title: Glucocorticoid receptor gene polymorphisms are associated with reduced first-phase glucose-stimulated insulin secretion and disposition index in women, but not in men.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. d.vanraalte@vumc.nl
authors.forename: D H
authors.initials: DH
authors.lastname: van Raalte
authors.forename: N
authors.initials: N
authors.lastname: van Leeuwen
authors.forename: A M
authors.initials: AM
authors.lastname: Simonis-Bik
authors.forename: G
authors.initials: G
authors.lastname: Nijpels
authors.forename: T W
authors.initials: TW
authors.lastname: van Haeften
authors.forename: S A
authors.initials: SA
authors.lastname: Schafer
authors.forename: D I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: M H H
authors.initials: MH
authors.lastname: Kramer
authors.forename: R
authors.initials: R
authors.lastname: J Heine
authors.forename: J A
authors.initials: JA
authors.lastname: Maassen
authors.forename: H
authors.initials: H
authors.lastname: Staiger
authors.forename: F
authors.initials: F
authors.lastname: Machicao
authors.forename: H-U
authors.initials: HU
authors.lastname: Häring
authors.forename: P E
authors.initials: PE
authors.lastname: Slagboom
authors.forename: G
authors.initials: G
authors.lastname: Willemsen
authors.forename: E J
authors.initials: EJ
authors.lastname: de Geus
authors.forename: J M
authors.initials: JM
authors.lastname: Dekker
authors.forename: A
authors.initials: A
authors.lastname: Fritsche
authors.forename: E M
authors.initials: EM
authors.lastname: Eekhoff
authors.forename: M
authors.initials: M
authors.lastname: Diamant
authors.forename: L M
authors.initials: LM
authors.lastname: 't Hart
mesh_terms: D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D018149:Glucose Intolerance / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012737:Sex Factors
chemical_list: D007328:Insulin; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid