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J. Biol. Chem., Vol. 277, Issue 16, 13620-13627, April 19, 2002

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Increases in Free, Unbound Insulin-like Growth Factor I Enhance Insulin Responsiveness in Human Hepatoma G2 Cells in Culture^*

Keiji Sakai, Henry B. Lowman^§, and David R. Clemmons^¶

From the  Department of Medicine, University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599 and ^§ Department of Protein Engineering, Genentech Inc., South San Francisco, California 94124

Insulin-like growth factor-binding protein (IGFBP)-1 binds to insulin-like growth factor (IGF)-I and -II with high affinity and has been shown to modulate IGF-I actions in vivo and in vitro. The synthesis of IGFBP-1 is suppressed by insulin, and administration of IGFBP-1 to rats results in impaired glucose metabolism. A synthetic peptide (bp1-01) has been shown to have a high affinity and specificity for human IGFBP-1 and to inhibit IGF-I binding. The current studies were undertaken to determine if, after incubation of bp1-01 with IGF-I·IGFBP-1 complexes, anabolic and insulin-like effects of IGF-I could be detected in human hepatoma (HepG2) cell cultures and to determine the receptor subtype(s) through which these effects were mediated. Incubation of HepG2 cells with bp1-01 (200 nM) increased IGF-I-stimulated protein synthesis by 44% and glycogen synthesis by 170% compared with stimulation by IGF-I alone. Incubation with bp1-01 also enhanced IGF-I-stimulated tyrosine phosphorylation of the IGF-I/insulin hybrid receptor and insulin receptor substrate 1. Exposure of the cells to bp1-01 alone enhanced glycogen synthesis and phosphorylation of IGF-I/insulin hybrid receptors. This was not a direct effect of bp1-01 because it did not bind to the receptor and did not activate tyrosine kinase activity in the presence of an anti-IGF-I receptor antibody. The addition of bp1-01 (200 nM) plus insulin to HepG2 cell culture medium resulted in increased tyrosine phosphorylation of the hybrid receptor, insulin receptor substrate 1, and the glycogen synthesis response compared with the effects of insulin alone. This enhancement of hybrid receptor phosphorylation and glycogen synthesis by bp1-01 peptide was diminished by preincubation with an inhibitory antibody for the  subunit of IGF-I receptor (IR3). bp1-01 stimulated the hybrid receptor phosphorylation response to IGF-I, and this effect was inhibited by prior incubation of the cells with IR3. In conclusion, bp1-01 competes with IGF-I for binding to IGFBP-1, which leads to release of free IGF-I from IGF-I·IGFBP-1 complexes. This released IGF-I stimulates biologic actions that are mediated predominantly through the IGF-I/insulin hybrid receptor.

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