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) 3GAAAAG(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 assess-ment?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. Diabetes 51:3128-3134,