ORIGINAL ARTICLE


JOP. J Pancreas (Online) 2001; 2(4):140-149.

Effect of Treatment with Different Doses of 17-b -Estradiol on Insulin Receptor Substrate-1.

Celestino González, Ana Alonso, Natalia A Grueso, Fernando Díaz, Manuel M Esteban, Serafina Fernández, Angeles M Patterson

Department of Functional Biology, Physiology Area, University of Oviedo, Oviedo, Spain.


Context Ovarian hormones modulate insulin sensitivity, but their exact role remains unclear.

Objective We tried to determine whether different doses of 17-b -estradiol cause changes in the regulation of insulin receptor substrate (IRS-1) levels, and if so, the possible implications in insulin sensitivity.

Design Ovariectomized rats were treated with different doses of 17-b -estradiol at 6, 11 and 16 days.

Main outcome measures Immunoprecipitation and Western blotting for IRS-1 were performed in different tissues.

Results We found that estradiol treatment has an influence on the amount of IRS-1 but that it acts in different ways depending on the tissue studied, on the length of treatment, and on the doses employed.

Conclusions Our results suggest that low concentrations of 17-b -estradiol could be responsible for the upregulation of insulin receptor substrate 1, increasing insulin sensitivity in muscle and adipose tissue. However, insulin receptor substrate 1 is downregulated with high concentrations of 17-b -estradiol, thus these high hormone plasma levels could favour insulin resistance in peripheral tissues. The role of 17-b -estradiol seems to modulate insulin receptor substrate 1 levels in insulin dependent tissues, but in a different manner in each tissue. These novel findings are important for improving knowledge about the possible risk for insulin resistance in women taking oral contraceptives or receiving hormone replacement therapy at menopause.

Full text HTML format  PDF format
Look up who cited this article

References

  1. Polderman KH, Gooren LJG, Asscheman H, Bakker A, Heine RJ. Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 1994; 79:265-71. [More details]

  2. Marsden PJ, Murdoch A, Taylor R. Adipocyte insulin action during the normal menstrual cycle. Hum Reprod 1996; 11:968-74. [More details]

  3. Saad MJA, Maeda L, Brenelli SL, Carvalho CRO, Paiva RS, Velloso LA. Defects in insulin signal transduction in liver and muscle of pregnant rats. Diabetologia 1997; 40:179-86. [More details]

  4. Godsland IF, Walton C, Felton C, Proudler A, Patel A, Wynn V. Insulin resistance, secretion, and metabolism in users of oral contraceptives. J Clin Endocrinol Metab 1992; 74:64-70. [More details]

  5. Watanabe RM, Azen CG, Roy S, Perlman JA, Bergman RN. Defects in carbohydrate metabolism in oral contraceptive users without apparent metabolic risk factors. J Clin Endocrinol Metabolism 1994; 79:1277-83. [More details]

  6. Becker AB, Roth RA. Insulin receptor structure and function in normal and pathological conditions. Annu Rev Med 1990; 41:99-115. [More details]

  7. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 1991; 352:73-7. [More details]

  8. White MF, Kahn CR. The insulin signaling system. J Biol Chem 1994; 269:1-4. [More details]

  9. Sun XJ, Miralpeix M, Myers MG, Glasheen EM, Backer JM, Kahn CR, White MF. Expression and function of IRS-1 in insulin signal transmission. J Biol Chem 1992; 267:22662-72. [More details]

  10. Myers MG, Sun XJ, White MF. The IRS-1 signaling system. Trends Biochem Sci 1994; 19: 290-3. [More details]

  11. Molloy CA, May FEB, Westley BR. Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line. J Biol Chem 2000; 275:12565-71. [More details]

  12. Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK, Yee D. Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Mol Endocrinol 1999; 13:787-96. [More details]

  13. Freiss G, Vignon F. Antiestrogens increase protein tyrosine phosphatase activity in human breast cancer cells. Mol Endocrinol 1994; 8:1389-96. [More details]

  14. Freiss G, Puech C, Vignon F. Extinction of insulin-like growth factor-1 mitogenic signalling by antiestrogen-stimulated fas-associated protein tyrosine phosphatase-1 in human breast cancer cells. Mol Endocrinol 1998; 12:568-79. [More details]

  15. Tanti JF, Grémeaux T, Van Obberghen E, Le Marchand-Brustel Y. Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling. J Biol Chem 1994; 269:6051-7. [More details]

  16. De Fea K, Roth RA. Modulation of insulin receptor substrate 1 tyrosine phosphorylation and function by mitogen-activated protein kinase. J Biol Chem 1997; 272:31400-6. [More details]

  17. De Fea K, Roth RA. Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 1997; 36:12939-47. [More details]

  18. Le Marchand-Brustel Y. Molecular mechanism of insulin action in normal and insulin-resistant states. Exp Clin Endocrinol Diabetes 1999; 107:126-32. [More details]

  19. González C, Díaz F, Fernández S, Patterson AM. Role of 17-b -estradiol and progesterone on glucose homeostasis: effects of food restriction (50%) in pregnant and non-pregnant rats. J Endocrinol Invest 1997; 20:397-403. [More details]

  20. González C, Díaz F, Fernández S, Patterson AM. Pregnancy in rats and food restriction (50%): insulin response in relation to serum lipids and lipoprotein levels. Nutr Research 1998; 18:1235-44. [More details]

  21. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities utilizing the principle of protein dye binding. Anal Biochem 1976; 72:248-54. [More details]

  22. Towbin H, Staehelin J, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets. Procedure and some applications. Proc Natl Acad Sci USA 1979; 76: 4350-4. [More details]

  23. González C, Alonso A, Alvarez N, Díaz F, Martínez M, Fernández S, Patterson AM. Role of 17-b -estradiol and/or progesterone on insulin sensitivity in the rat: implications during pregnancy. J Endocrinol 2000; 166:283-91. [More details]

  24. Kato S, Tora l, Yamauchi J, Masushige S, Bellard M, Chambon P. A far upstream estrogen response element of the ovalbumin gene contains several half-palindromic 5´-TGACC-3´ motifs acting synergistically. Cell 1992; 68:731-42. [More details]

  25. Thirone ACP, Carvalho CRO, Brenelli SL, Velloso LA, Saad MJ. Effect of chronic growth hormone treatment on insulin signal transduction in rat tissues. Mol Cell Endocrinol 1997; 130:33-42. [More details]

  26. Kawai M, Kishi K. Adaptation of pancreatic islet B-cells during the last third of pregnancy: regulation of B-cell function and proliferation by lactogenic hormones in rats. Eur J Endocrinology 1999; 141:419-25. [More details]

  27. Kojima T, Lindheim SR, Duffy DM, Vijod MA, Stanczyk FZ, Lobo RA. Insulin sensitivity is decreased in normal women by doses of ethinyl estradiol used in oral contraceptives. Am J Obstet Gynecol 1993; 169:1540-4. [More details]

  28. Lindheim SR, Duffy DM, Kojima T, Vijod MA, Stanczyk FZ, Lobo RA. The route of administration influences the effect of estrogen on insulin sensitivity in postmenopausal women. Fertil Steril 1994; 62:1176-80. [More details]

  29. Duckworth WC. Insulin degradation: mechanism, products, and significance. Endocr Reviews 1988; 9:319-45. [More details]

Key words Insulin; Insulin Resistance; Rats

Correspondence Celestino González González: tinog@correo.uniovi.es