Dose-dependent and tissue-specific adverse effects of exogenous glucocorticoids: insights for optimizing clinical practice

Purpose: There is limited data on dose-specific metabolic effects of exogenous glucocorticoids (GC) doses. This study aimed to investigate the differential tissue-specific and dose-dependent effects of low-to-intermediate prednisolone doses on insulin sensitivity and bone metabolism in healthy individuals. Methods: We performed a post-hoc pooled analysis of three independent clinical trials, each administering one week of daily prednisolone at 10 mg, 15 mg, or 20 mg, in a total of 30 different healthy male volunteers (aged 18–65; BMI 20–35 kg/m²; normal kidney function). Outcome measures included: changes in liver (endogenous glucose production-EGP, β-hydroxybutyrate-OHB), muscle (M/I value, Glucose disposal-Gd) and adipose tissue (NEFA, glycerol) insulin sensitivity assessed across a hyperinsulinemic-euglycemic clamp. Bone turnover was evaluated through osteocalcin levels. Results: Prednisolone 10 mg had minimal impact on metabolic parameters. 15 mg and 20 mg caused similar reductions (no dose effects) in liver (time effect p < 0.05 for EGP and OHB) and skeletal muscle (time effect p < 0.05 for M/I and Gd) insulin sensitivity. However, detrimental effects on adipose tissue were dose dependent (dose*time interaction p < 0.05 for NEFA and glycerol). Osteocalcin levels decreased similarly after both 15 mg and 20 mg of prednisolone (p = 0.199). Conclusions: Prednisolone-induced insulin resistance exhibits tissue-specific and dose-dependent effects. While 15 mg daily for 7 days appears to induce clinically relevant metabolic changes in this population, the dose-dependent effects observed in adipose tissue suggest tissue-specific variability in response. These findings highlight the importance of dose selection in GC therapy, particularly in individuals predisposed to metabolic complications, though further studies are needed in populations with underlying metabolic disorders.