O-glycosylation delays the clearance of human IGF-binding protein-6 from the circulation

Objective: The actions of insulin-like growth factors (IGF-I and IGF-II) are modulated by a family of six structurally related, high-affinity binding proteins (IGFBPs 1-6). IGFBP-6, an O-linked glycoprotein, preferentially binds IGF-II and inhibits its actions. The aim of this study was to investigate whether O-glycosylation modulates the pharmacokinetics of IGFBP-6. Design and Methods: The pharmacokinetic profiles of I-125-labelled glycosylated (g) and non-glycosylated (n-g) recombinant human IGFBP-6 were studied following intravenous bolus administration in anaesthetised rats. Results: The redistribution half-life of gIGFBP-6 was 2.3-fold greater than that of n-gIGFBP-6 (14.4 +/- 1.2 vs 6.3 +/- 1.5 min, P = 0.006). The elimination half-life of gIGFBP-6 was 121-fold greater than that of n-gIGFBP-6 (584.2. +/- 130.2 vs 28.0 +/- 4.2 min, P = 0.019). The effect of O-glycosylation on IGFBP-6 pharmacokinetics was not due to inhibition of intravascular proteolysis. Radioactivity was found in stomach, kidneys, lung, spleen, heart and liver but not brain 4 h after injection of g or n-gIGFBP-6, Conclusions: O-glycosylation delays the clearance of IGFBP-6 from the circulation and may therefore contribute to its role as a circulating inhibitor of TGF-II actions.