Inhibitors of Glucose Uptake Stimulate the Production of Insulin-Like Growth Factor-Binding Protein (IGFBP-1) by Human Fetal Liver*

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Abstract
Cultured human fetal hepatic explants were used to study the role of hexose uptake in regulating production of the GH-independent insulin-like growth factor-binding protein (IGFBP-1). Cytochalasin B (100 .mu.M), but not cytochalasin E, inhibited 2-deoxyglucose uptake by fetal liver explants and increased production of IGFBP-1 2-fold. Two agents which stimulate cyclic nucleotide-dependent pathways, cholera toxin and theophylline, also inhibited 2-deoxyglucose uptake in this system and both stimulated IGFBP-1 production. When added to a maximally inhibiting concentration of cytochalasin B (250 .mu.M), hexose uptake was not further inhibited by theophylline (5 mM) or cholera toxin (10 .mu.g/ml), suggesting that the three substances interact with the same hexose transport mechanism. However, the stimulatory effect of theophylline (5 mM) or cholera toxin (10 .mu.g/ml) on IGFBP-1 production was additive to the effect of 250 .mu.M cytochalasin B, suggesting that another pathway, possibly involving cyclic nucleotide accumulation, could further stimulate IGFBP-1 above the effects of blocking glucose transport. Insulin (300 nM) had no effect on hexose uptake by human fetal liver explants but inhibited IGFBP-1 production, both basally and when stimulated by cytochalasin B (100 .mu.M) or cholera toxin (1 .mu.g/ml). These results are consistent with the conclusion that a cyclic nucleotide-dependent pathway, activated by blocking hexose transport and inhibited by insulin, is involved in the regulation of EGFBP-1 synthesis.

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