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Impaired Blockade of Insulin-Like Growth Factor I (IGF-I)-Induced Hypoglycemia by IGF Binding Protein-3 Analog with Reduced Ternary Complex-Forming Ability

Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital (S.M.F., F.M., R.C.B.), St. Leonards, New South Wales 2065, Australia; and Faculty of Pharmacy, University of Sydney (A.J.M.), New South Wales 2006, Australia

Address all correspondence and requests for reprints to: Dr. Sue M. Firth, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. E-mail: . sfirth{at}med usyd.edu.au

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.

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