Skip to main content
SpringerLink
Log in
Book cover

Integrative Biology of Women’s Health pp 67–86Cite as

The Role of Estrogens in the Regulation of Peripheral Glucose Dynamics

  • Chapter
  • First Online:

Abstract

While estrogen is an important hormone regulating sexual function and reproduction, it also has numerous nonreproductive functions, including the regulation of glucose homeostasis. Clinical studies indicate that postmenopausal women are at greater risk for the development of type 2 diabetes, and new evidence in the literature supports a direct role for estrogen in regulating glucose metabolism. The primary estrogen receptors, ERα and ERβ, are now thought to play critical roles in the regulation of glucose in insulin-sensitive tissues. Increased adiposity occurs in humans and mice as a result of decreased ERα activation, and mice with global knockout of ERα exhibit impaired glucose tolerance and skeletal muscle insulin resistance. Based on this evidence, the beneficial effects of estrogens on glucose metabolism are thought to be mediated by ERα. ERα may regulate glucose by increasing insulin-signaling and insulin-stimulated glucose uptake, maintaining GLUT4 expression, and mitigating inflammation and oxidative stress implicated in the development of insulin resistance. ERα and ERβ are known to demonstrate a complex inter-regulatory relationship that varies with the target tissue. Both stimulated by estrogen, the ability of ERα or ERβ to regulate glucose may be dependent on the expression levels and activation of the two receptors in various metabolic tissues. ER isoform-specific agonists and antagonists may prove more beneficial in preventing insulin resistance in postmenopausal women than estrogen treatment alone and should be the focus of future research.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 285(19):2486–2497

    Google Scholar 

  2. Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB (2003) The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 163(4):427–436

    PubMed  Google Scholar 

  3. Lindheim SR, Buchanan TA, Duffy DM, Vijod MA, Kojima T, Stanczyk FZ, Lobo RA (1994) Comparison of estimates of insulin sensitivity in pre- and postmenopausal women using the insulin tolerance test and the frequently sampled intravenous glucose tolerance test. J Soc Gynecol Investig 1(2):150–154

    PubMed  CAS  Google Scholar 

  4. Lynch NA, Ryan AS, Berman DM, Sorkin JD, Nicklas BJ (2002) Comparison of VO2max and disease risk factors between perimenopausal and postmenopausal women. Menopause 9(6):456–462

    PubMed  Google Scholar 

  5. Nuutila P, Knuuti MJ, Maki M, Laine H, Ruotsalainen U, Teras M, Haaparanta M, Solin O, Yki-Jarvinen H (1995) Gender and insulin sensitivity in the heart and in skeletal muscles. Studies using positron emission tomography. Diabetes 44(1):31–36

    PubMed  CAS  Google Scholar 

  6. Donahue RP, Bean JA, Donahue RA, Goldberg RB, Prineas RJ (1997) Insulin response in a triethnic population: effects of sex, ethnic origin, and body fat. Miami Community Health Study. Diabetes Care 20(11):1670–1676

    PubMed  CAS  Google Scholar 

  7. Kuhl J, Hilding A, Ostenson CG, Grill V, Efendic S, Bavenholm P (2005) Characterisation of subjects with early abnormalities of glucose tolerance in the Stockholm Diabetes Prevention Programme: the impact of sex and type 2 diabetes heredity. Diabetologia 48(1):35–40

    PubMed  CAS  Google Scholar 

  8. Macotela Y, Boucher J, Tran TT, Kahn CR (2009) Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes 58(4):803–812

    PubMed  CAS  Google Scholar 

  9. Toth MJ, Tchernof A, Sites CK, Poehlman ET (2000) Effect of menopausal status on body composition and abdominal fat distribution. Int J Obes Relat Metab Disord 24(2):226–231

    PubMed  CAS  Google Scholar 

  10. Sites CK, Toth MJ, Cushman M, L’Hommedieu GD, Tchernof A, Tracy RP, Poehlman ET (2002) Menopause-related differences in inflammation markers and their relationship to body fat distribution and insulin-stimulated glucose disposal. Fertil Steril 77(1):128–135

    PubMed  Google Scholar 

  11. Svendsen OL, Hassager C, Christiansen C (1995) Age- and menopause-associated variations in body composition and fat distribution in healthy women as measured by dual-energy X-ray absorptiometry. Metabolism 44(3):369–373

    PubMed  CAS  Google Scholar 

  12. Brochu M, Starling RD, Tchernof A, Matthews DE, Garcia-Rubi E, Poehlman ET (2000) Visceral adipose tissue is an independent correlate of glucose disposal in older obese postmenopausal women. J Clin Endocrinol Metab 85(7):2378–2384

    PubMed  CAS  Google Scholar 

  13. Brochu M, Tchernof A, Dionne IJ, Sites CK, Eltabbakh GH, Sims EA, Poehlman ET (2001) What are the physical characteristics associated with a normal metabolic profile despite a high level of obesity in postmenopausal women? J Clin Endocrinol Metab 86(3):1020–1025

    PubMed  CAS  Google Scholar 

  14. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC (1994) Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 17(9):961–969

    PubMed  CAS  Google Scholar 

  15. Kissebah AH, Peiris AN (1989) Biology of regional body fat distribution: relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 5(2):83–109

    PubMed  CAS  Google Scholar 

  16. Despres JP (2006) Is visceral obesity the cause of the metabolic syndrome? Ann Med 38(1):52–63

    PubMed  CAS  Google Scholar 

  17. Lemieux C, Picard F, Labrie F, Richard D, Deshaies Y (2003) The estrogen antagonist EM-652 and dehydroepiandrosterone prevent diet- and ovariectomy-induced obesity. Obes Res 11(3):477–490

    PubMed  CAS  Google Scholar 

  18. Vague J (1956) The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 4(1):20–34

    PubMed  CAS  Google Scholar 

  19. Kvist H, Chowdhury B, Grangard U, Tylen U, Sjostrom L (1988) Total and visceral adipose-tissue volumes derived from measurements with computed tomography in adult men and women: predictive equations. Am J Clin Nutr 48(6):1351–1361

    PubMed  CAS  Google Scholar 

  20. Kissebah AH, Vydelingum N, Murray R, Evans DJ, Hartz AJ, Kalkhoff RK, Adams PW (1982) Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 54(2):254–260

    PubMed  CAS  Google Scholar 

  21. Galluzzo P, Rastelli C, Bulzomi P, Acconcia F, Pallottini V, Marino M (2009) 17beta-Estradiol regulates the first steps of skeletal muscle cell differentiation via ER-alpha-mediated signals. Am J Physiol Cell Physiol 297(5):C1249–C1262

    PubMed  CAS  Google Scholar 

  22. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K (1995) Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80(12):3689–3698

    PubMed  CAS  Google Scholar 

  23. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331(16):1056–1061

    PubMed  CAS  Google Scholar 

  24. Maffei L, Murata Y, Rochira V, Tubert G, Aranda C, Vazquez M, Clyne CD, Davis S, Simpson ER, Carani C (2004) Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. J Clin Endocrinol Metab 89(1):61–70

    PubMed  CAS  Google Scholar 

  25. Meyer MR, Clegg DJ, Prossnitz ER, Barton M (2011) Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol (Oxf) 203(1):259–269

    CAS  Google Scholar 

  26. Kanaya AM, Herrington D, Vittinghoff E, Lin F, Grady D, Bittner V, Cauley JA, Barrett-Connor E (2003) Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 138(1):1–9

    PubMed  CAS  Google Scholar 

  27. Margolis KL, Bonds DE, Rodabough RJ, Tinker L, Phillips LS, Allen C, Bassford T, Burke G, Torrens J, Howard BV (2004) Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia 47(7):1175–1187

    PubMed  CAS  Google Scholar 

  28. Andersson B, Mattsson LA, Hahn L, Marin P, Lapidus L, Holm G, Bengtsson BA, Bjorntorp P (1997) Estrogen replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in postmenopausal women with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 82(2):638–643

    PubMed  CAS  Google Scholar 

  29. Gower BA, Munoz J, Desmond R, Hilario-Hailey T, Jiao X (2006) Changes in intra-abdominal fat in early postmenopausal women: effects of hormone use. Obesity (Silver Spring) 14(6):1046–1055

    CAS  Google Scholar 

  30. Espeland MA, Hogan PE, Fineberg SE, Howard G, Schrott H, Waclawiw MA, Bush TL (1998) Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI investigators. Postmenopausal estrogen/progestin interventions. Diabetes Care 21(10):1589–1595

    PubMed  CAS  Google Scholar 

  31. Cagnacci A, Soldani R, Carriero PL, Paoletti AM, Fioretti P, Melis GB (1992) Effects of low doses of transdermal 17 beta-estradiol on carbohydrate metabolism in postmenopausal women. J Clin Endocrinol Metab 74(6):1396–1400

    PubMed  CAS  Google Scholar 

  32. Cagnacci A, Tuveri F, Cirillo R, Setteneri AM, Melis GB, Volpe A (1997) The effect of transdermal 17-beta-estradiol on glucose metabolism of postmenopausal women is evident during the oral but not the intravenous glucose administration. Maturitas 28(2):163–167

    PubMed  CAS  Google Scholar 

  33. 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(1):18–21

    PubMed  CAS  Google Scholar 

  34. Lobo RA, Pickar JH, Wild RA, Walsh B, Hirvonen E (1994) Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. The Menopause Study Group. Obstet Gynecol 84(6):987–995

    PubMed  CAS  Google Scholar 

  35. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD (2002) Postmenopausal hormone replacement therapy: scientific review. JAMA 288(7):872–881

    PubMed  CAS  Google Scholar 

  36. Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, Miller VM, Naftolin F, Santoro N (2005) KEEPS: the Kronos Early Estrogen Prevention Study. Climacteric 8(1):3–12

    PubMed  CAS  Google Scholar 

  37. Jayachandran M, Litwiller RD, Lahr BD, Bailey KR, Owen WG, Mulvagh SL, Heit JA, Hodis HN, Harman SM, Miller VM (2011) Alterations in platelet function and cell-derived microvesicles in recently menopausal women: relationship to metabolic syndrome and atherogenic risk. J Cardiovasc Transl Res 4(6):811–822

    PubMed  Google Scholar 

  38. Yakar S, Nunez NP, Pennisi P, Brodt P, Sun H, Fallavollita L, Zhao H, Scavo L, Novosyadlyy R, Kurshan N, Stannard B, East-Palmer J, Smith NC, Perkins SN, Fuchs-Young R, Barrett JC, Hursting SD, LeRoith D (2006) Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147(12):5826–5834

    PubMed  CAS  Google Scholar 

  39. Hong J, Stubbins RE, Smith RR, Harvey AE, Nunez NP (2009) Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutr J 8:11

    PubMed  Google Scholar 

  40. Nunez NP, Carpenter CL, Perkins SN, Berrigan D, Jaque SV, Ingles SA, Bernstein L, Forman MR, Barrett JC, Hursting SD (2007) Extreme obesity reduces bone mineral density: complementary evidence from mice and women. Obesity (Silver Spring) 15(8):1980–1987

    CAS  Google Scholar 

  41. Nunez NP, Perkins SN, Smith NC, Berrigan D, Berendes DM, Varticovski L, Barrett JC, Hursting SD (2008) Obesity accelerates mouse mammary tumor growth in the absence of ovarian hormones. Nutr Cancer 60(4):534–541

    PubMed  CAS  Google Scholar 

  42. Gomez-Perez Y, Amengual-Cladera E, Catala-Niell A, Thomas-Moya E, Gianotti M, Proenza AM, Llado I (2008) Gender dimorphism in high-fat-diet-induced insulin resistance in skeletal muscle of aged rats. Cell Physiol Biochem 22(5–6):539–548

    PubMed  CAS  Google Scholar 

  43. Wagner JD, Thomas MJ, Williams JK, Zhang L, Greaves KA, Cefalu WT (1998) Insulin sensitivity and cardiovascular risk factors in ovariectomized monkeys with estradiol alone or combined with nomegestrol acetate. J Clin Endocrinol Metab 83(3):896–901

    PubMed  CAS  Google Scholar 

  44. Kumagai S, Holmang A, Bjorntorp P (1993) The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol Scand 149(1):91–97

    PubMed  CAS  Google Scholar 

  45. Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjold M, Gustafsson JA (1997) Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 82(12):4258–4265

    PubMed  CAS  Google Scholar 

  46. Menasce LP, White GR, Harrison CJ, Boyle JM (1993) Localization of the estrogen receptor locus (ESR) to chromosome 6q25.1 by FISH and a simple post-FISH banding technique. Genomics 17(1):263–265

    PubMed  CAS  Google Scholar 

  47. Matthews J, Gustafsson JA (2003) Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol Interv 3(5):281–292

    PubMed  CAS  Google Scholar 

  48. Mueller SO, Korach KS (2001) Estrogen receptors and endocrine diseases: lessons from estrogen receptor knockout mice. Curr Opin Pharmacol 1(6):613–619

    PubMed  CAS  Google Scholar 

  49. Pettersson K, Gustafsson JA (2001) Role of estrogen receptor beta in estrogen action. Annu Rev Physiol 63:165–192

    PubMed  CAS  Google Scholar 

  50. Glass CK (2006) Going nuclear in metabolic and cardiovascular disease. J Clin Invest 116(3):556–560

    PubMed  CAS  Google Scholar 

  51. Deroo BJ, Korach KS (2006) Estrogen receptors and human disease. J Clin Invest 116(3):561–570

    PubMed  CAS  Google Scholar 

  52. Kelly MJ, Levin ER (2001) Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab 12(4):152–156

    PubMed  CAS  Google Scholar 

  53. Nadal A, Diaz M, Valverde MA (2001) The estrogen trinity: membrane, cytosolic, and nuclear effects. News Physiol Sci 16:251–255

    PubMed  CAS  Google Scholar 

  54. Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS (2000) Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci U S A 97(23):12729–12734

    PubMed  CAS  Google Scholar 

  55. Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P (2009) Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology 150(5):2109–2117

    PubMed  CAS  Google Scholar 

  56. Bryzgalova G, Gao H, Ahren B, Zierath JR, Galuska D, Steiler TL, Dahlman-Wright K, Nilsson S, Gustafsson JA, Efendic S, Khan A (2006) Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia 49(3):588–597. Epub 2006 Feb 4. PMID: 16463047

    PubMed  CAS  Google Scholar 

  57. Long SD, Pekala PH (1996) Regulation of GLUT4 gene expression by arachidonic acid. Evidence for multiple pathways, one of which requires oxidation to prostaglandin E2. J Biol Chem 271(2):1138–1144

    PubMed  CAS  Google Scholar 

  58. Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF (2002) Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes 51(5):1319–1336

    PubMed  CAS  Google Scholar 

  59. Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA (1996) The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 97(4):1111–1116

    PubMed  CAS  Google Scholar 

  60. Uysal KT, Wiesbrock SM, Hotamisligil GS (1998) Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology 139(12):4832–4838

    PubMed  CAS  Google Scholar 

  61. Sriwijitkamol A, Christ-Roberts C, Berria R, Eagan P, Pratipanawatr T, DeFronzo RA, Mandarino LJ, Musi N (2006) Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training. Diabetes 55(3):760–767

    PubMed  CAS  Google Scholar 

  62. Han X, Ploug T, Galbo H (1995) Effect of diet on insulin- and contraction-mediated glucose transport and uptake in rat muscle. Am J Physiol 269(3 Pt 2):R544–R551

    PubMed  CAS  Google Scholar 

  63. Kahn BB (1994) Dietary regulation of glucose transporter gene expression: tissue specific effects in adipose cells and muscle. J Nutr 124(8 Suppl):1289S–1295S

    PubMed  CAS  Google Scholar 

  64. Sevilla L, Guma A, Enrique-Tarancon G, Mora S, Munoz P, Palacin M, Testar X, Zorzano A (1997) Chronic high-fat feeding and middle-aging reduce in an additive fashion Glut4 expression in skeletal muscle and adipose tissue. Biochem Biophys Res Commun 235(1):89–93

    PubMed  CAS  Google Scholar 

  65. Galien R, Garcia T (1997) Estrogen receptor impairs interleukin-6 expression by preventing protein binding on the NF-kappaB site. Nucleic Acids Res 25(12):2424–2429

    PubMed  CAS  Google Scholar 

  66. Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS (1997) Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 277(5331):1508–1510

    PubMed  CAS  Google Scholar 

  67. Qin C, Singh P, Safe S (1999) Transcriptional activation of insulin-like growth factor-binding protein-4 by 17beta-estradiol in MCF-7 cells: role of estrogen receptor-Sp1 complexes. Endocrinology 140(6):2501–2508

    PubMed  CAS  Google Scholar 

  68. Paimela T, Ryhanen T, Mannermaa E, Ojala J, Kalesnykas G, Salminen A, Kaarniranta K (2007) The effect of 17beta-estradiol on IL-6 secretion and NF-kappaB DNA-binding activity in human retinal pigment epithelial cells. Immunol Lett 110(2):139–144

    PubMed  CAS  Google Scholar 

  69. Ray P, Ghosh SK, Zhang DH, Ray A (1997) Repression of interleukin-6 gene expression by 17 beta-estradiol: inhibition of the DNA-binding activity of the transcription factors NF-IL6 and NF-kappa B by the estrogen receptor. FEBS Lett 409(1):79–85

    PubMed  CAS  Google Scholar 

  70. Stein B, Yang MX (1995) Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol Cell Biol 15(9):4971–4979

    PubMed  CAS  Google Scholar 

  71. Rosenbaum D, Haber RS, Dunaif A (1993) Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 264(2 Pt 1):E197–E202

    PubMed  CAS  Google Scholar 

  72. Barros RP, Machado UF, Warner M, Gustafsson JA (2006) Muscle GLUT4 regulation by estrogen receptors ERbeta and ERalpha. Proc Natl Acad Sci U S A 103(5):1605–1608

    PubMed  CAS  Google Scholar 

  73. Ribas V, Nguyen MT, Henstridge DC, Nguyen AK, Beaven SW, Watt MJ, Hevener AL (2010) Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice. Am J Physiol Endocrinol Metab 298(2):E304–E319

    PubMed  CAS  Google Scholar 

  74. Wang J, Green PS, Simpkins JW (2001) Estradiol protects against ATP depletion, mitochondrial membrane potential decline and the generation of reactive oxygen species induced by 3-nitroproprionic acid in SK-N-SH human neuroblastoma cells. J Neurochem 77(3):804–811

    PubMed  CAS  Google Scholar 

  75. Duckles SP, Krause DN, Stirone C, Procaccio V (2006) Estrogen and mitochondria: a new paradigm for vascular protection? Mol Interv 6(1):26–35

    PubMed  Google Scholar 

  76. Zhou Z, Zhou J, Du Y (2012) Estrogen receptor alpha interacts with mitochondrial protein HADHB and affects beta-oxidation activity. Mol Cell Proteomics 11(7):M111 011056

    PubMed  Google Scholar 

  77. Chen JQ, Cammarata PR, Baines CP, Yager JD (2009) Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications. Biochim Biophys Acta 1793(10):1540–1570

    PubMed  CAS  Google Scholar 

  78. Gao H, Falt S, Sandelin A, Gustafsson JA, Dahlman-Wright K (2008) Genome-wide identification of estrogen receptor alpha-binding sites in mouse liver. Mol Endocrinol 22(1):10–22

    PubMed  CAS  Google Scholar 

  79. Yang SH, Sarkar SN, Liu R, Perez EJ, Wang X, Wen Y, Yan LJ, Simpkins JW (2009) Estrogen receptor beta as a mitochondrial vulnerability factor. J Biol Chem 284(14):9540–9548

    PubMed  CAS  Google Scholar 

  80. Yang SH, Liu R, Perez EJ, Wen Y, Stevens SM Jr, Valencia T, Brun-Zinkernagel AM, Prokai L, Will Y, Dykens J, Koulen P, Simpkins JW (2004) Mitochondrial localization of estrogen receptor beta. Proc Natl Acad Sci U S A 101(12):4130–4135

    PubMed  CAS  Google Scholar 

  81. Chen JQ, Delannoy M, Cooke C, Yager JD (2004) Mitochondrial localization of ERalpha and ERbeta in human MCF7 cells. Am J Physiol Endocrinol Metab 286(6):E1011–E1022

    PubMed  CAS  Google Scholar 

  82. Chen JQ, Eshete M, Alworth WL, Yager JD (2004) Binding of MCF-7 cell mitochondrial proteins and recombinant human estrogen receptors alpha and beta to human mitochondrial DNA estrogen response elements. J Cell Biochem 93(2):358–373

    PubMed  CAS  Google Scholar 

  83. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio DM (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7(1):45–56

    PubMed  CAS  Google Scholar 

  84. Sugishita K, Li F, Su Z, Barry WH (2003) Anti-oxidant effects of estrogen reduce [Ca2+]i during metabolic inhibition. J Mol Cell Cardiol 35(3):331–336

    PubMed  CAS  Google Scholar 

  85. Borras C, Gambini J, Lopez-Grueso R, Pallardo FV, Vina J (2010) Direct antioxidant and protective effect of estradiol on isolated mitochondria. Biochim Biophys Acta 1802(1):205–211

    PubMed  CAS  Google Scholar 

  86. Foryst-Ludwig A, Clemenz M, Hohmann S, Hartge M, Sprang C, Frost N, Krikov M, Bhanot S, Barros R, Morani A, Gustafsson JA, Unger T, Kintscher U (2008) Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genet 4(6):e1000108

    PubMed  Google Scholar 

  87. Clegg DJ (2012) Minireview: the year in review of estrogen regulation of metabolism. Mol Endocrinol 26(12):1957–1960

    PubMed  CAS  Google Scholar 

  88. Bjornholm M, Zierath JR (2005) Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Biochem Soc Trans 33(Pt 2):354–357

    PubMed  CAS  Google Scholar 

  89. Ribas V, Nguyen MT, Henstridge DC, Nguyen AK, Beaven SW, Watt MJ, Hevener AL (2009) Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα−deficient mice. Am J Physiol Endocrinol Metab 298:E304–E319

    PubMed  Google Scholar 

  90. Gorres BK, Bomhoff GL, Morris JK, Geiger PC (2011) In vivo stimulation of oestrogen receptor alpha increases insulin-stimulated skeletal muscle glucose uptake. J Physiol 589(Pt 8):2041–2054

    PubMed  CAS  Google Scholar 

  91. Lundholm L, Bryzgalova G, Gao H, Portwood N, Falt S, Berndt KD, Dicker A, Galuska D, Zierath JR, Gustafsson JA, Efendic S, Dahlman-Wright K, Khan A (2008) The estrogen receptor α-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms. J Endocrinol 199(2):275–286

    PubMed  CAS  Google Scholar 

  92. Tee MK, Rogatsky I, Tzagarakis-Foster C, Cvoro A, An J, Christy RJ, Yamamoto KR, Leitman DC (2004) Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell 15(3):1262–1272

    PubMed  CAS  Google Scholar 

  93. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA (2007) Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87(3):905–931

    PubMed  CAS  Google Scholar 

  94. Baltgalvis KA, Greising SM, Warren GL, Lowe DA (2010) Estrogen regulates estrogen receptors and antioxidant gene expression in mouse skeletal muscle. PLoS One 5(4):e10164

    PubMed  Google Scholar 

  95. Barros RP, Gabbi C, Morani A, Warner M, Gustafsson JA (2009) Participation of ERalpha and ERbeta in glucose homeostasis in skeletal muscle and white adipose tissue. Am J Physiol Endocrinol Metab 297(1):E124–E133

    PubMed  CAS  Google Scholar 

  96. Barros RP, Machado UF, Gustafsson JA (2006) Estrogen receptors: new players in diabetes mellitus. Trends Mol Med 12(9):425–431

    PubMed  CAS  Google Scholar 

  97. Shang Y, Brown M (2002) Molecular determinants for the tissue specificity of SERMs. Science 295(5564):2465–2468

    PubMed  CAS  Google Scholar 

  98. 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(2):385–397

    PubMed  CAS  Google Scholar 

  99. D’Eon TM, Rogers NH, Stancheva ZS, Greenberg AS (2008) Estradiol and the estradiol metabolite, 2-hydroxyestradiol, activate AMP-activated protein kinase in C2C12 myotubes. Obesity (Silver Spring) 16(6):1284–1288

    Google Scholar 

  100. 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(4):646–650

    PubMed  CAS  Google Scholar 

  101. Deng JY, Hsieh PS, Huang JP, Lu LS, Hung LM (2008) Activation of estrogen receptor is crucial for resveratrol-stimulating muscular glucose uptake via both insulin-dependent and -independent pathways. Diabetes 57(7):1814–1823

    PubMed  CAS  Google Scholar 

  102. Chen S, Murphy J, Toth R, Campbell DG, Morrice NA, Mackintosh C (2008) Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem J 409(2):449–459

    PubMed  CAS  Google Scholar 

  103. Treebak JT, Glund S, Deshmukh A, Klein DK, Long YC, Jensen TE, Jorgensen SB, Viollet B, Andersson L, Neumann D, Wallimann T, Richter EA, Chibalin AV, Zierath JR, Wojtaszewski JF (2006) AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits. Diabetes 55(7):2051–2058

    PubMed  CAS  Google Scholar 

  104. Geraghty KM, Chen S, Harthill JE, Ibrahim AF, Toth R, Morrice NA, Vandermoere F, Moorhead GB, Hardie DG, MacKintosh C (2007) Regulation of multisite phosphorylation and 14-3-3 binding of AS160 in response to IGF-1, EGF, PMA and AICAR. Biochem J 407(2):231–241

    PubMed  CAS  Google Scholar 

  105. Pehmoller C, Treebak JT, Birk JB, Chen S, Mackintosh C, Hardie DG, Richter EA, Wojtaszewski JF (2009) Genetic disruption of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscle. Am J Physiol Endocrinol Metab 297(3):E665–E675

    PubMed  Google Scholar 

  106. Murgia M, Jensen TE, Cusinato M, Garcia M, Richter EA, Schiaffino S (2009) Multiple signalling pathways redundantly control glucose transporter GLUT4 gene transcription in skeletal muscle. J Physiol 587(Pt 17):4319–4327

    PubMed  CAS  Google Scholar 

  107. Muraki K, Okuya S, Tanizawa Y (2006) Estrogen receptor alpha regulates insulin sensitivity through IRS-1 tyrosine phosphorylation in mature 3T3-L1 adipocytes. Endocr J 53(6):841–851

    PubMed  CAS  Google Scholar 

  108. Nagira K, Sasaoka T, Wada T, Fukui K, Ikubo M, Hori S, Tsuneki H, Saito S, Kobayashi M (2006) Altered subcellular distribution of estrogen receptor alpha is implicated in estradiol-induced dual regulation of insulin signaling in 3T3-L1 adipocytes. Endocrinology 147(2):1020–1028

    PubMed  CAS  Google Scholar 

  109. Takeda K, Toda K, Saibara T, Nakagawa M, Saika K, Onishi T, Sugiura T, Shizuta Y (2003) Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J Endocrinol 176(2):237–246

    PubMed  CAS  Google Scholar 

  110. Fisher CR, Graves KH, Parlow AF, Simpson ER (1998) Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci U S A 95(12):6965–6970

    PubMed  CAS  Google Scholar 

  111. Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly YM, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson JA (2000) Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice. Biochem Biophys Res Commun 278(3):640–645

    PubMed  CAS  Google Scholar 

  112. Shin JH, Hur JY, Seo HS, Jeong YA, Lee JK, Oh MJ, Kim T, Saw HS, Kim SH (2007) The ratio of estrogen receptor alpha to estrogen receptor beta in adipose tissue is associated with leptin production and obesity. Steroids 72(6–7):592–599

    PubMed  CAS  Google Scholar 

  113. Chen X, Yu QQ, Zhu YH, Bi Y, Sun WP, Liang H, Cai MY, He XY, Weng JP (2010) Insulin therapy stimulates lipid synthesis and improves endocrine functions of adipocytes in dietary obese C57BL/6 mice. Acta Pharmacol Sin 31(3):341–346

    PubMed  CAS  Google Scholar 

  114. D’Eon TM, Souza SC, Aronovitz M, Obin MS, Fried SK, Greenberg AS (2005) Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways. J Biol Chem 280(43):35983–35991

    PubMed  Google Scholar 

  115. Jiang L, Wang Q, Yu Y, Zhao F, Huang P, Zeng R, Qi RZ, Li W, Liu Y (2009) Leptin contributes to the adaptive responses of mice to high-fat diet intake through suppressing the lipogenic pathway. PLoS One 4(9):e6884

    PubMed  Google Scholar 

  116. Paquette A, Shinoda M, Rabasa Lhoret R, Prud'homme D, Lavoie JM (2007) Time course of liver lipid infiltration in ovariectomized rats: impact of a high-fat diet. Maturitas 58(2):182–190

    PubMed  CAS  Google Scholar 

  117. Phrakonkham P, Viengchareun S, Belloir C, Lombes M, Artur Y, Canivenc-Lavier MC (2008) Dietary xenoestrogens differentially impair 3T3-L1 preadipocyte differentiation and persistently affect leptin synthesis. J Steroid Biochem Mol Biol 110(1–2):95–103

    PubMed  CAS  Google Scholar 

  118. Bryzgalova G, Lundholm L, Portwood N, Gustafsson JA, Khan A, Efendic S, Dahlman-Wright K (2008) Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. Am J Physiol Endocrinol Metab 295(4):E904–E912

    PubMed  CAS  Google Scholar 

  119. Gupte AA, Bomhoff GL, Morris JK, Gorres BK, Geiger PC (2009) Lipoic acid increases heat shock protein expression and inhibits stress kinase activation to improve insulin signaling in skeletal muscle from high-fat-fed rats. J Appl Physiol 106(4):1425–1434

    PubMed  CAS  Google Scholar 

  120. Gupte AA, Bomhoff GL, Swerdlow RH, Geiger PC (2009) Heat treatment improves glucose tolerance and prevents skeletal muscle insulin resistance in rats fed a high-fat diet. Diabetes 58(3):567–578

    PubMed  Google Scholar 

  121. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420(6913):333–336

    PubMed  CAS  Google Scholar 

  122. Ropelle ER, Pauli JR, Prada PO, de Souza CT, Picardi PK, Faria MC, Cintra DE, Fernandes MF, Flores MB, Velloso LA, Saad MJ, Carvalheira JB (2006) Reversal of diet-induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS-1 serine phosphorylation. J Physiol 577(Pt 3):997–1007

    PubMed  CAS  Google Scholar 

  123. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293(5535):1673–1677

    PubMed  CAS  Google Scholar 

  124. Chung J, Nguyen AK, Henstridge DC, Holmes AG, Chan MH, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A, Febbraio MA (2008) HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci U S A 105(5):1739–1744

    PubMed  CAS  Google Scholar 

  125. Ahmed MA, Hassanein KM (2012) Effects of estrogen on hyperglycemia and liver dysfunction in diabetic male rats. Int J Physiol Pathophysiol Pharmacol 4(3):156–166

    PubMed  CAS  Google Scholar 

  126. Gao H, Bryzgalova G, Hedman E, Khan A, Efendic S, Gustafsson JA, Dahlman-Wright K (2006) Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol Endocrinol 20(6):1287–1299

    PubMed  CAS  Google Scholar 

  127. Zhu L, Brown WC, Cai Q, Krust A, Chambon P, McGuinness OP, Stafford JM (2013) Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance. Diabetes 62(2):424–434. doi:10.2337/db11-1718. Epub 2012 Sep 10. PMID: 22966069

    Google Scholar 

  128. Chow JD, Jones ME, Prelle K, Simpson ER, Boon WC (2011) A selective estrogen receptor alpha agonist ameliorates hepatic steatosis in the male aromatase knockout mouse. J Endocrinol 210(3):323–334

    PubMed  CAS  Google Scholar 

  129. Gutierrez-Grobe Y, Ponciano-Rodriguez G, Ramos MH, Uribe M, Mendez-Sanchez N (2010) Prevalence of non alcoholic fatty liver disease in premenopausal, posmenopausal and polycystic ovary syndrome women. The role of estrogens. Ann Hepatol 9(4):402–409

    PubMed  Google Scholar 

  130. Livingstone C, Collison M (2002) Sex steroids and insulin resistance. Clin Sci (Lond) 102(2):151–166

    CAS  Google Scholar 

  131. Gonzalez C, Alonso A, Diaz 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(3):367–379

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants P20 RR016475 from the National Center for Research Resources (NCRR) and AG031575 from the National Institutes of Health, and AHA grant 12POST9020018 to A. A. Gupte.

Author information

Authors and Affiliations

  1. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Hemenway Building Room 2097, MS 3043, Kansas City, KS, 66160, USA

    Paige C. Geiger Ph.D.

  2. Center for Diabetes Research, The Methodist Hospital Research Institute, Houston, TX, USA

    Anisha A. Gupte Ph.D.

Authors
  1. Paige C. Geiger Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anisha A. Gupte Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paige C. Geiger Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Kinesiology, University of Maryland School of Public Health, College Park, Maryland, USA

    Espen E. Spangenburg

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Geiger, P.C., Gupte, A.A. (2013). The Role of Estrogens in the Regulation of Peripheral Glucose Dynamics. In: Spangenburg, E. (eds) Integrative Biology of Women’s Health. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8630-5_5

Download citation

Publish with us

Policies and ethics

Search

Navigation