Abstract

Objective: The epidemic of obesity, insulin resistance and type 2 diabetes has heightened the need to understand mechanisms that contribute to their pathogenesis. Increased endogenous glucocorticoid (GC) production has been implicated based upon parallels with Cushing's syndrome. We have assessed the impact of weight loss upon GC secretion and metabolism (notably 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 5α-reductase (5αR) activity) and insulin sensitivity.

Research Design and Methods: 20 obese volunteers were investigated before and after weight loss. Patients underwent hyperinsulinemic euglycemic clamps with simultaneous adipose microdialysis and oral cortisone acetate administration. Changes in GC secretion and metabolism were assessed using 24h urine collections.

Results: Before weight loss, fat mass correlated with GC secretion rate (total fat, R=0.46, p<0.05; trunk fat, R=0.52, p<0.05); however, GC secretion rate was inversely related to insulin sensitivity (R=−0.51, p<0.05). Hyperinsulinemia failed to suppress adipose tissue interstitial fluid glycerol release (180±50 (basal) vs. 153±10μmol (steady state), p=ns). After oral cortisone (25mg), cortisol concentrations within adipose interstitial fluid increased (4.3±1.1 vs. 14.2±2.6nmol/L, p<0.01), but glycerol concentrations didn't change. Following weight loss, insulin sensitivity increased. Consistent with insulin sensitization, adipose tissue interstitial fluid glycerol concentrations fell under hyperinsulinemic conditions (186±16 vs. 117±9μmol, p<0.05). GC secretion decreased (11751±1520 vs. 7464±937μg/24h, p<0.05) as did 5αR activity (5αTHF/THF ratio 1.41±0.16 vs. 1.12±0.17, p<0.005).

Conclusions: Obesity is associated with insulin resistance within adipose tissue and increased cortisol secretion rates, both are reversed with weight loss. Reduced 5αR activity following weight loss may decrease hypothalamo-pituitary-adrenal (HPA) axis activation and reduce GC metabolite production.