Diabet. Med. 29, e211–e216 (2012)AbstractAim  Glucocorticoids are efficacious anti‐inflammatory agents, but, in susceptible individuals, these drugs may induce glucose intolerance and diabetes by affecting β‐cell function and insulin sensitivity. We assessed whether polymorphisms in the glucocorticoid receptor gene NR3C1 associate with measures of β‐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 glucose‐stimulated 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), 9β A/G (rs6198) and ThtIIII (rs10052957). Associations between these polymorphisms and β‐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 β‐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 β‐cell function in women, but not in men.