IDENTIFICATION OF INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-2 AS A BIOCHEMICAL SURROGATE MARKER FOR THE IN-VIVO EFFECTS OF RECOMBINANT HUMAN INSULIN-LIKE GROWTH-FACTOR-I IN MICE

Recent studies indicate that a daily s.c. injection of 1 mg/kg of reco mbinant human insulin-like growth factor-1 (rhIGF-1) for 17 days is ef ficacious in enhancing the functional recovery of injured sciatic nerv es in CD-1 mice. To identify and characterize surrogate marker(s) that are altered in association with the administration of an efficacious dose of rhIGF-1, dose-response curves (0.1, 1 and 10 mg/kg) and time c ourse effects (0, 0.5, 3, 6 and 24 hr) were determined after acute (si ngle) and chronic (once daily for 17 days) injections of rhIGF-1 in CD -1 mice. Plasma glucose levels decreased in a dose-dependent fashion a fter either acute or chronic injections of rhIGF-1 with maximal effect s at 0.5 to 1 hr after administration of rhIGF-1. Among the three insu lin-like growth factor binding proteins (IGFBPs) evaluated in the stud y, only IGFBP2 levels were consistently increased in a dose-dependent fashion with maximal effects 3 hr after the last of a series of inject ions of rhIGF-1. Furthermore, IGFBP2 levels increased at a dose of rhI GF-1 (1 mg/kg) that enhances the regeneration of injured sciatic nerve s in mice. Chronic administration of insulin at doses that cause compa rable decreases in plasma glucose to that of rhIGF-1 did not alter IGF BP2 levels or enhance hindlimb function suggesting that the beneficial effects of rhIGF-1 occur via activation of the type-I IGF receptor ra ther than the insulin receptor. Based on these criteria, IGFBP2 appear s to be useful as a surrogate marker for determining the in vivo effec ts of rhIGF-1.