Impaired blockade of insulin-like growth factor I (IGF-I)-induced hypoglycemia by IGF binding protein-3 analog with reduced ternary complex-forming ability.
The hypoglycemic potential of circulating IGFs is thought to be regulated through the formation of ternary complexes consisting of an IGF, either IGF binding protein-3 (IGFBP-3) or IGFBP-5, and the acid-labile subunit. These high molecular weight complexes are confined to the circulation and represent a reservoir of IGF with a prolonged half-life. In this study, we show that hypoglycemia, induced by a bolus injection of recombinant human IGF-I into rats, can be blocked by coadministering equimolar concentrations of either recombinant glycosylated IGFBP-3 or nonglycosylated IGFBP-3 (IGFBP-3NG). In contrast, an IGFBP-3 mutant with reduced acid- labile subunit affinity (IGFBP-3MUT) only partially blocked the IGF-I hypoglycemic effect. IGFBP-3 and IGFBP-3NG significantly enhanced IGF-I retention in the circulation, whereas IGFBP-3MUT had a smaller effect. IGFBP-3MUT clearance was more rapid than that of the other IGFBP-3 forms, and the retention of all IGFBP-3 forms was greatly enhanced by coadministration of IGF-I. Characterization of the molecular mass distribution of the IGFBP-3 analogs indicated that 60% of IGFBP-3 and IGFBP-3NG was initially found in ternary complexes compared with 30% of IGFBP-3MUT. These data confirm the hypothesis that regulation of IGF-I bioactivity in vivo by IGFBP-3 depends on its ability to form ternary complexes.
Firth
Sue M
SM
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. sfirth@med.usyd.edu.au
McDougall
Fiona
F
McLachlan
Andrew J
AJ
Baxter
Robert C
RC
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006031:Glycosylation; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced* / Q000517:prevention & control*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000031:analogs & derivatives* / Q000235:genetics / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D008970:Molecular Weight; D009154:Mutation / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology
D001786:Blood Glucose; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I