Source
University of Edinburgh, Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland, United Kingdom.
Abstract
CONTEXT:
In animals, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma agonists down-regulate 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARgamma agonists reduce ACTH secretion from corticotrope cells.
OBJECTIVE:
Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11beta-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARgamma agonists.
DESIGN AND SETTING:
Three randomized placebo-controlled crossover studies were conducted at a clinical research facility.
PATIENTS AND PARTICIPANTS:
Healthy men and patients with type 2 diabetes participated. INTERVENTIONS, OUTCOME MEASURES, AND RESULTS: In nine healthy men, 7 d of PPARalpha agonist (fenofibrate) or PPARgamma agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration, or tracer kinetics during 9,11,12,12-[(2)H](4)-cortisol infusion, although rosiglitazone marginally reduced cortisol generation in sc adipose tissue measured by in vivo microdialysis. In 12 healthy men, 4-5 wk of rosiglitazone increased insulin sensitivity during insulin infusion but did not change 11beta-HSD1 mRNA or activity in sc adipose tissue, and insulin sensitization was unaffected by glucocorticoid blockade with a combination of metyrapone and RU38486. In 12 men with type 2 diabetes 12 wk of rosiglitazone reduced arteriovenous cortisone extraction across abdominal sc adipose tissue and reduced 11beta-HSD1 mRNA in sc adipose tissue but increased plasma cortisol concentrations.
CONCLUSIONS:
Neither PPARalpha nor PPARgamma agonists down-regulate 11beta-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitizing effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11beta-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, e.g. mediated by changes in body fat.