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

PI3-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。Sh2-含肌醇5‘-磷酸酶2(SHIP2)是一种重要的生理功能脂磷酸酶，在胰岛素信号的负调控中起着将PI(3，4，5)P3分解为PI(3，4)P2的作用。我们研究了SHIP2是否与糖尿病db/db小鼠的胰岛素抵抗有关。与对照组db/m小鼠相比，db/db小鼠股四头肌和附睾脂组织中SHIP2蛋白的含量增加，而肝脏中SHIP2蛋白的含量无明显变化。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PI3-激酶活性略有降低。除了PI3-激酶水平的轻微下降外，作为PI3-激酶下游分子的Akt和非典型PKC的活性在db/db小鼠的骨骼肌和脂肪组织中降低得更严重，但在肝脏中却没有。用胰岛素增敏剂罗格列酮治疗，可以降低db/db小鼠骨骼肌和脂肪组织中SHIP2的表达水平。胰岛素诱导的Akt激活和非典型的PKC磷酸化恢复到对照水平，尽管在db/db小鼠的骨骼肌和脂肪组织中，胰岛素刺激的PI3-激酶激活受到的影响很小。这些结果表明，SHIP2是一个与骨骼肌和脂肪组织中的胰岛素抵抗有关的新分子，在糖尿病db/db小鼠中，SHIP2的表达增加至少部分地降低了胰岛素诱导的PI3-激酶下游分子的活性。

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.