Glucocorticoid receptor gene polymorphisms are associated with reduced first-phase glucose-stimulated insulin secretion and disposition index in women, but not in men

Aim Glucocorticoids are efficacious anti-inflammatory agents, but, in susceptible individuals, these drugs may induce glucose intolerance and diabetes by affecting b-cell function and insulin sensitivity. We assessed whether polymorphisms in the glucocorticoid receptor gene NR3C1 associate with measures of b-cell function and insulin sensitivity derived from hyperglycaemic clamps in subjects with normal or impaired glucose tolerance. Methods A cross-sectional cohort study was conducted in four academic medical centres in the Netherlands and Germany. Four hundred and forty-nine volunteers (188 men; 261 women) were recruited with normal glucose tolerance (n = 261) and impaired glucose tolerance (n = 188). From 2-h hyperglycaemic clamps, first- and second-phase glucosestimulated insulin secretion, as well as insulin sensitivity index and disposition index, were calculated. All participants were genotyped for the functional NR3C1 polymorphisms N363S (rs6195), BclI (rs41423247), ER22 ⁄23EK (rs6189 ⁄6190), 9b A ⁄G (rs6198) and ThtIIII (rs10052957). Associations between these polymorphisms and b-cell function parameters were assessed. Results In women, but not in men, the N363S polymorphism was associated with reduced disposition index (P =1 .06 10 )4 ). Also only in women, the ER22 ⁄23EK polymorphism was associated with reduced first-phase glucose-stimulated insulin secretion (P = 0.011) and disposition index (P = 0.003). The other single-nucleotide polymorphisms were not associated with b-cell function. Finally, none of the polymorphisms was related to insulin sensitivity. Conclusion The N363S and ER22 ⁄23EK polymorphisms of the NR3C1 gene are negatively associated with parameters of b-cell function in women, but not in men.