Role of Phosphatidylinositol 3-Kinase Activation on Insulin Action and Its Alteration in Diabetic Conditions

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  • Asano Tomoichiro
    Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University
  • Fujishiro Midori
    Department of Internal Medicine, Graduate School of Medicine, University of Tokyo
  • Kushiyama Akifumi
    Department of Internal Medicine, Graduate School of Medicine, University of Tokyo
  • Nakatsu Yusuke
    Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University
  • Yoneda Masayasu
    Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University
  • Kamata Hideaki
    Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University
  • Sakoda Hideyuki
    Department of Internal Medicine, Graduate School of Medicine, University of Tokyo

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Inositol phospholipids phosphorylated on D3-position of their inositol rings (3-phosphoinositides) are known to play important roles in various cellular events. Activation of PI (phosphatidylinositol) 3-kinase is essential for aspects of insulin-induced glucose metabolism, including translocation of GLUT4 to the cell surface and glycogen synthesis. The enzyme exists as a heterodimer containing a regulatory subunit and one of two widely-distributed isoforms of the p110 catalytic subunit: p110α or p110β. Activation of PI 3-kinase and its downstream AKT has been demonstrated to be essential for almost all of the insulin-induced glucose and lipid metabolism such as glucose uptake, glycogen synthesis, suppression of glucose output and triglyceride synthesis as well as insulin-induced mitogenesis. Accumulated PI(3,4,5)P3 activates several serine/threonine kinases containing a PH (pleckstrin homology) domain, including Akt, atypical PKCs, p70S6 kinase and GSK.<br>In the obesity-induced insulin resistant condition, JNK and p70S6K are activated and phosphorylate IRS-proteins, which diminishes the insulin-induced tyrosine phosphorylation of IRS-proteins and thereby impairs the PI 3-kinase/AKT activations. Thus, the drugs which restore the impaired insulin-induced PI 3-kinase/AKT activation, for example, by suppressing JNK or p70S6K, PTEN or SHIP2, could be novel agents to treat diabetes mellitus.

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