PPARgamma-agonists improve insulin sensitivity and discourage visceral fat accumulation but mechanisms remain uncertain. In rodents, PPARgamma-agonists downregulate 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) in adipose tissue (AT), thereby potentially decreasing intra-adipose glucocorticoid (GC) concentrations. We tested whether PPARgamma-agonists regulate 11b-HSD1 in humans, and if their insulin-sensitising effect is GC-dependent.
12 healthy men with BMI 2040 kg/m2 participated in a randomised double-blind crossover study comparing rosiglitazone 4 mg daily with placebo. On days 28 and 35 of each phase, volunteers were further randomised to GC blockade (RU38486 400 mg and metyrapone 1 g, 2 doses at bedtime and on the morning of study) or placebo; a subcutaneous abdominal AT biopsy was obtained; and an incremental insulin infusion performed (0, 10, 33 and 100 mU/kg/hr each for 1 h), with measurements of plasma insulin, glucose, free fatty acids (FFAs) and glycerol. Local ethical approval was obtained. Data presented as mean ±S.E.M.
Rosiglitazone did not alter glucose or insulin concentrations, but reduced plasma FFAs (302±21 vs 398±53 μmol/L, P<0.05) and glycerol (2.5±1.2 vs 18.5±4.7 μmol/L, P<0.05) at baseline, and during the insulin infusions (P<0.05). Rosiglitazone decreased plasma cortisol (P<0.05), but did not alter adipose tissue 11b-HSD1, GRalpha, H6PDH, adiponectin or leptin mRNA levels or 11b-HSD1 activity. GC blockade suppressed plasma cortisol by 62% (P<0.001), increased ACTH ∼5-fold (P<0.01), decreased AT 11b-HSD1 activity (2.0±0.2 vs 3.2±0.5 pmol/mcg/hour, P<0.05) and increased adipose leptin mRNA (P<0.05). However, GC blockade did not affect insulin sensitivity. The effect of rosiglitazone on insulin sensitivity was the same in the presence or absence of GC blockade.
We conclude that, unlike in rodents, short-term rosiglitazone treatment does not alter 11b-HSD1 expression or activity in AT, and changes in GC signalling do not mediate the acute insulin-sensitising effects of PPARgamma-agonists in humans.