Insulin Signaling After Exercise in Insulin Receptor Substrate-2-Deficient Mice

  1. Kirsten F. Howlett,
  2. Kei Sakamoto,
  3. Michael F. Hirshman,
  4. William G. Aschenbach,
  5. Matthew Dow,
  6. Morris F. White and
  7. Laurie J. Goodyear
  1. From the Research Division, Joslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts


    The period immediately after exercise is characterized by enhanced insulin action in skeletal muscle, and on the molecular level, by a marked increase in insulin-stimulated, phosphotyrosine-associated phosphatidylinositol (PI) 3-kinase activity. Because the increase in PI 3-kinase activity cannot be explained by increased insulin receptor substrate (IRS)-1 signaling, the present study examined whether this effect is mediated by enhanced IRS-2 signaling. In wild-type (WT) mice, insulin increased IRS-2 tyrosine phosphorylation (∼2.5-fold) and IRS-2−associated PI 3-kinase activity (∼3-fold). Treadmill exercise, per se, had no effect on IRS-2 signaling, but in the period immediately after exercise, there was a further increase in insulin-stimulated IRS-2 tyrosine phosphorylation (∼3.5-fold) and IRS-2−associated PI 3-kinase activity (∼5-fold). In IRS-2−deficient (IRS-2−/−) mice, the increase in insulin-stimulated, phosphotyrosine-associated PI 3-kinase activity was attenuated as compared with WT mice. However, in IRS-2−/− mice, the insulin-stimulated, phosphotyrosine-associated PI 3-kinase response after exercise was slightly higher than the insulin-stimulated response alone. In conclusion, IRS-2 tyrosine phosphorylation and associated PI 3-kinase activity are markedly enhanced by insulin in the immediate period after exercise. IRS-2 signaling can partially account for the increase in insulin-stimulated phosphotyrosine-associated PI 3-kinase activity after exercise.


    • Address correspondence and reprint requests to Laurie J. Goodyear, Metabolism Section, Joslin Diabetes Center, One Joslin Pl., Boston, MA 02215. E-mail:{at}

      Received for publication 20 June 2001 and accepted in revised form 1 November 2001.

      2DG, 2-deoxy-glucose; IRS, insulin receptor substrate; MAP, mitogen-activated protein; PI, phosphatidylinositol; PMSF, phenylmethylsulfonyl fluoride; WT, wild-type.

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