Wilson M E
Yerkes Primate Research Center, Emory University, Lawrenceville, Georgia 30043, USA.
J Clin Endocrinol Metab. 2000 Apr;85(4):1557-62. doi: 10.1210/jcem.85.4.6522.
Previous work from this laboratory has shown that the constant sc infusion of insulin-like growth factor I (IGF-I) to normal pituitary monkeys results in a sustained elevation in circulating concentrations of IGF-binding protein-3 (IGFBP-3), whereas the acute administration of IGF-I to monkeys pretreated with a GH receptor antagonist produces a brief, but significant, elevation in serum IGFBP-3. The present study tested the hypothesis that the constant infusion of IGF-I would normalize serum concentrations of IGFBP-3 in females treated with the GH receptor antagonist. To assess the biological significance of these effects, serum levels of the acid-labile subunit (ALS) and biomarkers for bone formation, osteocalcin, and collagen type I C-terminal propeptide, were also examined. Five female rhesus monkeys were studied over 21 consecutive days involving 7 days of baseline, 7 days of treatment with the GH receptor antagonist (1.0 mg/kg-week, sc), and 7 days of treatment with the GH receptor antagonist supplemented with IGF-I (120 microg/kg x day, sc infusion with osmotic minipump). Within 48 h of the initiation of treatment with the GH receptor antagonist, serum IGF-I and IGFBP-3 were decreased by 40% and 18% from baseline, respectively, and levels continued to decline through the remainder of treatment. However, within 48 h of the initiation of IGF-I administration during GH receptor antagonist treatment, both serum IGF-I and IGFBP-3 were elevated and normalized to baseline values. Serum concentrations of ALS were also decreased by GH antagonism, but levels increased in some (n = 2), but not all, subjects upon administration of IGF-I. Size exclusion ultrafiltration indicated that the amount of IGF-I found in the high molecular mass complex (>100 kDa) decreased significantly during GH antagonism, but was similar during the baseline and IGF-I infusion phases. Finally, treatment with the GH receptor antagonist also significantly reduced serum levels of osteocalcin and collagen type I C-terminal propeptide, an effect reversed by the addition of IGF-I. These data support the hypothesis that IGF-I increases serum concentrations of IGFBP-3 when endogenous GH action is compromised and that such treatment produces biologically active IGF-I, as evidenced by normalization of biomarkers for bone formation. These results indicate that IGF-I administration during GH receptor antagonism restores circulating levels of IGFBP-3 and the amount of IGF-I found in the high molecular mass complex to levels observed during baseline conditions. It remains to be determined whether IGF-I directly affects hepatic synthesis and secretion of IGFBP-3 and what role IGF-I has in the direct regulation of ALS in the monkey.
该实验室之前的研究表明，向正常垂体的猴子持续皮下输注胰岛素样生长因子I（IGF-I）会导致循环中IGF结合蛋白-3（IGFBP-3）浓度持续升高，而向用生长激素受体拮抗剂预处理的猴子急性给予IGF-I会使血清IGFBP-3出现短暂但显著的升高。本研究检验了以下假设：持续输注IGF-I会使接受生长激素受体拮抗剂治疗的雌性动物血清IGFBP-3浓度恢复正常。为评估这些效应的生物学意义，还检测了酸不稳定亚基（ALS）的血清水平以及骨形成的生物标志物骨钙素和I型胶原C端前肽。对5只雌性恒河猴进行了连续21天的研究，包括7天的基线期、7天用生长激素受体拮抗剂（1.0 mg/kg·周，皮下注射）治疗以及7天用生长激素受体拮抗剂并补充IGF-I（120 μg/kg·天，用渗透微型泵皮下输注）治疗。在开始用生长激素受体拮抗剂治疗的48小时内，血清IGF-I和IGFBP-3分别较基线水平降低了40%和18%，且在治疗的剩余时间内持续下降。然而，在生长激素受体拮抗剂治疗期间开始给予IGF-I的48小时内，血清IGF-I和IGFBP-3均升高并恢复到基线值。生长激素拮抗也使ALS的血清浓度降低，但在给予IGF-I后，部分（n = 2）而非全部受试者的ALS水平升高。尺寸排阻超滤表明，在生长激素拮抗期间，高分子质量复合物（>100 kDa）中发现的IGF-I量显著减少，但在基线期和IGF-I输注阶段相似。最后，用生长激素受体拮抗剂治疗也显著降低了骨钙素和I型胶原C端前肽的血清水平，添加IGF-I可逆转这一效应。这些数据支持以下假设：当内源性生长激素作用受损时，IGF-I会增加血清IGFBP-3浓度，且这种治疗会产生具有生物活性的IGF-I，骨形成生物标志物恢复正常即证明了这一点。这些结果表明，在生长激素受体拮抗期间给予IGF-I可使IGFBP-3的循环水平以及高分子质量复合物中发现的IGF-I量恢复到基线条件下观察到的水平。IGF-I是否直接影响肝脏合成和分泌IGFBP-3以及IGF-I在猴子中对ALS的直接调节作用还有待确定。
