Effects of Prednisolone Administration on Clock Gene Expression and Indices of Circadian Rhythms in Healthy Human Males.

Abstract

To investigate the impact of glucocorticoid (GC) exposure on clock gene expression in human skeletal muscle and fat, circadian variations in peripheral interstitial glucose levels, blood pressure, total and bioactive GC levels, and sleep quality. This randomized double-blind crossover trial included 10 healthy male individuals aged 18 to 34 years. Prednisolone (12.5 mg)/placebo was given in random order twice daily at 07:00 hours and 19:00 hours for 5 days with a 6-week washout. Prednisolone suppressed endogenous circadian cortisol levels while mean ± SD area under the curve (AUC) serum free GC activity (µmol/L*min) increased 4.5-fold (121.9 ± 30.8 [prednisolone] vs 27.2 ± 8.3 [placebo], P < .001). Prednisolone significantly abrogated the normal approximately 3-fold morning:evening variation in mRNA expression of 4 clock genes-BMAL1, NPAS2, PER3, and REV-ERB-β-in both adipose tissue and skeletal muscle. Prednisolone also increased nocturnal levels of interstitial glucose 67% (95% CI 36%-97%, P < .001) more than diurnal levels. Prednisolone increased mean ± SD nocturnal systolic blood pressure (mmHg) (123 ± 14 [prednisolone] vs 116 ± 7 [placebo], P = .05) and reduced mean ± SD sleep efficiency (%) (84% ± 4% [prednisolone] vs 87% ± 5% [placebo], P = .04). (1) Prednisolone abrogates the temporal pattern of clock gene expression in human skeletal muscle and adipose tissue. (2) This is accompanied by perturbations of circadian variations in interstitial glucose levels, blood pressure, as well as sleep quality. (3) We hypothesize that adverse effects of high-dose prednisolone treatment are partly mediated by disrupted clocks in metabolic tissues.