Endocrine Abstracts

Interindividual variations in tissue sensitivity to glucocorticoids (GC) have been partly attributed to polymorphisms in the glucocorticoid receptor (GR) gene. The aim of this study was to investigate whether BclI variant of the GR gene may contribute to metabolic abnormalities frequently present in patients with adrenal incidentaloma (AI). Biochemical tests and hormonal evaluation were performed in 106 consecutive women with AI. Non-diabetic patients underwent an oral glucose tolerance test with 75g glucose. Insulin resistance was assessed by homeostasis model assessment (HOMA-IR) index. The hypothalamic-pituitary-adrenal axis (HPA) activity was evaluated using the dexamethasone suppression tests (DST). Body composition was measured with dual-energy X-ray absorptiometry. DNA was obtained from peripheral blood leucocytes. The polymorphism was detected using PCR, RFLP and DNA sequencing. Carriers of the C allele of BclI had significantly less suppression of cortisol levels after 0.5 mg dexametasone (126.4±111.4 vs 80.9±75.7 nmol/l, P=0.026). Post low-dose DST cortisol levels negatively correlated with appendicular skeletal muscle mass (AMSS) (r=−0.023, P=0.004). 24-h urinary free cortisol level inversely correlated with total lean body mass (TLBM) (r=−0.196, P=0.007) and lag fat mass (r=−0.430, P=0.016). Fasting glucose (4.5±0.6 vs 4.8±0.8, P=0.046) and the 2-h post-challenge glucose levels (5.4±1.5 vs 6.7±2.6, P=0.010) were lower in carriers than non-carriers, as well as prevalence of type 2 diabetes mellitus (T2DM) (9.1% vs 26%, P=0.034) and impaired glucose tolerance (IGT) (2.6% vs 17.5%, P=0.031). We observed no differences in mean age (57±9.6 vs 56.5±11.8, P=0.823), BMI (29.3±6.0 vs 28.0±6.5, P=0.316), abdominal fat mass, dyslipidemia, HOMA-IR and hypertension. BclI polymorphism negatively correlated with T2DM (r=−0.219, P=0.034), IGT (r=−0.245, P=0.031), TLBM (r=−0.232, P=0.037), ASMM (r=−0.319, P=0.004), and positively correlated with percentage of leg fat (r=0.221, P=0.047). Our results indicate intra-individual tissue-specific sensitivity to GC. BclI polymorphism has been associated with relative GC resistance of the HPA axis and peripheral fat tissue, and GC hypersensitivity at the muscle level. Insulin sensitivity and glucose homeostasis could be possibly modulated by muscle and leg fat masses. This polymorphism has a protective role and reduces the risk of diabetes in women with AI, particularly in a state of subtle cortisol excess.