IGF-I AND IGF-BINDING PROTEIN-3 IN PLASMA OF GH-DEFICIENT RATS

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 l iver has been considered to be GH-dependent; however, recent data indi cate that GH does not directly regulate hepatic IGFBP-3 synthesis. To examine the role of insulin in regulating plasma IGFBP-3 levels, postp ubertal male GH-deficient (dw/dw) rats were treated every 8 h with inj ections (s.c.) of 0.9% saline, 20 mu g insulin/day, 200 mu g hIGF-I/da y, or 20 mu g insulin/day plus 200 mu g hIGF-I/ day, for 10 days with the animals being killed 2-3 h after the final injection. Hypoglycaemi a was not observed in any of the treatment groups. hIGF-I treatment in creased longitudinal growth and weight gain (P<0.05), while insulin tr eatment had no effect. Plasma IGF-I levels were increased in groups tr eated with hIGF-I (P<0.05), while insulin treatment resulted in a redu ction (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 com parison with saline control or the combined treatment groups. Plasma l evels of intact IGFBP-3, measured by ligand blot analysis, were increa sed 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=1 91.4 +/- 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 treat ment (P<0.05) but not by insulin treatment. Hepatic specific I-125-bov ine GH binding was not significantly different in any of the treatment groups. This study provides the first evidence in nondiabetic animals that insulin regulates hepatic IGF-I mRNA expression, plasma IGF-I an d plasma IGFBP-3 levels in the GH-deficient state without changes in h epatic GH receptors. The divergent response of plasma IGF-I and IGFBP- 3 levels to insulin treatment in the present study may indicate an eff ect of insulin on the clearance of IGF-I from the circulation.