| Research Abstract |
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.
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