Insufficient glucocorticoid receptor signaling and flattened salivary cortisol profile are associated with metabolic and inflammatory indices in type 2 diabetes

Impaired negative feedback and hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis characterizes type 2 diabetes mellitus (T2DM). The glucocorticoid receptor (GR) is a key mediator of HPA axis negative feedback; however, its role in linking hypercortisolemia and T2DM-associated hyperglycemia, hyperlipidemia and inflammation is not yet known. In peripheral mononuclear cells (PBMC) from 31 T2DM patients and 24 healthy controls, we measured various GR-signaling parameters such as phosphorylated GR (pGR-S211), GRα/GRβ gene expression and GC-sensitivity [using the basal and dexamethasone (DEX)-induced leucine zipper (GILZ) and FK506 binding-protein (FKBP5) mRNA levels as well as the basal interleukin (IL)-1β protein levels]. Diurnal salivary cortisol curve parameters such as the cortisol awaking response (CAR) and area under the curve (AUCtotal and AUCi) as well as inflammatory and metabolic indices were also determined. T2DM patients exhibited diminished pGR-S211 protein content, increased GRβ, decreased basal GILZ and FKBP5 mRNA levels and increased IL-1β levels. Flattened DEX-induced GILZ and FKBP5 response curves and a flattened salivary cortisol profile characterized T2DM patients. Significant associations of GR measures and saliva cortisol curve parameters with biochemical and clinical characteristics were found. Our novel data implicate an insufficient GR signaling in PBMCs in T2DM patients and HPA axis dysfunction. The significant associations of GR-signaling parameters with inflammatory and metabolic indices implicate that GR may be the critical link between HPA axis dysfunction, hypercortisolemia and diabetes-associated metabolic disturbances. Our findings provide significant insights into the contribution of GR-mediated mechanisms in T2DM aetiopathology and therapy.