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Chronic 17β-estradiol treatment improves skeletal muscle insulin signaling pathway components in insulin resistance associated with aging


Insulin resistance is a common feature of aging in both humans and rats. In the case of females, it seems to be related to loss of gonadal function, due mainly due to a decrease in plasma estrogen levels. Several causes have been postulated for this insulin resistance, among them changes in several steps of the insulin pathway. In view of these findings, the purpose of the present study was to examine the role of chronic 17β-estradiol treatment on insulin sensitivity during the aging process, and its effects on levels of the insulin-sensitive glucose transporter Glut4 (both total and plasma membrane localized), the interaction between p85α subunit of PI3-k and IRS-1, Tyr- and Ser-612 phosphorylation of IRS-1 levels, and Ser-473 phosphorylation of Akt. The present findings indicate that 17β-estradiol treatment is able to minimize the deleterious effect of aging on insulin sensitivity, at least at the level of plasma membrane localized Glut4. Nevertheless further research is needed to determine this conclusively.

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  1. Alonso A, Fernández R, Moreno M, Ordóñez P, González-Pardo H, Conejo NM, Díaz F, González C (2006) Positive effects of 17beta-estradiol on insulin sensitivity in aged ovariectomized female rats. J Gerontol A Biol Sci Med Sci 61:419–426

  2. Alonso A, Moreno M, Ordóñez P, Fernández R, Pérez C, Díaz F, Navarro A, Tolivia J, González C (2008) Chronic estradiol treatment improves brain homeostasis during aging in female rats. Endocrinology 149:57–72. doi:10.1210/en.2007-0627

  3. Anzalone CR, Hong LS, Lu JK, LaPolt PS (2001) Influences of age and ovarian follicular reserve on estrous cycle patterns, ovulation, and hormone secretion in the Long-Evans rat. Biol Reprod 64:1056–1062. doi:10.1095/biolreprod64.4.1056

  4. Barzilai N, Rossetti L, Lipton RB (2004) Einstein’s Institute for Aging Research: collaborative and programmatic approaches in the search for successful aging. Exp Gerontol 39:151–157. doi:10.1016/j.exger.2003.10.009

  5. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254. doi:10.1016/0003-2697(76)90527-3

  6. Carvalho CR, Brenelli SL, Silva AC, Nunes AL, Velloso LA, Saad MJ (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. doi:10.1210/en.137.1.151

  7. Colacurci N, Zarcone R, Mollo A, Russo G, Passaro M, de Seta L, de Franciscis P (1998) Effects of hormone replacement therapy on glucose metabolism. Panminerva Med 40:18–21

  8. Czech MP, Corvera S (1999) Signaling mechanisms that regulate glucose transport. J Biol Chem 274:1865–1868. doi:10.1074/jbc.274.4.1865

  9. D'Andrea-Merrins M, Chang L, Lam AD, Ernst SA, Stuenkel EL (2007) Munc18c interaction with syntaxin4 monomers and SNARE complex intermediates in GLUT4 vesicle trafficking. J Biol Chem 282:16553–16566. doi:10.1074/jbc.M610818200

  10. De Fea K, Roth RA (1997) Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 36:12939–12947. doi:10.1021/bi971157f

  11. DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223

  12. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP (1981) The effect of insulin on the disposal of intravenous glucose. Diabetes 30:1000–1007

  13. Delahaye L, Mothe-Satney I, Myers MG, White MF, Van Obberghen E (1998) Interaction of insulin receptor substrate-1 (IRS-1) with phosphatidylinositol 3-kinase: effect of substitution of serine for alanine in potential IRS-1 serine phosphorylation sites. Endocrinology 139:4911–4919. doi:10.1210/en.139.12.4911

  14. González C, Alonso A, Alvarez N, Díaz F, Martínez M, Fernández S, Patterson AM (2000) Role of 17beta-estradiol and/or progesterone on insulin sensitivity in the rat: implications during pregnancy. J Endocrinol 166:283–291. doi:10.1677/joe.0.1660283

  15. González C, Alonso A, Díaz F, Patterson AM (2003) Dose- and time-dependent effects of 17beta-oestradiol on insulin sensitivity in insulin-dependent tissues of rat: implications of IRS-1. J Endocrinol 176:367–379. doi:10.1677/joe.0.1760367

  16. Harukuni I, Hurn PD, Crain BJ (2001) Deleterious effect of beta-estradiol in a rat model of transient forebrain ischemia. Brain Res 900:137–142. doi:10.1016/S0006-8993(01)02278-8

  17. Herschkovitz A, Liu YF, Ilan E, Ronen D, Boura-Halfon S, Zick Y (2007) Common inhibitory serine sites phosphorylated by IRS-1 kinases, triggered by insulin and inducers of insulin resistance. J Biol Chem 282:18018–18027. doi:10.1074/jbc.M610949200

  18. Hirshman MF, Goodyear LJ, Wardzala LJ, Horton ED, Horton ES (1990) Identification of an intracellular pool of glucose transporters from basal and insulin-stimulated rat skeletal muscle. J Biol Chem 265:987–991

  19. Kahn BB, Flier JS (2000) Obesity and insulin resistance. J Clin Invest 106:473–481. doi:10.1172/JCI10842

  20. Karjalainen A, Paassilta M, Heikkinen J, Bäckström AC, Savolainen M, Kesäniemi YA (2001) Effects of peroral and transdermal oestrogen replacement therapy on glucose and insulin metabolism. Clin Endocrinol 54:165–173. doi:10.1046/j.1365-2265.2001.01208.x

  21. Kumagai S, Holmäng A, Björntorp P (1993) The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol Scand 149:91–97. doi:10.1111/j.1748-1716.1993.tb09596.x

  22. Levin ER (2005) Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol 19:1951–1959. doi:10.1210/me.2004-0390

  23. Matt DW, Sarver PL, Lu JK (1987) Relation of parity and estrous cyclicity to the biology of pregnancy in aging female rats. Biol Reprod 37:421–430. doi:10.1095/biolreprod37.2.421

  24. Mlinar B, Marc J, Janez A, Pfeifer M (2007) Molecular mechanisms of insulin resistance and associated diseases. Clin Chim Acta 375:20–35. doi:10.1016/j.cca.2006.07.005

  25. Nass TE, LaPolt PS, Judd HL, Lu JK (1984) Alterations in ovarian steroid and gonadotrophin secretion preceding the cessation of regular oestrous cycles in ageing female rats. J Endocrinol 100:43–50. doi:10.1677/joe.0.1000043

  26. Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–789. doi:10.1016/S0140-6736(63)91500-9

  27. Reaven GM, Reaven EP (1985) Age, glucose intolerance, and non-insulin-dependent diabetes mellitus. J Am Geriatr Soc 33:286–290

  28. Rincon J, Holmang A, Wahlstrom EO, Lonnroth P, Bjorntorp P, Zierath JR, Wallberg-Henriksson H (1996) Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment. Diabetes 45:615–621. doi:10.2337/diabetes.45.5.615

  29. Rogers NH, Witczak CA, Hirshman MF, Goodyear LJ, Greenberg AS (2009) Estradiol stimulates Akt, AMP-activated protein kinase (AMPK) and TBC1D1/4, but not glucose uptake in rat soleus. Biochem Biophys Res Commun 382:646–650. doi:10.1016/j.bbrc.2009.02.154

  30. Segars JH, Driggers PH (2002) Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes. Trends Endocrinol Metab 13:349–354. doi:10.1016/S1043-2760(02)00633-1

  31. Shewan AM, van Dam EM, Martin S, Luen TB, Hong W, Bryant NJ, James DE (2003) GLUT4 recycles via a trans-Golgi network (TGN) subdomain enriched in Syntaxins 6 and 16 but not TGN38: involvement of an acidic targeting motif. Mol Biol Cell 14:973–986. doi:10.1091/mbc.E02-06-0315

  32. Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76:4350–4354. doi:10.1073/pnas.76.9.4350

  33. Tucker MZ, Turcotte LP (2003) Aging is associated with elevated muscle triglyceride content and increased insulin-stimulated fatty acid uptake. Am J Physiol 285:E827–E835

  34. Vasconsuelo A, Milanesi L, Boland R (2008) 17Beta-estradiol abrogates apoptosis in murine skeletal muscle cells through estrogen receptors: role of the phosphatidylinositol 3-kinase/Akt pathway. J Endocrinol 196:385–397. doi:10.1677/JOE-07-0250

  35. Weiss JM, Huller H, Polack S, Friedrich M, Diedrich K, Treeck O, Pfeiler G, Ortmann O (2007) Estradiol differentially modulates the exocytotic proteins SNAP-25 and munc-18 in pituitary gonadotrophs. J Mol Endocrinol 38:305–314. doi:10.1677/jme.1.02114

  36. White MF (2006) Regulating insulin signaling and beta-cell function through IRS proteins. Can J Physiol Pharmacol 84:725–737. doi:10.1139/Y06-008

  37. Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI (2002) Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 277:50230–50236. doi:10.1074/jbc.M200958200

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This study was supported by Fondo de Investigaciones Sanitarias (FIS Ref: PI020324).

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Correspondence to C. González.

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Moreno, M., Ordoñez, P., Alonso, A. et al. Chronic 17β-estradiol treatment improves skeletal muscle insulin signaling pathway components in insulin resistance associated with aging. AGE 32, 1–13 (2010). https://doi.org/10.1007/s11357-009-9095-2

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  • Aging
  • Insulin resistance
  • 17β-estradiol
  • Glut4
  • Akt, p85α
  • IRS-1