ atypical PKC

项目摘要

PI3-kinase product, PI(3,4,5)P3, is a key mediator of insulin-induced metabolic action of insulin. SH2-containing inositol 5'-phosphatase 2 (SHIP2) is a physiologically important lipid phosphatase, which functions to hydrolyze PI(3,4,5)P3 to PI(3,4)P2 in the negative regulation of insulin signaling. We examined whether SHIP2 is associated with the insulin resistance of diabetic db/db mice. The amount of SHIP2 protein was increased in the quadriceps muscle and the epididymal fat tissue, but not in the liver of db/db mice compared to that of control db/+m mice. Insulin-stimulated PI3-kinase activity was modestly decreased in the skeletal muscle, the fat tissue, and the liver of db/db mice compared to that of db/+m mice. In addition to the modest decrease at the level of PI3-kinase, the activity of Akt and atypical PKC, which are downstream molecules of PI3-kinase, was more severely reduced in the skeletal muscle and the fat tissue, but not in the liver, of db/db mice. Treatment with an insulin-sensitizing agent, rosiglitazone, decreased the elevated expression of SHIP2 in the skeletal muscle and the fat tissue of db/db mice. Insulin-induced Akt activation and atypical PKC phosphorylation were restored to the control level, although insulin-stimulated PI3-kinase activation was minimally affected in the skeletal muscle and the fat tissue of db/db mice. These results indicate that SHIP2 is a novel molecule associated with the insulin resistance in the skeletal muscle and the fat tissue, and that insulin-induced activity of the downstream molecules of PI3-kinase is decreased, at least in part, by the elevated expression of SHIP2 in diabetic db/db mice.

PI 3-激酶产物PI（3，4，5）P3是胰岛素诱导的胰岛素代谢作用的关键介质。含SH 2的肌醇5 '-磷酸酶2（SHIP 2）是一种生理上重要的脂质磷酸酶，其功能是在胰岛素信号传导的负调节中将PI（3，4，5）P3水解为PI（3，4）P2。我们研究了SHIP 2是否与糖尿病db/db小鼠的胰岛素抵抗相关。与对照db/+m小鼠相比，db/db小鼠的四头肌和附睾脂肪组织中SHIP 2蛋白的量增加，但肝脏中没有增加。与db/+m小鼠相比，db/db小鼠骨骼肌、脂肪组织和肝脏中胰岛素刺激的PI 3激酶活性适度降低。除了PI 3激酶水平的适度降低外，Akt和非典型PKC（PI 3激酶的下游分子）的活性在db/db小鼠的骨骼肌和脂肪组织中更严重地降低，但在肝脏中未降低。用胰岛素增敏剂罗格列酮治疗可降低db/db小鼠骨骼肌和脂肪组织中SHIP 2的表达。胰岛素诱导的Akt活化和非典型PKC磷酸化恢复到对照水平，尽管胰岛素刺激的PI 3-激酶活化在db/db小鼠的骨骼肌和脂肪组织中受到的影响最小。这些结果表明，SHIP 2是一种与骨骼肌和脂肪组织中的胰岛素抵抗相关的新分子，并且胰岛素诱导的PI 3-激酶下游分子的活性至少部分地通过糖尿病db/db小鼠中SHIP 2的表达升高而降低。