重组胰岛素样生长因子-I在生长激素受体缺乏/拉伦综合征中的激素和代谢效应及药代动力学

Hormonal and metabolic effects and pharmacokinetics of recombinant insulin-like growth factor-I in growth hormone receptor deficiency/Laron syndrome.

作者信息

Vaccarello M A, Diamond F B, Guevara-Aguirre J, Rosenbloom A L, Fielder P J, Gargosky S, Cohen P, Wilson K, Rosenfeld R G

机构信息

Department of Pediatrics, Gainesville 32610.

出版信息

J Clin Endocrinol Metab. 1993 Jul;77(1):273-80. doi: 10.1210/jcem.77.1.7686916.

DOI:10.1210/jcem.77.1.7686916

PMID:7686916

Abstract

Profound growth failure despite elevated GH levels in GH receptor deficiency (GHRD) results from reduced insulin-like growth factor-I (IGF-I) synthesis. Recent reports of improved growth velocity in children with GHRD during IGF-I therapy indicate growth-promoting potential in humans. We evaluated the pharmacokinetics and metabolic/hormonal effects of recombinant human IGF-I (40 micrograms/kg every 12 h) given sc for 7 days to six adults with GHRD. Hypoglycemia (< 2.5 mmol/L) did not occur, and mean 2 h postprandial insulin levels were reduced. Urinary calcium increased 2-fold (P < 0.01), and serum calcium was unchanged. The mean integrated 24-h GH level was suppressed (6.5 +/- 2.1 to 1 +/- 0.2 micrograms/L), as were the number of peaks, area under the curve, and clonidine-stimulated GH release (all P < 0.05). The mean pretreatment IGF-I level (36 +/- 2 micrograms/L) was 19% of the Ecuadorian control value (190 +/- 15 micrograms/L), it achieved a peak (253 +/- 11 micrograms/L) between 2-6 h after IGF-I injection, and at 12 h it was 137 +/- 8 micrograms/L. There were no significant changes in the half-life (8.2 +/- 1.5 to 9.7 +/- 1.9 h) or metabolic clearance (0.35 +/- 0.1 to 0.24 +/- 0.05 mL/kg.min) between days 1 and 7; however, distribution volume increased (183 +/- 10 to 266 +/- 36 mL/kg; P < 0.03). Baseline IGF-II levels were 47% of the control value and decreased during IGF-I therapy (273 +/- 10 to 178 +/- 9 micrograms/L; P < 0.01), correlating inversely with IGF-I levels (r = -0.3; P < 0.001). Although IGF-binding protein-3 (IGFBP-3) levels were not significantly influenced, baseline IGFBP-2 levels (153% of the control) increased 45% (P < 0.01). We conclude that IGF-I (40 micrograms/kg every 12 h) given sc to adults with GHRD is safe; achieves normal levels of IGF-I; reduces insulin, IGF-II, and GH levels; and increases IGFBP-2 concentrations and urinary excretion of calcium.

摘要

生长激素受体缺乏症（GHRD）患者尽管生长激素水平升高但仍出现严重生长发育迟缓，这是由于胰岛素样生长因子-I（IGF-I）合成减少所致。最近有报道称，IGF-I治疗期间GHRD患儿的生长速度有所提高，表明其在人类中有促进生长的潜力。我们评估了重组人生长激素-I（每12小时40微克/千克，皮下注射7天）对6名GHRD成年患者的药代动力学以及代谢/激素效应。未发生低血糖（<2.5毫摩尔/升），餐后2小时平均胰岛素水平降低。尿钙增加了2倍（P<0.01），血清钙未改变。24小时平均整合生长激素水平受到抑制（从6.5±2.1微克/升降至1±0.2微克/升），峰值数量、曲线下面积以及可乐定刺激的生长激素释放均受到抑制（均P<0.05）。治疗前平均IGF-I水平（36±2微克/升）为厄瓜多尔对照值（190±15微克/升）的19%，在注射IGF-I后2 - 6小时达到峰值（253±11微克/升），12小时时为137±8微克/升。第1天和第7天之间半衰期（从8.2±1.5小时至9.7±1.9小时）或代谢清除率（从0.35±0.1毫升/千克·分钟至0.24±0.05毫升/千克·分钟）无显著变化；然而，分布容积增加（从183±10毫升/千克至266±36毫升/千克；P<0.03）。基线IGF-II水平为对照值的47%，在IGF-I治疗期间降低（从273±10微克/升降至178±9微克/升；P<0.01），与IGF-I水平呈负相关（r = -0.3；P<0.001）。尽管IGF结合蛋白-3（IGFBP-3）水平未受到显著影响，但基线IGFBP-2水平（为对照值的153%）增加了45%（P<0.01）。我们得出结论，皮下注射IGF-I（每12小时40微克/千克）对GHRD成年患者是安全的；可使IGF-I水平达到正常；降低胰岛素、IGF-II和生长激素水平；并增加IGFBP-2浓度和尿钙排泄。