HPA axis dysregulation, NR3C1 polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome

Context Metabolic syndrome (MetS) shares several similarities with hypercortisolism. Objectives To evaluate hypothalamic-pituitary-adrenal (HPA) axis sensitivity to dexamethasone (DEX), NR3C1 single nucleotide polymorphisms (SNPs), and expression of glucocorticoid receptor (GR) isoforms and cytokines in peripheral immune cells of MetS patients and controls. Design Prospective study with 40 MetS patients and 40 controls was conducted at the Ribeirao Preto Medical School University Hospital. Methods Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5, and 1 mg of DEX given at 2300 h. In addition, p. N363S (rs6195), p. ER22/23EK (rs6189-6190), and BclI (rs41423247) SNPs were evaluated by quantitative polymerase chain reaction allelic discrimination. Exons 3 to 9 and exon/intron boundaries of NR3C1 were sequenced. GR isoforms and cytokines (IL1B, IL2, IL4, IL6, IL8, IL10, IFN gamma, TNF alpha) expression were assessed by quantitative polymerase chain reaction. Results Plasma and salivary cortisol (nmol/L) after 1-mg DEX were higher in MetS patients compared with controls (PF: 70.2 +/- 17.3 vs 37.9 +/- 2.6, P = .02, and SF: 4.9 +/- 1.7 vs 2.2 +/- 0.3, P <.0001). After all DEX doses, a lower number of MetS patients suppressed plasma and salivary cortisol compared with controls. The BclI genotypic frequencies (%) differed between patients (CC: 56/CG: 44) and controls (CC: 50/CG: 32.5/GG: 17.5) (P = .03). The GR beta was overexpressed (fold = 100.0; P = .002) and IL4 (fold = -265.0; P <.0001) was underexpressed in MetS. Conclusion MetS patients exhibited decreased HPA sensitivity to glucocorticoid feedback. Moreover, the BclI polymorphism lower frequency, GR beta overexpression, and IL4 underexpression might underlie the molecular mechanism of glucocorticoid resistance in MetS. Thus, HPA axis dysregulation might contribute to MetS pathogenesis.