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Effects of Dexamethasone on Insulin Receptor in Aging

Acta Biologica Hungarica volume 59, pages 17–29 (2008)Cite this article

Abstract

The aim of this study was to examine the effects of dexamethasone (Dex) on functional properties of the rat insulin receptor (IR). Male Mill Hill hooded rats, 3, 6, 12, 18 and 21 months old, were injected with Dex (4 mg/kg) and rat liver and erythrocytes were used for experiments 18 h after Dex administration. Treatment with Dex lowered the specific binding (SB) of insulin (INS) in the liver of 3- and 18-month-old rats and concentration of INS binding sites (N1 N2) and the dissociation constant of low-affinity binding sites (Kd2) in the liver of 6- and 18-month-old rats. In addition, Dex treatment lowered the liver IR protein level in all analyzed groups, except 21-month-old rats where it remained unchanged, but raised the IR mRNA level in 18-month-old rats. In erythrocytes, treatment with Dex decreased SB and Kd2 (in animals 3 and 6 months old) and N] (in ones 3 and 18 months old). Following Dex treatment, the INS plasma level increased (in rats 3,18 and 21 months old), while glucose (Glu) concentration increased in 3 and 12 months old, but decreased in 6- and 21-month-old rats. In summary, Dex exerts the strongest effect on the erythrocyte IR of 3- and 6-month-old rats and the hepatic IR of 18-month-old rats. IR in both tissues is almost insensitive to Dex in 12- and 21-month-old rats. The pattern of age-related changes of IR induced by Dex does not correlate with changes of plasma Glu and INS.

References

  1. 1.

    Andrews R. C., Walker B. R. (1999) Glucocorticoids and insulin resistance: old hormones, new targets. Clin. Sci. (Lond.) 96, 513–523.

    CAS  Article  Google Scholar 

  2. 2.

    Barbera M., Fierabracci V., Novelli M., Bombara M., Masiello P., Bergamini E., De Tata V. (2001) Dexamethasone-induced insulin resistance and pancreatic adaptive response in aging rats are not modified by oral vanadyl sulfate treatment. Eur. J. Endocrinol. 145, 799–806.

    CAS  Article  Google Scholar 

  3. 3.

    Carvalho C. R., Brenelli S. L., Silva, A. C., Nunes A. L., Velloso, L. A., Saad M. J. (1996) Effect of aging on insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of rats. Endocrinology 137, 151–159.

    CAS  Article  Google Scholar 

  4. 4.

    Dardevet D., Sornet C., Savary I., Debras E., Patureau-Mirand P., Grizard J. (1998) Glucocorticoid effects on insulin- and IGF-I-regulated muscle protein metabolism during aging. J. Endocrinol. 156, 83–89.

    CAS  Article  Google Scholar 

  5. 5.

    De Meyts P. (2004) Insulin and its receptor: structure, function and evolution. Bioessays 26, 1351–1362.

    Article  Google Scholar 

  6. 6.

    Delaunay F., Khan A., Cintra A., Davani B., Ling, Z.-C., Andersson A., Ostenson, C.-G., Gustafsson, J.-A., Efendic S., Okret S. (1997) Pancreatic b cells are important targets for the diabetogenic effects of glucocorticoids. J. Clin. Invest. 100, 2094–2098.

    CAS  Article  Google Scholar 

  7. 7.

    Ellis L., Clauser E., Morgan D. O., Edery M., Roth, R. A, Rutter W. J. (1986) Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucose. Cell 45, 721–732.

    CAS  Article  Google Scholar 

  8. 8.

    Folli R., Saad M. J., Kahn C. R. (1996) Insulin receptor/IRS-1/PI 3-kinase signaling system in cor-ticosteroid-induced insulin resistance. Acta Diabetol. 33, 185–192.

    CAS  Article  Google Scholar 

  9. 9.

    Fulop T., Larbi A., Douziech N. (2003) Insulin receptor and ageing. Pathol. Biol. (Paris) 51, 574–580.

    CAS  Article  Google Scholar 

  10. 10.

    Gambhir K. K., Archer J. A., Carter L. (1977) Insulin radioreceptor assay for human erythrocytes. Clin. Chem. 23, 1590–1595.

    CAS  PubMed  Google Scholar 

  11. 11.

    Giorgino F., Almahfouz A., Goodyear L. J., Smith R. J. (1993) Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. J. Clin. Invest. 91, 2020–2030.

    CAS  Article  Google Scholar 

  12. 12.

    Harding J. D., Przybyla A. E., MacDonald R. J., Pictet R. L., Rutter W. J. (1978) Effects of Dexamethasone and 5-bromodeoxyuridine on the synthesis of amylase mRNA during pancreatic development in vitro. J. Biol. Chem. 253, 7531–7537.

    CAS  PubMed  Google Scholar 

  13. 13.

    Hines D., Hug V., Levy J. R. (1994) Dexamethasone mediated stabilization of insulin receptor mRNA. J. Recept. Res. 14, 297–305.

    CAS  Article  Google Scholar 

  14. 14.

    Hoffman K., Romovacek H., Titus G., Ridge K., Raffensperger J. A., Finn F. M. (1987) The rat liver insulin receptor. Biochemistry 26, 7384–7390.

    Article  Google Scholar 

  15. 15.

    Klein H. H., Ullmann S., Drenckhan M., Grimmsmann T., Unthan-Fechner K., Probst I. (2002) Differential modulation of insulin actions by Dexamethasone: studies in primary cultures of adult rat hepatocytes. J. Hepatol. 37, 432–440.

    CAS  Article  Google Scholar 

  16. 16.

    Koricanac G., Isenovic E., Stojanovic-Susulic V., Miskovic D., Zakula Z., Ribarac-Stepic N. (2006) Time dependent effect of dexamethasone on serum insulin level and insulin receptors in rat liver and erythrocytes. General Physiol. Biophys. 25, 11–24.

    CAS  Google Scholar 

  17. 17.

    Koricanac G., Vulovic M., Radivojsa S., Zakula Z., Ribarac-Stepic N. (2004) Age-related changes of insulin receptors, plasma insulin and glucose level. Biogerontology 5, 345–353.

    CAS  Article  Google Scholar 

  18. 18.

    Lee, J.-K., Tsai S. Y. (1994) Multiple hormone response elements can confer glucocorticoid regulation on the human insulin receptor gene. Mol. Endocrinol. 8, 625–634.

    CAS  PubMed  Google Scholar 

  19. 19.

    Lowry H. D., Rosenbrough J. N., Farr A. L., Randall J. R. (1951) Protein measurement with Folin phenol reagent. J. Biol. Chem. 153, 265–275.

    Google Scholar 

  20. 20.

    Mamula P. W., Mc Donald A. R., Brunetti A., Okabayashi Y., Wong, K. Y, Maddux B. A., Logsdon, C., Goldfine I. D. (1990) Regulating insulin-receptor-gene expression by differentiation and hormones. Diabetes Care 13, 288–301.

    CAS  Article  Google Scholar 

  21. 21.

    Masella R., Cantafora, A, Maffi D., Volpe R., Ginnetti, M. G, Ricci, G, Mace N. L., Buxton G. M., Peterson S. W. (1995) Insulin receptor processing and lipid composition of erythrocyte membrane in patients with hyperlipidemia. J. Biomed. Sci. 2, 242–248.

    CAS  Article  Google Scholar 

  22. 22.

    Moldenhauer I., Lasch J., Hirschelmann R. (1994) Alteration of structural order of human erythrocyte ghost membrane by glucocorticoids and the influence of the glucocorticoid receptor antagonist RU 486. Int. J. Tissue. React. 16, 113–119.

    CAS  PubMed  Google Scholar 

  23. 23.

    Munson P. J., Rodbard D. (1980) Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal. Biochem. 107, 220–239.

    CAS  Article  Google Scholar 

  24. 24.

    Novelli M., De Tata V., Bombara M., Lorenzini A., Masini M., Pollera M., Bergamini E., Masiello P. (1999) Insufficient adaptive capability of pancreatic endocrine function in Dexamethasone-treated ageing rats. J. Endocrinol. 162, 425–432.

    CAS  Article  Google Scholar 

  25. 25.

    Opherk C., Tranche, E, Kellendonk C., Kohlmuller D., Schulze A., Schmid W., Schutz G. (2004) Inactivation of the glucocorticoid receptor in hepatocytes leads to fasting hypoglycemia and ameliorates hyperglycemia in streptozotocin-induced diabetes mellitus. Mol. Endocrinol. 18, 1346–1353.

    CAS  Article  Google Scholar 

  26. 26.

    Peterson S. W., Miller A. L., Kelleher R. S., Murray E. F. (1983) Insulin receptor down regulation in human erythrocytes. J. Biol. Chem. 258, 9605–9607.

    CAS  PubMed  Google Scholar 

  27. 27.

    Rave N., Crkvenjakov R., Boedtker H. (1979) Identification of procollagen mRNAs transferred to diazobenzyloxymethyl paper from formaldehyde agarose gels. Nucleic Acids Res. 6, 3559–3567.

    CAS  Article  Google Scholar 

  28. 28.

    Rouiller D. G., McKeon C., Taylor S. I., Gorden P. (1988) Hormonal regulation of insulin receptor gene expression. Hydrocortisone and insulin act by different mechanisms. J. Biol. Chem. 263, 13185–13190.

    CAS  PubMed  Google Scholar 

  29. 29.

    Rutter G. A. (2000) Diabetes: the importance of the liver. Curr. Biol. 10, R736-R738.

  30. 30.

    Saad M. J., Folli F., Araki E., Hashimoto N., Csermely P., Kahn C. R. (1994) Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. Effects of differentiation, insulin, and Dexamethasone. Mol. Endocrinol. 8, 545–557.

    CAS  PubMed  Google Scholar 

  31. 31.

    Saad M. J., Folli F., Kahn C. R. (1995) Insulin and Dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. Endocrinology 136, 1579–1588.

    CAS  Article  Google Scholar 

  32. 32.

    Sambrook J., Fritsch E. F., Maniatis T. (1989) In: Nolan C., Ferguson M. (eds) Molecular Cloning: A Laboratory Manual. 2nd edn. Cold Spring Harbour Laboratory Press, New York.

  33. 33.

    Sevaljevic L., Isenovic E., Vulovic M., Macvanin M., Zakula Z., Kanazir D., Ribarac-Stepic N. (2001) The responses of rat liver glucocorticoid receptors and genes for tyrosine aminotransferase, alpha-2-macroglobulin and gamma-fibrinogen to adrenalectomy-, dexamethasone- and inflammation-induced changes in the levels of glucocorticoids and proinflammatory cytokines. Biol. Signals Recept. 10, 299–309.

    CAS  Article  Google Scholar 

  34. 34.

    Smith P. K., Krohn R. I., Hermanson G. T., Mallia A. K., Gartner F. H., Provenzano M. D., Fujimoto E. K., Goeke N. M., Olson B. J., Klenk D. C. (1985) Measurement of protein using bicin-choninic acid. Anal. Biochem. 150, 76–85.

    CAS  Article  Google Scholar 

  35. 35.

    Taniguchi C. M., Emanuelli B., Kahn C. R. (2006) Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell. Biol. 7, 85–96.

    CAS  Article  Google Scholar 

  36. 36.

    Tikhonova N. E., Tatarinova, G. Sh., Pivina S. G., Shaliapina V. G. (1991) Changes in the receptor binding of Dexamethasone and insulin by blood cells in rats after hydrocortisone administration in early postnatal ontogenesis. Probl. Endokrinol. (Mosk.) 37, 47–50.

    CAS  Google Scholar 

  37. 37.

    Yen S. S., Laughlin G. A. (1998) Aging and the adrenal cortex. Exp. Gerontol. 33, 897–910.

    CAS  Article  Google Scholar 

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Affiliations

  1. Laboratory for Molecular Biology and Endocrinology, “Vinca” Institute of Nuclear Sciences, P.O. Box 522, 11001, Belgrade, Serbia

    G. Koricanac, Mojca Stojiljkovic, Snezana Radivojsa, Zorica Zakula & Nevena Ribarac-Stepic

  2. Laboratory for Radiobiology and Molecular Genetics, “Vinca” Institute of Nuclear Sciences, P.O. Box 522, 11001, Belgrade, Serbia

    Esma R. Isenovic

Authors
  1. G. Koricanac
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  2. Mojca Stojiljkovic
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  3. Snezana Radivojsa
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  4. Zorica Zakula
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  5. Nevena Ribarac-Stepic
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  6. Esma R. Isenovic
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Correspondence to G. Koricanac.

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Koricanac, G., Stojiljkovic, M., Radivojsa, S. et al. Effects of Dexamethasone on Insulin Receptor in Aging. BIOLOGIA FUTURA 59, 17–29 (2008). https://doi.org/10.1556/ABiol.59.2008.1.2

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Keywords

  • Dexamethasone
  • insulin receptor
  • aging
  • liver
  • erythrocytes