Effects of prednisolone on serum and tissue fluid IGF-I receptor activation and post-receptor signaling in humans

Nilani Ramshanker, Maiken Aagaard, Rikke Hjortebjerg, Thomas Schmidt Voss, Niels Møller, Jens Otto Lunde Jørgensen, Niels Jessen, Peter Bjerring, Nils Erik Magnusson, Mette Bjerre, Claus Oxvig, Jan Frystyk

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Context: Short-term glucocorticoid exposure increases serum insulinlike growth factor I (IGF-I) concentrations but antagonizes IGF-I tissue signaling. The underlying mechanisms remain unknown. Objective: To identify at which levels glucocorticoid inhibits IGF-I signaling. Design and Methods: Nineteen healthy males received prednisolone (37.5 mg/d) and placebo for 5 days in a randomized, double-blinded, placebo-controlled crossover study. Serum was collected on days 1, 3, and 5, and abdominal skin suction blister fluid (SBF; ~interstitial fluid) was taken on day 5 (n = 9) together with muscle biopsy specimens (n = 19). The ability of serum and SBF to activate the IGF-I receptor (IGF-IR) (bioactive IGF) and its downstream signaling proteins was assessed using IGF-IR-transfected cells. Results: Prednisolone increased IGF-I concentrations and bioactive IGF in serum (P#0.001) but not in SBF, which, compared with serum, contained less bioactive IGF (~28%) after prednisolone (P,0.05). This observation was unexplained by SBF concentrations of IGFs and IGF-binding proteins (IGFBPs) 1 to 4. However, following prednisolone treatment, SBF contained less IGFBP-4 fragments (P , 0.05) generated by pregnancy-associated plasma protein A (PAPP-A). Concomitantly, prednisolone increased SBF levels of stanniocalcin 2 (STC2) (P = 0.02) compared with serum. STC2 blocks PAPPA from cleaving IGFBP-4. Finally, prednisolone suppressed post-IGF-IR signaling pathways at the level of insulin receptor substrate 1 (P,0.05) but did not change skeletal muscle IGF-IR, IGF-I, or STC2 messenger RNA. Conclusion: Prednisolone increased IGF-I concentrations and IGF bioactivity in serum but not in tissue fluid. The latter may relate to a STC2-mediated inhibition of PAPP-A in tissue fluids. Furthermore, prednisolone induced post-IGF-IR resistance. Thus, glucocorticoid may exert distinct, compartment-specific effects on IGF action.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number11
Pages (from-to)4031-4040
Number of pages10
ISSN0021-972X
DOIs
Publication statusPublished - Nov 2017

Keywords

  • Adult
  • Blood Chemical Analysis
  • Cross-Over Studies
  • Double-Blind Method
  • Extracellular Fluid/metabolism
  • Humans
  • Insulin-Like Growth Factor Binding Proteins/blood
  • Insulin-Like Growth Factor I/metabolism
  • Insulin-Like Growth Factor II/metabolism
  • Male
  • Muscles/drug effects
  • Placebos
  • Prednisolone/pharmacology
  • Receptor, IGF Type 1/blood
  • Signal Transduction/drug effects
  • Young Adult

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