The majority of IGF-I circulates in a large (150 kDa) ternary complex with IGF-binding protein-3 (IGFBP-3) and a non-IGF-binding acid-labile subunit. The secretion of ternary complex into the circulation from liver has been considered to be GH-dependent; however, recent data indicate that GH does not directly regulate hepatic IGFBP-3 synthesis. To examine the role of insulin in regulating plasma IGFBP-3 levels, postpubertal male GH-deficient (dw/dw) rats were treated every 8 h with injections (s.c.) of 0·9% saline, 20 μg insulin/day, 200 μg hIGF-I/day, or 20 μg insulin/day plus 200 μg hIGF-I/day, for 10 days with the animals being killed 2–3 h after the final injection. Hypoglycaemia was not observed in any of the treatment groups. hIGF-I treatment increased longitudinal growth and weight gain (P<0·05), while insulin treatment had no effect. Plasma IGF-I levels were increased in groups treated with hIGF-I (P<0·05), while insulin treatment resulted in a reduction (P<0-05): saline=267·1 ± 15·6 (ng/ml ± s.e.m.), insulin=219·3 ± 17·5, hIGF-I=391·7 ± 17·6, insulin plus hIGF-I=357·5 ± 31·8. Hepatic IGF-I mRNA expression was increased in insulin-treated dw/dw rats in comparison with hIGF-I-treated animals (P<0·05) but not in comparison with saline control or the combined treatment groups. Plasma levels of intact IGFBP-3, measured by ligand blot analysis, were increased in all treatment groups compared with saline (P<0·05): saline=100·0 ± 9·4% (% of saline ± s.e.m.), insulin=149·9 ± 17·5%, hIGF-I= 191·4 ± 17·3%, insulin plus hIGF-I=205·4 ± 15·3%. The levels of the 28/32 kDa IGFBPs and IGFBP-4 in plasma were increased by hIGF-I treatment (P<0·05) but not by insulin treatment. Hepatic specific 125I-bovine GH binding was not significantly different in any of the treatment groups. This study provides the first evidence in non-diabetic animals that insulin regulates hepatic IGF-I mRNA expression, plasma IGF-I and plasma IGFBP-3 levels in the GH-deficient state without changes in hepatic GH receptors. The divergent response of plasma IGF-I and IGFBP-3 levels to insulin treatment in the present study may indicate an effect of insulin on the clearance of IGF-I from the circulation.
Journal of Endocrinology (1996) 150, 67–76
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