Endocrine Abstracts

Glucocorticoid (GC) excess, Cushing’s syndrome, is characterized by central obesity, proximal myopathy, insulin resistance and potentially type 2 diabetes mellitus. Current dogma dictates that GCs cause insulin resistance across all tissues. We have previously demonstrated that GCs cause insulin sensitization of human adipose tissue in vitro, whilst inducing insulin resistance in human skeletal muscle. No prior study has evaluated whether these observations translate clinically. 10 healthy volunteers (age 36±3.0 years, BMI 27.2±1.1 kg/m², fasting glucose 4.7±0.1 mmol/L) were recruited into a double-blind, randomized, placebo controlled, cross-over study in which they received both an overnight saline and hydrocortisone (HC) infusion (0.2 mg/kg/h) in a random order. Volunteers underwent a 2-step hyperinsulinaemic (low dose and high dose) euglycaemic clamp. Adipose tissue microdialysis was performed to determine insulin-stimulated pyruvate generation and insulin-mediated suppression of glycerol release (lipolysis). HC infusion elevated fasting glucose levels (4.4±0.1 vs. 5.9±0.2 mmol/L, P<0.0001) and caused systemic insulin resistance as measured by HOMA-IR (1.1±0.3 vs. 2.2±0.3, P<0.05) and decreased glucose infusion rates (M-value) following high dose insulin (9.0±0.5 vs. 7.6±0.8, P<0.05). In adipose tissue, in the fasting state, pyruvate release was similar between HC and saline. Insulin stimulated pyruvate release (99±13 vs. 136±20 µmol/L/h, P<0.05) which was significantly enhanced following overnight HC infusion consistent with insulin sensitization (36±14 vs. 186±29 µmol/L/h, P<0.001). As expected, HC infusion increased adipose tissue lipolysis (235±47 vs. 365±53 µmol/L/h, P=0.05) which was suppressed by insulin. However, this was significantly enhanced following overnight HC infusion (114±25 vs. 196±39 µmol/L/h, P=0.05). This study represents the first description of adipose tissue insulin sensitization by GC in vivo and clearly demonstrates tissue specific actions of GCs to interact with and modify insulin sensitivity and action. This study defines an important advance in our understanding of the actions of both endogenous and exogenous GCs and may have implications for the development and targeting of future GC therapies.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: This work has been supported by the Medical Research Council (senior clinical fellowship ref. G0802765, JWT).