Impact of the Liver-Specific Expression of SHIP2 (SH2-Containing Inositol 5′-Phosphatase 2) on Insulin Signaling and Glucose Metabolism in Mice

  1. Kazuhito Fukui1,
  2. Tsutomu Wada1,
  3. Syota Kagawa2,
  4. Kiyofumi Nagira1,
  5. Mariko Ikubo1,
  6. Hajime Ishihara3,
  7. Masashi Kobayashi1 and
  8. Toshiyasu Sasaoka2
  1. 1First Department of Internal Medicine, Toyama Medical & Pharmaceutical University, Toyama, Japan
  2. 2Department of Clinical Pharmacology, Toyama Medical & Pharmaceutical University, Toyama, Japan
  3. 3Sainou Hospital, Toyama, Japan
  1. Address correspondence and reprint requests to Toshiyasu Sasaoka, MD, PhD, Department of Clinical Pharmacology, Toyama Medical & Pharmaceutical University, 2630 Sugitani, Toyama, 930-0194, Japan. E-mail: tsasaoka-tym{at}


We investigated the role of hepatic SH2-containing inositol 5′-phosphatase 2 (SHIP2) in glucose metabolism in mice. Adenoviral vectors encoding wild-type SHIP2 (WT-SHIP2) and a dominant-negative SHIP2 (ΔIP-SHIP2) were injected via the tail vein into db/+m and db/db mice, respectively. Four days later, amounts of hepatic SHIP2 protein were increased by fivefold. Insulin-induced phosphorylation of Akt in liver was impaired in WT-SHIP2–expressing db/+m mice, whereas the reduced phosphorylation was restored in ΔIP-SHIP2–expressing db/db mice. The abundance of mRNA for glucose-6-phosphatase (G6Pase) and PEPCK was increased, that for glucokinase (GK) was unchanged, and that for sterol regulatory element–binding protein 1 (SREBP)-1 was decreased in hepatic WT-SHIP2–overexpressing db/+m mice. The increased expression of mRNA for G6Pase and PEPCK was partly suppressed, that for GK was further enhanced, and that for SREBP1 was unaltered by the expression of ΔIP-SHIP2 in db/db mice. The hepatic expression did not affect insulin signaling in skeletal muscle and fat tissue in both mice. After oral glucose intake, blood glucose levels and plasma insulin concentrations were elevated in WT-SHIP2–expressing db/+m mice, while elevated values were decreased by the expression of ΔIP-SHIP2 in db/db mice. These results indicate that hepatic SHIP2 has an impact in vivo on the glucose metabolism in both physiological and diabetic states possibly by regulating hepatic gene expression.


    • Accepted April 11, 2005.
    • Received November 15, 2004.
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