Butler A A, Gallaher B W, Ambler G R, Gluckman P D, Breier B H
Research Centre for Developmental Medicine and Biology, School of Medicine, University of Auckland, New Zealand.
J Endocrinol. 1996 Jul;150(1):67-76. doi: 10.1677/joe.0.1500067.
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 micrograms insulin/day, 200 micrograms hIGF-I/day, or 20 micrograms insulin/day plus 200 micrograms 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 nondiabetic 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.
大多数胰岛素样生长因子-I（IGF-I）以一种大的（150 kDa）三元复合物形式循环，该复合物与胰岛素样生长因子结合蛋白-3（IGFBP-3）和一种非IGF结合的酸性不稳定亚基结合。从肝脏分泌三元复合物进入循环被认为是依赖生长激素（GH）的；然而，最近的数据表明GH并不直接调节肝脏IGFBP-3的合成。为了研究胰岛素在调节血浆IGFBP-3水平中的作用，对青春期后雄性生长激素缺乏（dw/dw）大鼠每8小时皮下注射一次，分别注射0.9%生理盐水、每天20微克胰岛素、每天200微克人胰岛素样生长因子-I（hIGF-I）或每天20微克胰岛素加200微克hIGF-I，持续10天，在最后一次注射后2 - 3小时处死动物。在任何治疗组中均未观察到低血糖。hIGF-I治疗增加了纵向生长和体重增加（P < 0.05），而胰岛素治疗无效果。用hIGF-I治疗的组中血浆IGF-I水平升高（P < 0.05），而胰岛素治疗导致其降低（P < 0.05）：生理盐水组 = 267.1 ± 15.6（纳克/毫升 ± 标准误），胰岛素组 = 219.3 ± 17.5，hIGF-I组 = 391.7 ± 17.6，胰岛素加hIGF-I组 = 357.5 ± 31.8。与用hIGF-I治疗的动物相比，胰岛素治疗的dw/dw大鼠肝脏IGF-I mRNA表达增加（P < 0.05），但与生理盐水对照组或联合治疗组相比无增加。通过配体印迹分析测量的完整IGFBP-3血浆水平，与生理盐水组相比，所有治疗组均升高（P < 0.05）：生理盐水组 = 100.0 ± 9.4%（生理盐水组的百分比 ± 标准误），胰岛素组 = 149.9 ± 17.5%，hIGF-I组 = 191.4 ± 17.3%，胰岛素加hIGF-I组 = 205.4 ± 15.3%。血浆中28/32 kDa的IGFBPs和IGFBP-4水平通过hIGF-I治疗升高（P < 0.05），但胰岛素治疗无此作用。在任何治疗组中肝脏特异性125I - 牛生长激素结合均无显著差异。本研究在非糖尿病动物中首次提供证据表明，在生长激素缺乏状态下，胰岛素在不改变肝脏生长激素受体的情况下调节肝脏IGF-I mRNA表达、血浆IGF-I和血浆IGFBP-3水平。在本研究中血浆IGF-I和IGFBP-3水平对胰岛素治疗的不同反应可能表明胰岛素对IGF-I从循环中的清除有影响。
