A Polymorphism in the Glucocorticoid Receptor Gene, Which Decreases Sensitivity to Glucocorticoids In Vivo, Is Associated With Low Insulin and Cholesterol Levels
- Elisabeth F.C. van Rossum1,
- Jan W. Koper1,
- Nannette A.T.M. Huizenga1,
- André G. Uitterlinden1,
- Joop A.M.J.L. Janssen1,
- Albert O. Brinkmann2,
- Diederick E. Grobbee3,
- Frank H. de Jong1,
- Cornelia M. van Duyn4,
- Huibert A.P. Pols1 and
- Steven W.J. Lamberts1
- 1Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
- 2Department of Endocrinology & Reproduction, Erasmus Medical Center, Rotterdam, the Netherlands
- 3Department of Julius Center, University of Utrecht, Utrecht, the Netherlands
- 4Department of Epidemiology & Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands
Abstract
We investigated whether a polymorphism in codons 22 and 23 of the glucocorticoid (GC) receptor gene [GAGAGG(GluArg) → GAAAAG(GluLys)] is associated with altered GC sensitivity, anthropometric parameters, cardiovascular risk factors, and sex steroid hormones. In a subgroup of 202 healthy elderly subjects of the Rotterdam Study, we identified 18 heterozygotes (8.9%) for the 22/23EK allele (ER22/23EK carriers). In the highest age group, the number of ER22/23EK carriers was higher (67–82 years, 12.9%) than in the youngest age group (53–67 years, 4.9%; P < 0.05). Two dexamethasone (DEX) suppression tests with 1 and 0.25 mg DEX were performed, and serum cortisol and insulin concentrations were compared between ER22/23EK carriers and noncarriers. After administration of 1 mg DEX, the ER22/23EK group had higher serum cortisol concentrations (54.8 ± 18.3 vs. 26.4 ± 1.4 nmol/l, P < 0.0001), as well as a smaller decrease in cortisol (467.0 ± 31.7 vs. 484.5 ± 10.3 nmol/l, P < 0.0001). ER22/23EK carriers had lower fasting insulin concentrations (P < 0.001), homeostasis model assessment- insulin resistance (IR) (index of IR, P < 0.05), and total (P < 0.02) and LDL cholesterol concentrations (P < 0.01). Our data suggest that carriers of the 22/23EK allele are relatively more resistant to the effects of GCs with respect to the sensitivity of the adrenal feedback mechanism than noncarriers, resulting in a better metabolic health profile.
Footnotes
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Address correspondence and reprint requests to J.W. Koper, Department of Internal Medicine, Room Bd 277, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. E-mail: koper{at}inw3.fgg.eur.nl.
Received for publication 10 April 2002 and accepted in revised form 2 July 2002.
CBG, cortisol-binding globulin; DEX, dexamethasone; DST, DEX suppression test; DHEAS, dehydroepiandrosterone-sulfate; GC, glucocorticoid; GR, GC receptor; HOMA, homeostasis model assessment; HOMA-B, HOMA β-cell function; HPA, hypothalamo-pituitary-adrenal; IGF-BP1, IGF-binding protein 1; IR, insulin resistance; RFLP, restriction fragment-length polymorphism; RIA, radioimmunoassay; SHBG, sex hormone-binding globulin.
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