Hori Hiroyuki, Sasaoka Toshiyasu, Ishihara Hajime, Wada Tsutomu, Murakami Shihou, Ishiki Manabu, Kobayashi Masashi
First Department of Internal Medicine, Toyama Medical & Pharmaceutical University, Toyama, Japan.
Diabetes. 2002 Aug;51(8):2387-94. doi: 10.2337/diabetes.51.8.2387.
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 db/db 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 db/db mice.
含SH2结构域的肌醇5'-磷酸酶2（SHIP-2）是一种在生理上具有重要意义的脂质磷酸酶，在胰岛素信号的负调控中发挥作用，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。相对于对照db/+m小鼠，db/db小鼠股四头肌和附睾脂肪组织中SHIP-2蛋白的量升高，但肝脏中未升高。与SHIP-2表达增强一致，其在膜制剂中的定位在db/db小鼠的骨骼肌和脂肪组织中增加。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激酶活性略有降低。除了PI 3激酶水平略有下降外，PI 3激酶的下游分子Akt和蛋白激酶C（PKC）-ζ/λ的活性在db/db小鼠的骨骼肌和脂肪组织中降低更为严重，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的高表达。胰岛素诱导的Akt激活和PKC-ζ/λ磷酸化恢复到对照水平，尽管胰岛素刺激的PI 3激酶激活在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胰岛素抵抗相关的新分子，并且在糖尿病db/db小鼠中，胰岛素诱导的PI 3激酶下游分子的活性至少部分因SHIP-2的高表达而降低。
