A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels
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.
|Keywords||*Polymorphism, Restriction Fragment Length, Aged, Aged, 80 and over, Blood Glucose, Cholesterol/*blood, Coronary Disease/epidemiology/*genetics, Dexamethasone/diagnostic use, Diabetes Mellitus/epidemiology/*genetics, Female, Genetic Predisposition to Disease/epidemiology, Glucocorticoids/diagnostic use, Gonadal Steroid Hormones/blood, Heterozygote, Humans, Hypothalamo-Hypophyseal System/physiology, Insulin/*blood, Male, Middle aged, Pituitary-Adrenal System/physiology, Receptors, Glucocorticoid/*genetics, Research Support, Non-U.S. Gov't, Risk Factors|
Lamberts, S.W.J., Koper, J.W., Huizenga, N.A.T.M., Uitterlinden, A.G., Brinkmann, A.O., Grobbee, D.E., … van Rossum, E.F.C.. (2002). A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. Diabetes. Retrieved from http://hdl.handle.net/1765/9983