Niels Jessen

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

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Context: Short-term glucocorticoid exposure increases serum 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 daily) and placebo for 5 days in a randomized, double-blinded, placebo-controlled cross-over study. Serum was collected on day 1, 3 and 5, abdominal skin suction blister fluid (SBF; ≈interstitial fluid) on day 5 (n=9) together with muscle biopsies (n=19). The ability of serum and SBF to activate the IGF-I receptor (IGF-IR) (bioactive IGF) and its down-stream signaling proteins (IRS-1, Akt and mTOR) were 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 when compared to 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 -3. 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) when compared to serum. STC2 blocks PAPP-A from cleaving IGFBP-4. Finally, prednisolone suppressed post-IGF-IR signaling pathways at the level of IRS-1(P<0.05), but did not change skeletal muscle IGF-IR, IGF-I or STC2 mRNA.

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.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Endocrinology and Metabolism
Vol/bind102
Nummer11
Sider (fra-til)4031-4040
Antal sider10
ISSN0021-972X
DOI
StatusUdgivet - nov. 2017

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