Increased Insulin Sensitivity and Hypoinsulinemia in APS Knockout Mice

  1. Asako Minami1,
  2. Masanori Iseki2,
  3. Kazuhiro Kishi1,
  4. Miao Wang1,
  5. Makoto Ogura13,
  6. Noboru Furukawa13,
  7. Sanae Hayashi1,
  8. Mizuki Yamada1,
  9. Toshiyuki Obata1,
  10. Yukari Takeshita3,
  11. Yutaka Nakaya3,
  12. Yoshimi Bando4,
  13. Keisuke Izumi4,
  14. Shonna A. Moodie5,
  15. Fumiko Kajiura6,
  16. Mitsuru Matsumoto6,
  17. Kiyoshi Takatsu2,
  18. Satoshi Takaki2 and
  19. Yousuke Ebina1
  1. 1Division of Molecular Genetics, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan
  2. 2Division of Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
  3. 3Department of Nutrition, School of Medicine, University of Tokushima, Tokushima, Japan
  4. 4Molecular and Environmental Pathology, School of Medicine, University of Tokushima, Tokushima, Japan
  5. 5Metabolex, Hayward, California
  6. 6Division of Informative Cytology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan
  1. Address correspondence and reprint requests to Prof. Yousuke Ebina, Division of Molecular Genetics, Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. E-mail: ebina{at}ier.tokushima-u.ac.jp

Abstract

A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS−/−) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS−/− mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS−/− mice. APS−/− mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS−/− mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS−/− mice was increased over that of APS+/+ mice. APS−/− mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.

Footnotes

    • Accepted July 30, 2003.
    • Received February 25, 2003.
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