Skip to main content
SpringerLink
Log in

Regulation of insulin receptor substrate-2 tyrosine phosphorylation in animal models of insulin resistance

  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Insulin induces a wide variety of growth and metabolic responses in many cell types. These actions are initiated by insulin binding to its receptor and involve a series of alternative and complementary pathways created by the multiple substrates of the insulin receptor (insulin receptor substrates [IRSs]). We investigated IRS-1 and IRS-2 tyrosine phosphorylation; their association with phosphatidylinositol-3-OH kinase (PI3-K); and the phosphorylation of Akt, a serine-threonine kinase situated downstream of PI3-K, in liver and muscle of two animal models of insulin resistance: epinephrine- or dexamethasone-treated rats. We used in vivo insulin infusion followed by tissue extraction, immunoprecipitation, and immunoblotting. IRS-1 and IRS-2 protein expression did not change in liver and muscle of the epinephrine-treated rats, but in dexamethasone-treated rats IRS-1 presented an increase in liver and a decrease in muscle tissue. PI3-K and Akt protein expression did not change in liver or muscle of the two animal models of insulin resistance. There was a downregulation in insulin-induced IRS-1 and IRS-2 tyrosine phosphorylation and association with PI3-K in both models of insulin resistance. In parallel, insulin-induced Akt phosphorylation was reduced in both tissues of epinephrine-treated rats, and in liver but not in muscle of dexamethasonetreated rats. The reduction in insulin-induced Akt phosphorylation may help to explain the insulin resistance in liver and muscle of epinephrine-treated rats and in the liver of dexamethasone-treated rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Wilden, P. A., Khan, C. R., Siddle, K., and White, M. F. (1992). J. Biol. Chem. 23, 16660–16668.

    Google Scholar 

  2. Sun, X. J., Rothenberg, P. L., Khan, C. R., Backer, J. M., Araki, E., and Wilden, P. A. (1991). Nature 352, 73–77.

    Article  PubMed  CAS  Google Scholar 

  3. Rothenberg, P. L., Lane, W. S., Karasik, A., Backer, J., White, M. F., and Khan, C. R. (1991). J. Biol. Chem. 266, 8203–8311.

    Google Scholar 

  4. Tamemoto, H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., and Furuta, Y. (1994). Nature 372, 182–186.

    Article  PubMed  CAS  Google Scholar 

  5. Araki, E., Lipes, M. A., Patti, M. A., et al. (1994). Nature 372, 186–190.

    Article  PubMed  CAS  Google Scholar 

  6. Sun, X. J., Wang, L. M., Zhang, Y., Yenush, L., Myers, M. G., and Glasheen, E. M. (1995). Nature 337, 173–177.

    Article  Google Scholar 

  7. Skolnik, E. Y., Lee, C. H., Batzer, A., Vicentini, L. M., Zhou, M., and Daly, R. (1993). EMBO J. 12, 1929–1936.

    PubMed  CAS  Google Scholar 

  8. Smith-Hall, J., Pons, S., Patti, M. A., Burks, D. J., Yenush, L., and Sun, X. J. (1997). Biochemistry 36, 8304–8310.

    Article  PubMed  CAS  Google Scholar 

  9. Wilks, A. F., Harpur, A. G., Kirban, R. R., Rooph, S. J., Zuercker, G., and Ziemiecki, A. (1992). Mol. Cell. Biol. 11, 2057–2065.

    Google Scholar 

  10. Myers, M. G. Jr. and White, M. F. (1996). Annu. Rev. Pharmacol. Toxicol. 36, 615–658.

    Article  PubMed  CAS  Google Scholar 

  11. Cheatham, B., Vlahos, C. J., Cheatam, L., Wang, L., Blenis, J., and Kahn, C. R. (1994). Mol. Cell. Biol. 14, 4902–4911.

    PubMed  CAS  Google Scholar 

  12. Okada, T., Kawano, Y., Sahihara, T., Hazeki, O., and Ui, M. (1994). J. Biol. Chem. 269, 3568–3573.

    PubMed  CAS  Google Scholar 

  13. Shepherd, P. R., Nave, B. T., and Siddle, K. (1991). Biochem. J. 271, 1890–1897.

    Google Scholar 

  14. Gabbay, R. A., Sutherland, C., Gnudi, L., et al. (1996). J. Biol. Chem. 271, 1890–1897.

    Article  PubMed  CAS  Google Scholar 

  15. Cohen, P., Alessi, D. R., and Cross, D. A. (1997). FEBS Lett. 1, 3–10.

    Article  Google Scholar 

  16. Klippel, A., Kavanaugh, W. M., Pot, D., and Williams, L. T. (1997). Mol. Cell. Biol. 1997 17, 338–344.

    PubMed  CAS  Google Scholar 

  17. Tanti, J. L., Grillo, S., Gremeaux, T., Coffer, P. J., Van Obberghen, E., and Le-Marchand-Brustel, Y. (1997). Endocrinology 138, 2005–2010.

    Article  PubMed  CAS  Google Scholar 

  18. Donward, J. (1998). Science 279, 673,674.

    Article  Google Scholar 

  19. Kitamura, T., Ogawa, W., Sakaue, H., et al. (1998). Mol. Cell. Biol. 18, 3708–3717.

    PubMed  CAS  Google Scholar 

  20. Cho, H., Mu, J., Kim, J. K., et al. (2001). Science 292, 1728–1731.

    Article  PubMed  CAS  Google Scholar 

  21. Saad, M. J. A., Araki, E., Miralpeix, M., Rothenberg, P. L., White, M. F., and Kahn, C. R. (1992). J. Clin. Invest. 90, 1839–1849.

    PubMed  CAS  Google Scholar 

  22. Folli, F., Saad, M. J. A., Backer, J. M., and Kahn, C. R. (1993). J. Clin. Invest. 92, 1787–1794.

    PubMed  CAS  Google Scholar 

  23. Saad, M. J. A., Folli, F., Kahn, J. A., and Kahn, C. R. (1993). J. Clin. Invest. 92, 2065–2072.

    PubMed  CAS  Google Scholar 

  24. Saad, M. J. A., Folli, F., and Kahn, C. R. (1995). Endocrinology 136, 1579–1588.

    Article  PubMed  CAS  Google Scholar 

  25. Saad, M. J. A., Hartmann, L. G. C., Carvalho, D. S., Galoro, C. A. O., Brenelli, S. L., and Carvalho, C. R. O. (1995). Endocrine 3, 755–759.

    Article  CAS  Google Scholar 

  26. Myers, M. G. Jr., Sun, X. L., Cheatham, B., et al. (1993). Endocrinology 132, 1421–1430.

    Article  PubMed  CAS  Google Scholar 

  27. Withers, D. J., Sanchez-Gutierrez, J., Towery, H., et al. (1998). Nature 391, 900–904.

    Article  PubMed  CAS  Google Scholar 

  28. Haring, H., Kirseh, D., Obermaier, B., Ermel, B., and Machicao, F. (1986). Biochem. J. 234, 59–66.

    PubMed  CAS  Google Scholar 

  29. Kirsch, D., Kemmler, W., and Haring, H. U. (1983). Biochem. Biophys. Res. Commun. 1, 389–405.

    Google Scholar 

  30. Wilson, G. F. and Kaczmarek, L. K. (1993). Nature 366, 433–438.

    Article  PubMed  CAS  Google Scholar 

  31. Kohn, A. D., Kovacina, K. S., and Roth, R. A. (1995). EMBO J. 14, 4288–4295.

    PubMed  CAS  Google Scholar 

  32. Burgering, B. M. T. and Coffer, P. J. (1995). Nature 376, 599–602.

    Article  PubMed  CAS  Google Scholar 

  33. Franke, T. F., Yang, S. I., Chan, T. O., et al. (1995). Cell 81, 727–736.

    Article  PubMed  CAS  Google Scholar 

  34. Didichenko, S. A., Tilton, B., Hemmings, B. A., Ballmer-Hofer, K., and Thelen, M. (1996). Curr. Biol. 6, 1271–1278.

    Article  PubMed  CAS  Google Scholar 

  35. Klippel, A., Reinhard, C., Kavanaugh, M., Apell, G., Escobedo, M. A., and Williams, T. L. (1996). Mol. Cell. Biol. 16, 4117–4127.

    PubMed  CAS  Google Scholar 

  36. Alessi, D. R., James, S. R., Downes, C. P., et al. (1997). Curr. Biol. 7, 261–269.

    Article  PubMed  CAS  Google Scholar 

  37. Kohn, A. D., Summers, S. A., Birnbaun, M. J., and Roth, R. A. (1996). J. Biol. Chem. 271, 31372–31378.

    Article  PubMed  CAS  Google Scholar 

  38. Amatruda, J. M., Livingston, J. N., and Lockwood, D. H. (1985). Diabetes Metab. Rev. 3, 293–317.

    Article  Google Scholar 

  39. Knutson, V. O. (1986). J. Biol. Chem. 261, 10306–10312.

    PubMed  CAS  Google Scholar 

  40. Moller, D. E. and Flier, J. S. N. (1991). N. Engl. J. Med. 325, 939–948.

    Google Scholar 

  41. Giorgino, F., Almahfouz, A., Goodyear, L. D., and Schmith, R. J. (1993). J. Clin. Invest. 91, 2020–2030.

    Article  PubMed  CAS  Google Scholar 

  42. O’Brien, R. M. and Granner, D. K. (1991). Biochem. J. 278, 609–619.

    PubMed  CAS  Google Scholar 

  43. Hofmann, C., Lorenz, K., Williams, D., Palazuk, B. J., and Colca, J. R. (1995). Metabolism 44, 384–389.

    Article  PubMed  CAS  Google Scholar 

  44. Valera, A., Pujol, A., Pelegrin, M., and Bosh, F. (1994). Proc. Natl. Acad. Sci. USA 91, 9151–9154.

    Article  PubMed  CAS  Google Scholar 

  45. Rosella, G., Zajac, J. D., Baker, L., et al. (1995). Mol. Endocrinol. 9, 1396–1404.

    Article  PubMed  CAS  Google Scholar 

  46. Liao, J., Barthel, A., Nakatami, K., and Roth, R. A. (1998). J. Biol. Chem. 42, 27320–27324.

    Article  Google Scholar 

  47. Yamauchi, T., Tobe, K., Tamemoto, H., et al. (1996). Mol. Cell. Biol. 16, 3074–3084.

    PubMed  CAS  Google Scholar 

  48. Laemmli, U. K. (1970). Nature 227, 680–685.

    Article  PubMed  CAS  Google Scholar 

  49. Towin, H., Staehlin, J., and Gordon, J. (1979). Proc. Natl. Acad. Sci. USA 76, 4350–4354.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Clínica Medica, FCM-UNICAMP, 13081-970, Campinas, SP, Brasil

    Fernanda Alvarez Rojas, Aparecida Emiko Hirata & Mario J. A. Saad

Authors
  1. Fernanda Alvarez Rojas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aparecida Emiko Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mario J. A. Saad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mario J. A. Saad.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rojas, F.A., Hirata, A.E. & Saad, M.J.A. Regulation of insulin receptor substrate-2 tyrosine phosphorylation in animal models of insulin resistance. Endocr 21, 115–122 (2003). https://doi.org/10.1385/ENDO:21:2:115

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1385/ENDO:21:2:115

Key Words

Search

Navigation