Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1 (5-Year IF – 2.0)
Journal Citation Indicator (JCI) (2023) – 0.4
Scopus CiteScore – 3.7 (CiteScore Tracker – 4.0)
Index Copernicus  – 171.00; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2017, vol. 26, nr 1, January-February, p. 143–148

doi: 10.17219/acem/41231

Publication type: review

Language: English

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Glucocorticoid receptor polymorphism in obesity and glucose homeostasis

Agnieszka Majer-Łobodzińska1,A,B,C,D, Joanna Adamiec-Mroczek2,A,E,F

1 Department and Clinic of Angiology, Hypertension and Diabetology, Wroclaw Medical University, Poland

2 Department and Clinic of Ophtalmology, Wroclaw Medical University, Poland

Abstract

Glucocorticoid receptor (GR) activity plays a significant role in the etiology of obesity and is essential for glucose homeostasis, the development of hyperinsulinaemia and subsequent increased fat deposition. Several polymorphisms in the GR gene have been described, and at least three of them seem to be associated with altered glucocorticoid sensitivity and changes in glucose homeostasis, and other metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to glucocorticoides, increased insulin response to dexamethasone and increased plasma glucose level. BclI polymorphism is associated with increased abdominal obesity, hyperinsulinaemia and increased insulin resistance. Another polymorphism, ER22/23EK, in contrast to the others, is associated with relative resistance to glucocoricides actions and more beneficial metabolic profile-lower insulin resistance level, decreased lower cardiovascular risk and subseuent prolongation of life time. More research is still needed to understand the mechanisms behind these associations at the molecular level.

Key words

obesity, glucocorticoid receptor polymorphism, N363S, BclI, ER22/23EK

References (37)

  1. Koper JW, van Rossum EF, van den Akker EL. Glucocorticoid receptor polymorphisms and haplotypes and their expression in health and disease. Steroids. 2014; 92: 62–73.
  2. DeRijk RH, Schaaf M, de Kloet ER. Glucocorticoid receptor variants: Clinical implications. J Steroid Biochem. 2002;81:103–122.
  3. Kadmiel M, Cidlowski JA. Glucocorticoid receptor signaling in health and disease Trends Pharmacol Sci. 2013;34:518– 530.
  4. Bjorntorp P, Rosmond R. Obesity and cortisol. Nutrition. 2000;16: 924–936.
  5. Hauner H, Schmid P, Pfeiffer EF. Glucocorticoids and insulin promote the differentiation of human adipocyte precursor cells into fat cells. J Clin Endocrinol Metab. 1987;64:832–835.
  6. Whorwood CB, Donovan SJ, Flanagan D, et al. Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes 2002;5:1066–1075.
  7. Giguere V, Hollenberg SM, Rosenfeld MG, et al. Functional domains of the human glucocorticoid receptor. Cell. 1986; 46:645–652.
  8. Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem. 2006;102(1):11–21.
  9. Rousseau GG. Structure and regulation of the glucocorticoid hormone receptor. Mol Cell Endocrinol. 1984;38:1–11.
  10. Wehling M. Specific, nongenomic actions of steroid hormones. Annu Rev Physiol. 1997;59:365–393.
  11. Oakley RH, Jewell CM, Yudt MR, et al. The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action J Biol Chem. 1999;274(39):27857–27866.
  12. Huizenga NA, Koper JW, de Lange P, et al. Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals. J Clin En-docrinol Metab. 1998;83(1):47–54.
  13. Huizenga NA, Koper JW, De Lange P, et al. A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensi-tivity to glucocorticoids in vivo. J Clin Endocrinol Metab. 1998;83(1):144–151.
  14. Lin RC, Wang WY, Morris BJ. High penetrance, overweight, and glucocorticoid receptor variant: Case-control study. Brit Med J. 1999;319(7221):1337–1338.
  15. Di Blasio AM, van Rossum EF, Maestrini S, et al. The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients. Clin Endocrinol (Oxf). 2003;59:68–74.
  16. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: A simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85(7):2402–2410.
  17. Rosmond R, Bouchard C, Bjorntorp P. Tsp509I polymorphism in exon 2 of the glucocorticoid receptor gene in relation to obesity and cortisol secretion: Cohort study. B Med J. 2001;322:652–653.
  18. Dobson MG, Redfern CP, Unwin N, Weaver JU. The N363S polymorphism of the glucocorticoid receptor: Potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus. J Clin Endocrinol Metab. 2001;86:2270–2274.
  19. Marti A, Ochoa C, Sánchez-Villegas A, Martinez JA. Meta-analysis on the effect of the N363S polymorphism of the glucocorticoid receptor gene (GRL) on human obesity. BMC Med Genet. 2006;7:50.
  20. Buemann B, Black E, Holst C, et al. The N363S polymorphism of the glucocorticoid receptor and metabolic syndrome factors in men. Obes Res. 2005;13:862– 867.
  21. Panek M, Kupryś-Lipińska I, Pietras T, et al. Polimorfizm genu receptora glikokortykosteridowego h-GR/NR3C1 w populacji polskiej. http://www.mojaastma.org.pl/files/polimorfizm_genu_recept_gliko_w_pop_pol.pdf.
  22. van Rossum EF, Koper JW, Arp P, et al. Identification of the Bcl I Polymorphism in the Glucocorticoid Receptor Gene: association with sensi-tivity to glucocorticoids in vivo, and body mass index. Clin Endocrinol. 2003;59(5):585–592.
  23. Weaver JU, Hitman GA, Kopelman PG. An association between a Bcl1 restriction fragment length polymorphism of the glucocorticoid re-ceptor locus and hyperinsulinaemia in obese women. J Mol Endocrinol. 1992;9(3):295–300.
  24. Buemann B, Vohl MC, Chagnon M, et al. Abdominal visceral fat is associated with a BclI restriction fragment length polymorphism at the glucocorticoid receptor gene locus. Obes Res. 1997;5:186–192.
  25. Rosmond R, Holm G. A 5-year follow-up study of 3 polymorphisms in the human glucocorticoid receptor gene in relation to obesity, hyper-tension, and diabetes. J Cardiometab Syndr. 2008;3(3):132–135.
  26. Giordano R, Marzotti S, Berardelli R, et al. BclI polymorphism of the glucocorticoid receptor gene is associated with increased obesity, im-paired glucose metabolism and dyslipidemia in patients with addison’s disease. Clin Endocrinol (Oxf). 2012;77:863–870.
  27. Tremblay A, Bouchard L, Bouchard C, et al. Long-term adiposity changes are related to a glucocorticoid receptor polymorphism in young females. J Clin Endocrinol Metab. 2003;88(7):3141–145.
  28. Geelen CC, van Greevenbroek MM, van Rossum, et al. Bcl I Glucocorticoid receptor polymorphism is associated with greater body fatness: The Hoorn and CODAM studies. J Clin Endocrinol Metab. 2013;98(3):E595–E599.
  29. Barat P, Corcuff JB, Tauber M, et al. Associations of glucocorticoid receptor and corticosteroid-binding globulin gene polymorphisms on fat mass and fat mass distribution in prepubertal obese children. J Physiol Biochem. 2012;68:645–650.
  30. Maciel GAR, Moreira RP, Bugano DD, et al. Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in polycystic ovary syndrome. Clinics 2014;69(3):179–184.
  31. Murray JC, Smith RF, Ardinger HA, Weinberge C. RFLP for the glucocorticoid receptor (GRL) located at 5q11–5q13. Nucleic Acids Res. 1987;15:6765
  32. van Rossum EFC, Koper JW, Huizenga NA, et al. A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to gluco-corticoids in vivo, is associated with low insulin and cholesterol levels. Diabetes. 2002;51(10):3128–3131
  33. van Rossum EFC, Voorhoeve PG, te Velde SJ, et al. The ER22/23EK polymorphism in the glucocorticoid receptor gene is associated with a beneficial body composition and muscle strength in young adults. J Clin Endocrin Metab. 2004;89(8):4004–4009.
  34. Russcher H, Lamberts SWJ, van Rossum EFC, et al. Impaired translation of glucocorticoid receptor mRNA as a result of the ER22/23EK poly-morphism. Program of the 85th Annual Meeting of The Endocrine Society. Philadelphia, PA; 2003:315 (Abstract P2-31).
  35. van Rossum EFC, Feelders RA, Van Den Beld AW, et al. Association of the ER22/23EK polymorphism in the glucocorticoid receptor gene with survival and C-reactive protein levels in elderly men. Am J Med. 2004;117(3):158–162.
  36. Kuningas M, Mooijaart SP, Slagboom PE, et al. Genetic variants in the glucocorticoid receptor gene (NR3C1) and cardiovascular disease risk. The Leiden 85-plus study. Biogerontology. 2006;7:231–238.
  37. Finken MJ, Meulenbelt I, Dekker FW, et al. The 23K variant of the R2 3K polymorphism in the glucocorticoid receptor gene protects against postnatal growth failure and insulin resistance after preterm birth. J Clin Endocrinol Metab. 2007;92:4777–4782.
© Wroclaw Medical University