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Antidiabetic actions of estrogen: Insight from human and genetic mouse models

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Abstract

There is increasing evidence both in humans and rodents linking the endogenous estrogen 17β-estradiol (E2) to the maintenance of glucose homeostasis. Postmenopausal women develop visceral obesity and insulin resistance and are at increased risk for type 2 diabetes mellitus, but hormone replacement therapy leads to a reduction in the incidence of diabetes. In various spontaneous rodent models of type 2 diabetes, female rodents are protected against hyperglycemia unless they are ovariectomized, and E2 perfusion reverses diabetes in male rodents. Finally, the study of transgenic mice and mice with genetic alteration of E2 secretion or E2 action has shed light on the antidiabetic properties of E2 at a tissue-specific level. Thus, E2 secretion and action in rodents seems to be implicated 1) in adipose tissue biology and the prevention of obesity, 2) in the stimulation of liver fatty acid metabolism and suppression of hepatic glucose production, and 3) in the protection of pancreatic β-cell function/survival and insulin secretion in conditions of oxidative stress.

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References and Recommended Reading

  1. King H, Aubert RE, Herman WH: Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 1998, 21:1414–1431.

    Article  PubMed  CAS  Google Scholar 

  2. Narayan KM, Boyle JP, Thompson TJ, et al.: Lifetime risk for diabetes mellitus in the United States. JAMA 2003, 290:1884–1890.

    Article  PubMed  CAS  Google Scholar 

  3. McGarry JD: Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 2002, 51:7–18.

    Article  PubMed  CAS  Google Scholar 

  4. Evans JL, Goldfine ID, Maddux BA, Grodsky GM: Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003, 52:1–8.

    Article  PubMed  CAS  Google Scholar 

  5. Prentki M, Joly E, El-Assaad W, Roduit R: Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes 2002, 51(suppl 3):S405-S413.

    Article  PubMed  CAS  Google Scholar 

  6. Berne RM, Levy NM: Physiology. St. Louis, MO: Mosby; 1998.

    Google Scholar 

  7. Espeland MA, Hogan PE, Fineberg SE, et al.: Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Diabetes Care 1998, 21:1589–1595.

    Article  PubMed  CAS  Google Scholar 

  8. Crespo CJ, Smit E, Snelling A, et al.: Hormone replacement therapy and its relationship to lipid and glucose metabolism in diabetic and nondiabetic postmenopausal women: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 2002, 25:1675–1680.

    Article  PubMed  CAS  Google Scholar 

  9. Saglam K, Polat Z, Yilmaz MI, et al.: Effects of postmenopausal hormone replacement therapy on insulin resistance. Endocrine 2002, 18:211–214.

    Article  PubMed  CAS  Google Scholar 

  10. Li C, Samsioe G, Borgfeldt C, et al.: Low-dose hormone therapy and carbohydrate metabolism. Fertil Steril 2003, 79:550–555.

    Article  PubMed  Google Scholar 

  11. Andersson B, Mattsson LA, Hahn L, et al.: Estrogen replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in postmenopausal women with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997, 82:638–643.

    Article  PubMed  CAS  Google Scholar 

  12. Brussaard HE, Gevers Leuven JA, Frolich M, et al.: Short-term oestrogen replacement therapy improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM. Diabetologia 1997, 40:843–849.

    Article  PubMed  CAS  Google Scholar 

  13. Friday KE, Dong C, Fontenot RU: Conjugated equine estrogen improves glycemic control and blood lipoproteins in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab 2001, 86:48–52.

    Article  PubMed  CAS  Google Scholar 

  14. Perera M, Sattar N, Petrie JR, et al.: The effects of transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with type 2 diabetes: a randomized, placebo- controlled study. J Clin Endocrinol Metab 2001, 86:1140–1143.

    Article  PubMed  CAS  Google Scholar 

  15. Cagnacci A, Soldani R, Carriero PL, et al.: Effects of low doses of transdermal 17 beta-estradiol on carbohydrate metabolism in postmenopausal women. J Clin Endocrinol Metab 1992, 74:1396–1400.

    Article  PubMed  CAS  Google Scholar 

  16. Lindheim SR, Duffy DM, Kojima T, et al.: The route of administration influences the effect of estrogen on insulin sensitivity in postmenopausal women. Fertil Steril 1994, 62:1176–1180.

    PubMed  CAS  Google Scholar 

  17. Kanaya AM, Herrington D, Vittinghoff E, et al.: Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003, 138:1–9.

    PubMed  CAS  Google Scholar 

  18. Knowler WC, Barrett-Connor E, Fowler SE, et al.: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002, 346:393–403.

    Article  PubMed  CAS  Google Scholar 

  19. Morishima A, Grumbach MM, Simpson ER, et al.: Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995, 80:3689–3698.

    Article  PubMed  CAS  Google Scholar 

  20. Bilezikian JP, Morishima A, Bell J, Grumbach MM: Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 1998, 339:599–603.

    Article  PubMed  CAS  Google Scholar 

  21. Smith EP, Boyd J, Frank GR, et al.: Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994, 331:1056–1061.

    Article  PubMed  CAS  Google Scholar 

  22. Barnes BO, Regan JF, Nelson WO: Improvement in experimental diabetes following the administration of ammniotin. JAMA 1933, 101:926–927.

    Google Scholar 

  23. Nelson WO, Overholser M: The effect of estrogenic hormones on experimental pancreatic diabetes in the monkey. Endocrinology 1936, 20:473–480.

    CAS  Google Scholar 

  24. Rodriguez RR: Influence of oestrogens and androgens on the production and prevention of diabetes. In On The Nature and Treatment of Diabetes. Edited by Wrenshall GA, Leibel BS. New York: Excerpta Medica Foundation; 1965:288–307.

    Google Scholar 

  25. Clark JB, Palmer CJ, Shaw WN: The diabetic Zucker fatty rat. Proc Soc Exp Biol Med 1983, 173:68–75.

    PubMed  CAS  Google Scholar 

  26. Leiter EH, Chapman HD: Obesity-induced diabetes (diabesity) in C57BL/KsJ mice produces aberrant trans-regulation of sex steroid sulfotransferase genes. J Clin Invest 1994, “93:2007–2013.

    PubMed  CAS  Google Scholar 

  27. Klebig ML, Wilkinson JE, Geisler JG, Woychik RP: Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur. Proc Natl Acad Sci U S A 1995, 92:4728–4732.

    Article  PubMed  CAS  Google Scholar 

  28. Paik SG, Michelis MA, Kim YT, Shin S: Induction of insulin-dependent diabetes by streptozotocin. Inhibition by estrogens and potentiation by androgens. Diabetes 1982, 31:724–729.

    Article  PubMed  CAS  Google Scholar 

  29. Puah JA, Bailey CJ: Insulinotropic effect of ovarian steroid hormones in streptozotocin diabetic female mice. Horm Metab Res 1985, 17:216–218.

    PubMed  CAS  Google Scholar 

  30. Duncan AC, Lyall H, Roberts RN, et al.: The effect of estradiol and a combined estradiol/progestagen preparation on insulin sensitivity in healthy postmenopausal women. J Clin Endocrinol Metab 1999, 84:2402–2407.

    Article  PubMed  CAS  Google Scholar 

  31. O’Sullivan AJ, Ho KK: A comparison of the effects of oral and transdermal estrogen replacement on insulin sensitivity in postmenopausal women. J Clin Endocrinol Metab 1995, 80:1783–1788.

    Article  PubMed  CAS  Google Scholar 

  32. Vehkavaara S, Westerbacka J, Hakala-Ala-Pietila T, et al.: Effect of estrogen replacement therapy on insulin sensitivity of glucose metabolism and preresistance and resistance vessel function in healthy postmenopausal women. J Clin Endocrinol Metab 2000, 85:4663–4670.

    Article  PubMed  CAS  Google Scholar 

  33. Rincon J, Holmang A, Wahlstrom EO, et al.: Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment. Diabetes 1996, 45:615–621.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  35. Puah JA, Bailey CJ: Effect of ovarian hormones on glucose metabolism in mouse soleus muscle. Endocrinology 1985, 117:1336–1340.

    PubMed  CAS  Google Scholar 

  36. Khan A, Brysgalova G, Nilsson S, et al.: Evidence that estrogen receptor-alpha regulates hepatic insulin sensitivity [abstract]. Diabetologia 2003, 46(suppl 2):A211.

    Google Scholar 

  37. Wade GN, Gray JM, Bartness TJ: Gonadal influences on adiposity. Int J Obes 1985, 9(suppl 1):83–92.

    PubMed  CAS  Google Scholar 

  38. Tchernof A, Calles-Escandon J, Sites CK, Poehlman ET: Menopause, central body fatness, and insulin resistance: effects of hormone-replacement therapy. Coronary Artery Dis 1998, 9:503–511.

    Article  CAS  Google Scholar 

  39. Heine PA, Taylor JA, Iwamoto GA, et al.: Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci U S A 2000, 97:12729–12734.

    Article  PubMed  CAS  Google Scholar 

  40. Ohlsson C, Hellberg N, Parini P, et al.: Obesity and disturbed lipoprotein profile in estrogen receptor-alpha- deficient male mice. Biochem Biophys Res Commun 2000, 278:640–645.

    Article  PubMed  CAS  Google Scholar 

  41. Jones ME, Thorburn AW, Britt KL, et al.: Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci U S A 2000, 97:12735–12740.

    Article  PubMed  CAS  Google Scholar 

  42. Couse JF, Korach KS: Estrogen receptor null mice: what have we learned and where will they lead us? Endocrine Rev 1999, 20:358–417.

    Article  CAS  Google Scholar 

  43. Misso ML, Murata Y, Boon WC, et al.: Cellular and molecular characterization of the adipose phenotype of the aromatase-deficient mouse. Endocrinology 2003, 144:1474–1480.

    Article  PubMed  CAS  Google Scholar 

  44. Matute ML, Kalkhoff RK: Sex steroid influence on hepatic gluconeogenesis and glucogen formation. Endocrinology 1973, 92:762–768.

    PubMed  CAS  Google Scholar 

  45. Takeda K, Toda K, Saibara T, et al.: Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J Endocrinol 2003, 176:237–246.

    Article  PubMed  CAS  Google Scholar 

  46. Mauvais-Jarvis F, Kulkarni RN, Kahn CR: Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance. Clin Endocrinol (Oxford) 2002, 57:1–9.

    Article  CAS  Google Scholar 

  47. Nemoto Y, Toda K, Ono M, et al.: Altered expression of fatty acid-metabolizing enzymes in aromatase- deficient mice. J Clin Invest 2000, 105:1819–1825.

    PubMed  CAS  Google Scholar 

  48. Hewitt KN, Pratis K, Jones ME, Simpson ER: Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout (ArKO) mouse. Endocrinology 2003, In press.

  49. Costet P, Legendre C, More J, et al.: Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J Biol Chem 1998, 273:29577–29585.

    Article  PubMed  CAS  Google Scholar 

  50. Djouadi F, Weinheimer CJ, Saffitz JE, et al.: A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor alpha- deficient mice. J Clin Invest 1998, 102:1083–1091.

    Article  PubMed  CAS  Google Scholar 

  51. Poitout V, Robertson RP: Minireview: secondary beta-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity. Endocrinology 2002, 143:339–342.

    Article  PubMed  CAS  Google Scholar 

  52. Pick A, Clark J, Kubstrup C, et al.: Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat. Diabetes 1998, 47:358–364.

    Article  PubMed  CAS  Google Scholar 

  53. Lee Y, Hirose H, Zhou YT, et al.: Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM. Diabetes 1997, 46:408–413.

    Article  PubMed  CAS  Google Scholar 

  54. Geisler JG, Zawalich W, Zawalich K, et al.: Estrogen can prevent or reverse obesity and diabetes in mice expressing human islet amyloid polypeptide. Diabetes 2002, 51:2158–2169.

    Article  PubMed  CAS  Google Scholar 

  55. Efrat S: Sexual dimorphism of pancreatic beta-cell degeneration in transgenic mice expressing an insulin-ras hybrid gene. Endocrinology 1991, 128:897–901.

    Article  PubMed  CAS  Google Scholar 

  56. Zhu M, Noma Y, Mizuno A, et al.: Poor capacity for proliferation of pancreatic beta-cells in Otsuka-Long-Evans-Tokushima Fatty rat: a model of spontaneous NIDDM. Diabetes 1996, 45:941–946.

    Article  PubMed  CAS  Google Scholar 

  57. Zhu M, Mizuno A, Kuwajima M, et al.: Ovarian hormone-induced beta-cell hypertrophy contributes to the homeostatic control of beta-cell mass in OLETF female rat, a model of Type II diabetes. Diabetologia 1998, 41:799–805.

    Article  PubMed  CAS  Google Scholar 

  58. Contreras JL, Smyth CA, Bilbao G, et al.: 17beta-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality. Transplantation 2002, 74:1252–1259.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, One Baylor Plaza, 520B, 77030, Houston, TX, USA

    Jean-Francois Louet PhD, Cedric LeMay PhD & Franck Mauvais-Jarvis MD

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  1. Jean-Francois Louet PhD
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  3. Franck Mauvais-Jarvis MD
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Louet, JF., LeMay, C. & Mauvais-Jarvis, F. Antidiabetic actions of estrogen: Insight from human and genetic mouse models. Curr Atheroscler Rep 6, 180–185 (2004). https://doi.org/10.1007/s11883-004-0030-9

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