The Role of Oestrogen Receptor Beta (ERβ) in the Aetiology and Treatment of Type 2 Diabetes Mellitus

Author(s): Wendy Amy Ofosu, Dahir Mohamed, Olivia Corcoran*, Opeolu Oyejide Ojo*.

Journal Name: Current Diabetes Reviews

Volume 15 , Issue 2 , 2019

Submit Manuscript
Submit Proposal

Abstract:

Introduction: Challenges facing the treatment of type 2 diabetes necessitate the search for agents which act via alternative pathways to provide better therapeutic outcomes. Recently, an increasing body of evidence implicates the activation of oestrogen receptors (ERα and ERβ) in the development and treatment of underlying conditions in type 2 diabetes. This article summarizes available evidence for the involvement of oestrogen receptors in insulin secretion, insulin resistance as well as glucose uptake and highlights the potential of ERβ as a therapeutic target.

Background: Recent studies indicate an association between the activation of each of the isoforms of ER and recent findings indicate that ERβ shows promise as a potential target for antidiabetic drugs. In vitro and in vivo studies in receptor knockout mice indicate beneficial actions of selective agonists of ERβ receptor and underscore its therapeutic potential.

Conclusion: Studies are needed to further elucidate the exact mechanism underlying the role of ERβ activation as a therapeutic approach in the management of type 2 diabetes.

Keywords: Oestrogen receptor, ERα, ERβ, GPER, insulin resistance, type 2 diabetes, GLUT4.

[1]
Stumvoll M, Goldstein BJ, Van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005; 365(9467): 1333-46.
[2]
Alberti KG, Zimmet P, Shaw J. The metabolic syndrome — a new worldwide definition. Lancet 2005; 366: 1059-62.
[3]
Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of Type 2 Diabetes: Perspectives on the past, present and future. Lancet 2014; 383(9922): 1068-83.
[4]
Bjornholm M, Zierath JR. Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Biochem Soc Trans 2005; 33: 354-7.
[5]
Alonso-Magdalena P, Ropero AB, García-Arévalo M, et al. Antidiabetic actions of an estrogen receptor β selective agonist. Diabetes 2013; 62(6): 2015-25.
[6]
Chambon P. The nuclear receptor superfamily: A personal retrospect on the first two decades. Mol Endocrinol 2005; 19: 1418-28.
[7]
Bryzgalova G, Gao H, Ahren B, et al. Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: Insulin sensitivity in the liver. Diabetologia 2006; 49(3): 588-97.
[8]
Jensen EV. On the mechanism of estrogen action. Perspect Biol Med 1962; 6: 47-54.
[9]
Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996; 93: 5925-30.
[10]
Prossnitz ER, Barton M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 2011; 7(12): 715-26.
[11]
Krege JH, Hodgin JB, Couse JF, et al. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci USA 1998; 95(26): 15677-82.
[12]
McDevitt MA, Glidewell-Kenney C, Jimenez MA, et al. New insights into the classical and non-classical actions of estrogen: evidence from estrogen receptor knock-out and knock-in mice. Mol Cell Endocrinol 2008; 290(1): 24-30.
[13]
Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA 2000; 97(23): 12735-40.
[14]
Barros RP, Gustafsson JA. Estrogen receptors and the metabolic network. Cell Metab 2011; 14(3): 289-99.
[15]
Patrone C, Pollio G, Vegeto E, et al. Estradiol induces differential neuronal phenotypes by activating estrogen receptor alpha or beta. Endocrinology 2000; 141(5): 1839-45.
[16]
Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 2000; 127(19): 4277-91.
[17]
Alonso-Magdalena P, Ropero AB, Carrera MP, et al. Pancreatic insulin content regulation by the estrogen receptor ERα. PLoS One 2008; 3(4): e2069.
[18]
Helguero LA, Faulds MH, Gustafsson JA, Haldosén LA. Estrogen receptors alpha (ERα) and beta (ERβ) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11. Oncogene 2005; 24: 6605-16.
[19]
Heldring N, Pike A, Andersson S, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007; 87: 905-31.
[20]
Nilsson S, Makela S, Treuter E, et al. Mechanisms of estrogen action. Physiol Rev 2001; 81: 1535-65.
[21]
Alonso-Magdalena P, Ropero AB, Carrera MP, et al. Pancreatic insulin content regulation by the estrogen receptor ERa. PLoS One 2008; 3(4): e2069.
[22]
Ropero AB, Alonso-Magdalena P, Quesada I, Nadal A. The role of estrogen receptors in the control of energy and glucose homeostasis. Steroids 2008; 73(9): 874-9.
[23]
Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA 2000; 97: 12735-40.
[24]
Weigt C, Hertrampf T, Flenker U, et al. Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats. J Steroid Biochem Mol Biol 2015; 154: 12-22.
[25]
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: 237-46.
[26]
Nadal A, Alonso-Magdalena P, Soriano S, Quesada I, Ropero AB. The pancreatic beta-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Mol Cell Endocrinol 2009; 304(1-2): 63-8.
[27]
Koehler KF, Helguero LA, Haldosén LA, Warner M, Gustafsson JA. Reflections on the discovery and significance of estrogen receptor beta. Endocr Rev 2005; 26(3): 465-78.
[28]
Bansal S, Chopra K. Distinct role of estrogen receptor-alpha and beta on postmenopausal diabetes-induced vascular dysfunction. Gen Comp Endocrinol 2014; 206: 51-9.
[29]
Barros RP, Gabbi C, Morani A, Warner M, Gustafsson JA. Participation of ERalpha and ERbeta in glucose homeostasis in skeletal muscle and white adipose tissue. Am J Physiol Endocrinol Metab 2009; 297(1): E124-33.
[30]
Barros RP, Machado UF, Gustafsson JA. Estrogen receptors: new players in diabetes mellitus. Trends Mol Med 2006; 12: 425-31.
[31]
Foryst-Ludwig A, Clemenz M, Hohmann S, et al. Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genet 2008; 4(6): e1000108.
[32]
Pedram A, Razandi M, Aitkenhead M, Hughes CC, Levin ER. Integration of the non-genomic and genomic actions of estrogen membrane-initiated signaling by steroid to transcription and cell biology. J Biol Chem 2002; 277(52): 50768-75.
[33]
Wyckoff MH, Chambliss KL, Mineo C, et al. Plasma membrane estrogen receptors are coupled to endothelial nitric-oxide synthase through Gαi. J Biol Chem 2001; 276(29): 27071-6.
[34]
Razandi M, Pedram A, Greene GL, Levin ER. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: Studies of ERα and ERβ expressed in Chinese hamster ovary cells. Mol Endocrinol 1999; 3(2): 307-19.
[35]
Sharma G, Prossnitz ER. Mechanisms of estradiol-induced insulin secretion by the G protein-coupled estrogen receptor GPR30/GPER in pancreatic β-cells. Endocrinology 2011; 152(8): 3030-9.
[36]
Prossnitz ER, Barton M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 2011; 7(12): 715-26.
[37]
Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest 2006; 116(3): 561-70.
[38]
Soriano S, Ropero AB, Alonso-Magdalena P, et al. Rapid regulation of K(ATP) channel activity by 17beta-estradiol in pancreatic beta-cells involves the estrogen receptor beta and the atrial natriuretic peptide receptor. Mol Endocrinol 2009; 23(12): 1973-82.
[39]
Ropero AB, Fuentes E, Rovira JM, Ripoll C, Soria B, Nadal A. Non‐genomic actions of 17β‐oestradiol in mouse pancreatic β‐cells are mediated by a cGMP‐dependent protein kinase. J Physiol 1999; 521(2): 397-407.
[40]
Barros RP, Machado UF, Warner M, Gustafsson JA. Muscle GLUT4 regulation by estrogen receptors ERbeta and ERalpha. Proc Natl Acad Sci USA 2006; 103(5): 1605-8.
[41]
Follettie MT, Pinard M, Keith JC, et al. Organ messenger ribonucleic acid and plasma proteome changes in the adjuvant-induced arthritis model: responses to disease induction and therapy with the estrogen receptor-β selective agonist ERB-041. Endocrinology 2006; 147(2): 714-23.
[42]
Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR. Bazedoxifene acetate: A selective estrogen receptor modulator with improved selectivity. Endocrinology 2005; 146(9): 3999-4008.
[43]
Park YM, Pereira RI, Erickson CB, Swibas TA, Cox-York KA, Van Pelt RE. Estradiol-mediated improvements in adipose tissue insulin sensitivity are related to the balance of adipose tissue estrogen receptor α and β in postmenopausal women. PLoS One 2017; 12(5): e0176446.
[44]
Pitteloud N, Hardin M, Dwyer AA, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab 2005; 90(5): 2636-41.
[45]
Lin Z, Shen H, Huang J, et al. Butyl 4-(butyryloxy)benzoate functions as a new selective estrogen receptor beta agonist and induces GLUT4 expression in CHO-K1 cells. J Steroid Biochem Mol Biol 2008; 110(1-2): 150-6.
[46]
Harrington WR, Sheng S, Barnett DH, Petz LN, Katzenellenbogen JA, Katzenellenbogen BS. Activities of estrogen receptor - and -selective ligands at diverse estrogen responsive gene sites mediating transactivation or transrepression. Mol Cell Endocrinol 2003; 206: 13-22.
[47]
Kaestner KH, Christy RJ, Lane MD. Mouse insulin-responsive glucose transporter gene: Characterization of the gene and trans-activation by the CCAAT/enhancer binding protein. Proc Natl Acad Sci USA 1990; 87: 251-5.
[48]
Long SD, Pekala PH. Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3-L1 adipocytes. Biochem J 1996; 319: 179-84.
[49]
Kanda N, Watanabe S. 17b-estradiol inhibits MCP-1 production in human keratinocytes. J Invest Dermatol 2003; 120: 1058-66.
[50]
Salvatori L, Pallante P, Ravenna L, et al. Oestrogens and selective oestrogen receptor (ER) modulators regulate EGF receptor gene expression through human ER α and β subtypes via an Sp1 site. Oncogene 2003; 22: 4875-81.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 15
ISSUE: 2
Year: 2019
Page: [100 - 104]
Pages: 5
DOI: 10.2174/1573399814666180119141836
Price: $58

Article Metrics

PDF: 27
HTML: 2
EPUB: 1