Impaired blockade of insulin-like growth factor I (IGF-I)-induced hypoglycemia by IGF binding protein-3 analog with reduced ternary complex-forming ability

Sue M. Firth*, Fiona McDougall, Andrew J. McLachlan, Robert C. Baxter

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1669-1676
Number of pages8
JournalEndocrinology
Volume143
Issue number5
DOIs
Publication statusPublished - 1 May 2002
Externally publishedYes

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