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- Title
Effects of Prednisolone on Serum and Tissue Fluid IGF-I Receptor Activation and Post-Receptor Signaling in Humans.
- Authors
Ramshanker, Nilani; Aagaard, Maiken; Hjortebjerg, Rikke; Voss, Thomas Schmidt; Møller, Niels; Jørgensen, Jens Otto Lunde; Jessen, Niels; Bjerring, Peter; Magnusson, Nils Erik; Bjerre, Mette; Oxvig, Claus; Frystyk, Jan
- Abstract
<bold>Context: </bold>Short-term glucocorticoid exposure increases serum insulinlike growth factor I (IGF-I) concentrations but antagonizes IGF-I tissue signaling. The underlying mechanisms remain unknown.<bold>Objective: </bold>To identify at which levels glucocorticoid inhibits IGF-I signaling.<bold>Design and Methods: </bold>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.<bold>Results: </bold>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 PAPP-A 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.<bold>Conclusion: </bold>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.
- Subjects
BLOOD testing; CARRIER proteins; CELLULAR signal transduction; COMPARATIVE studies; CROSSOVER trials; EXTRACELLULAR fluid; RESEARCH methodology; MEDICAL cooperation; MUSCLES; PLACEBOS; RESEARCH; SOMATOMEDIN; EVALUATION research; RANDOMIZED controlled trials; BLIND experiment; PREDNISOLONE; PHARMACODYNAMICS
- Publication
Journal of Clinical Endocrinology & Metabolism, 2017, pN.PAG
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2017-00696