Departments of Endocrinology and Diabetes (W.H., N.S., T.B.) and Nuclear Medicine (N.C.), Birmingham Children's Hospital, B4 6NH Birmingham, United Kingdom; Department of Paediatric Endocrinology and Diabetes (D.D.M.), University Children's Hospital, D-72074 Tübingen, Germany; Wellcome Trust Clinical Research Facility (P.N.), Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom; School of Clinical and Experimental Medicine (J.T., T.B.), University of Birmingham, Birmingham B15 2TT, United Kingdom; William Harvey Research Institute (L.M.), Barts and the London School of Medicine, Queen Mary University of London, London E1 1BB, United Kingdom; Department of Paediatrics (R.R.), Oregon Health Sciences University, Portland, Oregon 97239; Department of Paediatrics (S.R.), Heartlands Hospital, B9 5SS Birmingham, United Kingdom; Department of Paediatrics (J.W.), Portsmouth Hospital, Portsmouth PO6 3LY, United Kingdom; and Medical Research Laboratory (J.F.), Department of Clinical Medicine, Faculty of Health, Aarhus University, and Department of Endocrinology and Internal Medicine, Aarhus University Hospital, DK-8000 C Aarhus, Denmark.
J Clin Endocrinol Metab. 2014 Apr;99(4):E703-12. doi: 10.1210/jc.2013-3718. Epub 2014 Jan 13.
Acid labile subunit (ALS) deficiency, caused by IGFALS mutations, is a subtype of primary IGF-I deficiency (PIGFD) and has been associated with insulin resistance (IR) and osteopenia. Whether patients respond to recombinant human IGF-I (rhIGF-I) is unknown.
This study determined the 14-hour pharmacokinetic response of free and total IGF-I and IGF binding protein 3 (IGFBP-3) to a single sc dose of rhIGF-I (120 μg/kg) in four ALS-deficient patients, compared with severe PIGFD, moderate PIGFD, and controls. Intravenous glucose tolerance tests, fasting blood levels, dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and metacarpal radiogrammetry were performed in the four patients and 12 heterozygous family members.
IGF-I and IGFBP-3 increased above baseline (P < .05) for 2.5 hours, returning to baseline 7 hours after rhIGF-I injection. Mean (SD) IGF-I Z-score increased by 2.49 (0.90), whereas IGFBP-3 Z-score increased by 0.57 (0.10) only. IGF-I elimination rates in ALS deficiency were similar, but the IGF-I increment was lower than those for severe PIGFD. Significant gene dosage effects were found for all IGF-I peptides, height, forearm muscle size, and metacarpal width. Bone analysis showed that ALS deficiency creates a phenotype of slender bones with normal size-corrected density. Abnormal glucose handling and IR was found in three of four patients and 6 of 12 carriers.
These gene dosage effects demonstrate that one functional IGFALS allele is insufficient to maintain normal ALS levels, endocrine IGF-I action, full growth potential, muscle size, and periosteal expansion. Similar gene dosage effects may exist for parameters of IR. Despite similar IGF-I elimination compared with severe PIGFD, ALS-deficient patients cannot mount a similar response. Alternative ways of rhIGF-I administration should be sought.
酸不稳定亚基（ALS）缺乏症由 IGFALS 突变引起，是原发性 IGF-I 缺乏症（PIGFD）的一个亚型，与胰岛素抵抗（IR）和骨质疏松症有关。目前尚不清楚患者对重组人生长激素 IGF-I（rhIGF-I）的反应如何。
本研究旨在比较四种 ALS 缺乏症患者与严重 PIGFD、中度 PIGFD 和对照组单次皮下注射 rhIGF-I（120μg/kg）后游离和总 IGF-I 及 IGF 结合蛋白 3（IGFBP-3）的 14 小时药代动力学反应。对四名患者和 12 名杂合子家族成员进行了静脉葡萄糖耐量试验、空腹血水平、双能 X 射线吸收法、外周定量计算机断层扫描和掌骨放射测量。
rhIGF-I 注射后 2.5 小时 IGF-I 和 IGFBP-3 均高于基线（P<0.05），7 小时后恢复基线。IGF-I Z 评分平均（SD）增加 2.49（0.90），而 IGFBP-3 Z 评分仅增加 0.57（0.10）。ALS 缺乏症的 IGF-I 消除率相似，但 IGF-I 增量低于严重 PIGFD。所有 IGF-I 肽、身高、前臂肌肉大小和掌骨宽度均发现明显的基因剂量效应。骨分析表明，ALS 缺乏症导致骨骼细长，骨密度正常校正。四名患者中有三名和十二名携带者中的六名存在葡萄糖代谢异常和 IR。
这些基因剂量效应表明，一个功能正常的 IGFALS 等位基因不足以维持正常的 ALS 水平、内分泌 IGF-I 作用、充分的生长潜能、肌肉大小和骨膜扩张。IR 的参数可能存在类似的基因剂量效应。尽管与严重 PIGFD 相比，ALS 缺乏症患者的 IGF-I 消除率相似，但他们无法产生类似的反应。应寻求替代 rhIGF-I 给药方式。
