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 125 I-labelled glycosylated (g) and non-glycosylated (n-g) recombinant human

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... GFBP-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 Ϯ 1.2 vs 6.3 Ϯ 1.5 min, P ¼ 0.006). The elimination half-life of gIGFBP-6 was 21-fold greater than that of n-gIGFBP-6 (584.2 Ϯ 130.2 vs 28.0 Ϯ 4.2 min, P ¼ 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 IGF-II actions.