A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels
Open accessAbstract
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.
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Interindividual sensitivity to glucocorticoids is influenced, in part, by polymorphisms in the glucocorticoid receptor gene, which have been associated with altered receptor function and differential metabolic responses to cortisol.
“This variability is influenced, in part, by polymorphisms in the glucocorticoid receptor gene, which have been associated with altered receptor function and differential metabolic responses to cortisol (102-108).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [107]
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References 20 · Cited by 329
- Authors
- van Rossum, E. F. C., Koper, J. W., Huizenga, N. A. T. M., Uitterlinden, A. G., Janssen, J. A. M. J. L., Brinkmann, A. O., Grobbee, D. E., de Jong, F. H., van Duyn, C. M., Pols, H. A. P., & Lamberts, S. W. J.
- Affiliations
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
- Erasmus MC (NL)
- Utrecht University (NL)
- Department of Epidemiology & Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-10-01
- Volume
- 51
- Issue
- 10
- Pages
- 3128-3134
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2113647082
- Cited by
- 329
- References
- 20
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 10 · 2022: 3 · 2021: 12 · 2020: 9 · 2019: 8 · 2018: 14 · 2017: 11 · 2016: 15 · 2015: 18 · 2014: 14 · 2013: 13 · 2012: 18
- FWCI
- 7.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- glucocorticoid receptor gene, glucocorticoid sensitivity, dexamethasone suppression test, serum cortisol, insulin resistance, insulin, LDL cholesterol, total cholesterol, older adults, sex hormones, cardiovascular risk factors, anthropometric parameters
- MeSH terms
- Aged, Aged, 80 and over, Blood Glucose, Cholesterol, Coronary Disease, Dexamethasone, Diabetes Mellitus, Female, Glucocorticoids, Heterozygote, Humans, Hypothalamo-Hypophyseal System, Insulin, Male, Middle Aged, Pituitary-Adrenal System, Receptors, Glucocorticoid, Polymorphism, Restriction Fragment Length, Risk Factors, Gonadal Steroid Hormones, Genetic Predisposition to Disease
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