PURPOSE: 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.
METHODS: Randomized double-blind crossover trial with ten healthy males aged 18-34 years. Prednisolone (12.5 mg)/placebo given in random order twice daily at 07:00h and 19:00h for five days with a 6-week washout.
MAIN FINDINGS: Prednisolone suppressed endogenous circadian cortisol levels while mean±SD AUC serum free GC activity (µmol/l*min) increased 4.5-fold [121.9±30.8 (prednisolone) vs 27.2±8.3 (placebo), p < 0.001]. Prednisolone significantly abrogated the normal ≈ threefold morning:evening variation in mRNA expression of four 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 to 97, p < 0.001] more than diurnal levels. Prednisolone increased mean±SD nocturnal systolic blood pressure (mmHg) [123±14 (prednisolone) vs 116±7 (placebo), p = 0.05] and reduced mean±SD sleep efficiency (%) [84±4 (prednisolone) vs 87±5 (placebo), p = 0.04].
CONCLUSIONS AND PERSPECTIVES: Prednisolone abrogates the temporal pattern of clock gene expression in human skeletal muscle and adipose tissue This is accompanied by perturbations of circadian variations in interstitial glucose levels, blood pressure as well as sleep quality We hypothesize that adverse effects of high-dose prednisolone treatment are partly mediated by disrupted clocks in metabolic tissues.
Circadian Biology