Rosiglitazone decreases 11β-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue

Abstract

Objective: The peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone increases insulin sensitivity, which, in animal models, is comparable to the effect of a reduction in 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. We therefore investigated whether rosiglitazone-induced insulin sensitivity is associated with changes in 11β-HSD1 activity in different tissues. Methods: An oral glucose tolerance test (OGTT) and a euglycaemic hyperinsulinaemic clamp were performed in seven male volunteers [age 59.3 ± 3.0 years, body mass index (BMI) 29.3 ± 4.1 kg/m2] with impaired glucose tolerance before and after 8 weeks of rosiglitazone treatment. To assess hepatic 11β-HSD1 activity, serum cortisol levels were measured after oral administration of cortisone acetate. 11β-HSD1 activity and mRNA expression were assessed in abdominal subcutaneous fat biopsies. Total-body 11β-HSD activities were estimated by calculating the urinary ratios of glucocorticoid metabolites. Results: As expected, rosiglitazone improved insulin resistance and postprandial hyperglycaemia. In parallel, 11β-HSD1 mRNA expression [100 ± 0% (reference) vs. 68.5 ± 9.3%, P < 0.01] and activity [0.18 ± 0.02 vs. 0.13 ± 0.02 pmol/min/mg, P < 0.05] decreased in abdominal subcutaneous fat, while an increase in hepatic 11β-HSD1 activity was detected [the area under the curve (AUC) for the cortisol/cortisone ratio was 1319 ± 76 vs. 955 ± 59; P < 0.05]. No changes in BMI, waist-to-hip ratio (WHR) and whole-body 11β-HSD1 activity were found. Conclusions: Part of the beneficial effects of rosiglitazone may be mediated by a reduction in the 11β-HSD1 mRNA expression and activity in subcutaneous abdominal fat. © 2007 The Authors.