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

TY - JOUR

T1 - Effects of prednisolone on serum and tissue fluid IGF-I receptor activation and post-receptor signaling in humans

AU - Ramshanker, Nilani

AU - Aagaard, Maiken

AU - Hjortebjerg, Rikke

AU - Voss, Thomas Schmidt

AU - Møller, Niels

AU - Jørgensen, Jens Otto Lunde

AU - Jessen, Niels

AU - Bjerring, Peter

AU - Magnusson, Nils Erik

AU - Bjerre, Mette

AU - Oxvig, Claus

AU - Frystyk, Jan

PY - 2017/11

Y1 - 2017/11

N2 - 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.

AB - 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.

KW - Journal Article

UR - https://www.scopus.com/pages/publications/85037991605

U2 - 10.1210/jc.2017-00696

DO - 10.1210/jc.2017-00696

M3 - Journal article

C2 - 28945869

SN - 0021-972X

VL - 102

SP - 4031

EP - 4040

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 11

ER -