Context: In animals, PPAR and PPAR agonists down-regulate 11-HSD1 mRNA and activity in liver and adipose tissue, respectively, and PPAR agonists reduce ACTH secretion from corticotroph cells.

Objective: To test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11-HSD1 in humans, and whether reduced cortisol action contributes to metabolic effects of PPAR agonists.

Design: Three randomised placebo-controlled crossover studies.

Setting: A Clinical Research Facility.

Patients and Participants: Healthy men and patients with type 2 diabetes.

Interventions, Outcome Measures and Results: In 9 healthy men, 7 days of PPAR agonist (fenofibrate) or PPAR agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration or tracer kinetics during 9,11,12,12-[²H]₄-cortisol infusion, although rosiglitazone marginally reduced cortisol generation in subcutaneous adipose tissue measured by in vivo microdialysis. In 12 healthy men, 4-5 weeks of rosiglitazone increased insulin sensitivity during insulin infusion, but did not change 11-HSD1 mRNA or activity in subcutaneous adipose tissue, and insulin sensitisation was unaffected by ‘glucocorticoid blockade’ with a combination of metyrapone and RU38486. In 12 men with type 2 diabetes 12 weeks of rosiglitazone reduced arteriovenous cortisone extraction across abdominal subcutaneous adipose tissue and reduced 11-HSD1 mRNA in subcutaneous adipose tissue, but increased plasma cortisol concentrations.

Conclusions: Neither PPAR nor PPAR agonists down-regulate 11-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitising effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, eg mediated by changes in body fat.