Association of SH2-containing inositol phosphatase 2 with the insulin resistance of diabetic db/db mice
Association of SH2-containing inositol phosphatase 2 with the insulin resistance of diabetic db/db mice
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DOI：
10.2337/diabetes.51.8.2387
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发表时间：
2002-08-01
期刊：
影响因子：
7.7
通讯作者：
Kobayashi, M
中科院分区：
文献类型：
--
作者：
Hori, H;Sasaoka, T;Kobayashi, M
含SH-2的肌醇5 '-磷酸酶2（SHIP-2）是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磷脂酰肌醇（PI）3-激酶产物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小鼠的胰岛素抵抗有关。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蛋白的量升高，但肝脏中没有。与SHIP-2表达增强一致，其在db/db小鼠骨骼肌和脂肪组织中膜制备物的定位增加。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PI 3-激酶活性适度降低。除了PI 3-激酶水平的适度降低外，PI 3-激酶下游分子Akt和蛋白激酶C（PKC）-zeta/lambda的活性在骨骼肌和脂肪组织中更严重地降低，但在db/db小鼠的肝脏中没有。用胰岛素增敏剂罗格列酮治疗可降低dbldb小鼠骨骼肌和脂肪组织中SHIP-2的高表达。胰岛素诱导的Akt活化和PKC-zeta/lambda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最小影响。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dbldb小鼠中SHIP-2的表达升高而降低。
SH-2-containing inositol 5'-phosphatase 2 (SHIP-2) is a physiologically important lipid phosphatase that functions to hydrolyze phosphatidylinositol (PI) 3-kinase product PI(3,4,5)P3 to PI(3,4)P2 in the negative regulation of insulin signaling. We investigated whether SHIP-2 is associated with the insulin resistance of diabetic db/db mice. The amount of SHIP-2 protein was elevated in quadriceps muscle and epididymal fat tissue, but not in the liver, of db/db mice relative to that in control db/+m mice. In accordance with the enhanced expression of SHIP-2, its localization at the membrane preparation was increased in the skeletal muscle and fat tissue of db/db mice. Insulin stimulation of PI 3-kinase activity was modestly decreased in skeletal muscle, fat tissue, and liver of db/db mice compared with that of db/+m mice. In addition to the modest decrease at the level of PI 3-kinase, the activity of Akt and protein kinase C (PKC)-zeta/lambda, which are downstream molecules of PI 3-kinase, was more severely reduced in the skeletal muscle and fat tissue, but not in liver of db/db mice. Treatment with the insulin-sensitizing agent rosiglitazone decreased the elevated expression of SHIP-2 in the skeletal muscle and fat tissue of dbldb mice. Insulin-induced Akt activation and PKC-zeta/lambda phosphorylation were restored to the control level, although insulin-stimulated PI 3-kinase activation was minimally affected in the skeletal muscle and fat tissue of db/db mice. These results indicate that SHIP-2 is a novel molecule associated with insulin resistance in the skeletal muscle and fat tissue, and that insulin-induced activity of the downstream molecules of PI 3-kinase is decreased, at least in part, by the elevated expression of SHIP-2 in diabetic dbldb mice.