Endocrine Abstracts

The epidemic of obesity, insulin resistance and type 2 diabetes has heightened the need to understand the mechanisms that contribute to their pathogenesis. Endogenous glucocorticoid (GC) production and metabolism have been implicated based upon parallels with Cushing’s syndrome. The interaction between GC metabolism and insulin sensitivity in the context of significant weight loss has not been explored. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that generates active cortisol from cortisone, has been postulated as a therapeutic target, and selective inhibition in rodents causes insulin sensitization and alterations in adipose tissue biology.

Twenty healthy obese volunteers (10 men and 10 women) were investigated before and after significant weight loss using a very low calorie diet (425–559 kcal/day). Patients underwent hyperinsulinaemic euglycaemic clamps with simultaneous adipose tissue microdialysis, as well as oral cortisone acetate administration to measure 11β-HSD1 activity. In addition, global changes in GC metabolism were assessed using 24 h urine collections analysed by gas chromatography and mass spectrometry. Prior to weight loss, fat mass (DEXA) correlated with glucocorticoid metabolite production rates (total fat, R=0.58, P=0.01; trunk fat, R=0.62, P=0.008) and was inversely related to insulin sensitivity (M/I value) (R=−0.51, P<0.05). Consistent with underlying insulin resistance, hyperinsulinaemia failed to suppress adipose tissue interstitial fluid glycerol release (180±50 (basal) versus 153±10 μmol (steady state), P=ns). After oral cortisone (25 mg) administration, cortisol concentrations within adipose interstitial fluid increased significantly (4.3±1.1 vs 14.2±2.6 nmol/l, P<0.01), but glycerol concentrations did not change. Following weight loss, mean BMI fell from 36.6±1.3 to 31.4±1.0 kg/m² (P<0.0001) with significant decreases in fat and fat free mass. Insulin sensitivity increased in all subjects. Consistent with insulin sensitization and in contrast to before weight loss, adipose tissue interstitial fluid glycerol concentrations fell under hyperinsulinaemic conditions (186±16 vs 117±9 μmol, P<0.05). Globally, total glucocorticoid metabolite production decreased (11751±1520 vs 7464±937 μg/24 h, P<0.05) as did 5α-reduactase activity (5αTHF/THF ratio 1.41±0.16 vs 1.12±0.17, P<0.005), however there was no change in global 11β-HSD1 activity.Our data have shown that obesity is associated with insulin resistance within adipose tissue and that weight loss is associated with a decreased HPA axis activation. Whilst we did not observe global changes in 11β-HSD1 activity (consistent with our previous observations), reduced 5α-reduactase activity following weight loss and insulin sensitization, may decrease HPA axis activation and reduce GC metabolite production.