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-1 in mice.
Recent studies indicate that a daily s.c. injection of 1 mg/kg of recombinant human insulin-like growth factor-1 (rhIGF-1) for 17 days is efficacious in enhancing the functional recovery of injured sciatic nerves 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 course effects (0, 0.5, 3, 6 and 24 hr) were determined after acute (single) and chronic (once daily for 17 days) injections of rhIGF-1 in CD-1 mice. Plasma glucose levels decreased in a dose-dependent fashion after either acute or chronic injections of rhIGF-1 with maximal effects at 0.5 to 1 hr after administration of rhIGF-1. Among the three insulin-like growth factor binding proteins (IGFBPs) evaluated in the study, only IGFBP2 levels were consistently increased in a dose-dependent fashion with maximal effects 3 hr after the last of a series of injections of rhIGF-1. Furthermore, IGFBP2 levels increased at a dose of rhIGF-1 (1 mg/kg) that enhances the regeneration of injured sciatic nerves in mice. Chronic administration of insulin at doses that cause comparable decreases in plasma glucose to that of rhIGF-1 did not alter IGFBP2 levels or enhance hindlimb function suggesting that the beneficial effects of rhIGF-1 occur via activation of the type-I IGF receptor rather than the insulin receptor. Based on these criteria, IGFBP2 appears to be useful as a surrogate marker for determining the in vivo effects of rhIGF-1.
Bhat
R V
RV
Department of Pharmacology, Cephalon, Inc., West Chester, Pennsylvania 19380, USA.
Engber
T M
TM
Zhu
Y
Y
Miller
M S
MS
Contreras
P C
PC
D000818:Animals; D015415:Biomarkers; D001786:Blood Glucose / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology
D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D018971:Insulin-Like Growth Factor Binding Protein 2; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I