Objective

Mutations in the pregnancy-associated plasma protein A2 (PAPP-A2) gene have recently been shown to cause postnatal growth failure in two prepubertal patients from a non-consanguineous Spanish family due to the resulting decrease in IGF1 bioavailability. Although a specific pharmacological treatment of this entity is yet to be established, both children received progressive subcutaneous doses (40 to 120 μg/kg) of rhIGF1 twice daily for 2 years. The improvements in growth, hyperinsulinemia and bone mineral density have been previously reported. The objective of this study was to analyze the changes in metabolism associated with these responses to rhIGF1 treatment.

Design

Herein we present a detailed characterization of the acute and long-term changes in the metabolic profiles of these two siblings with PAPP-A2 deficiency after the initial injections of rhIGF1 and after two years of treatment.

Results

By using a GC-MS-based untargeted metabolomics approach, metabolic fingerprinting yielded the identification of 70 serum metabolites including amino acids (46%), organic acids (21%) carbohydrates (16%), fatty acids (14%), and purine bases (3%). Free fatty acids (FFAs) and amino acids showed the largest changes in the compared metabolic profiles, suggesting that rhIGF1 treatment has the greatest effects on lipid and protein metabolic pathways in the PAPP-A2 deficient subjects.

Conclusions

The administration of rhIGF1 resulted in changes related to crucial metabolic pathways, including lipid and protein metabolism, and this could be associated with the previously reported treatment-induced improvement in the mild basal hyperinsulinemia.

中文翻译：

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响应rhIGF1治疗的PAPP-A2缺乏症患者的代谢组学变化。

目的

最近已证明，与妊娠相关的血浆蛋白A2（PAPP-A2）基因的突变会导致两名来自西班牙非血缘家庭的青春期前患者的出生后生长衰竭，原因是导致IGF1生物利用度降低。尽管尚未确定对该实体的具体药物治疗方法，但两名儿童均连续2年每天两次接受渐进性皮下剂量的rhIGF1（40至120μg/ kg）。先前已经报道了生长，高胰岛素血症和骨矿物质密度的改善。这项研究的目的是分析与对rhIGF1治疗的这些反应相关的代谢变化。

设计

在本文中，我们介绍了首次注射rhIGF1和治疗两年后这两个PAPP-A2缺乏症兄弟姐妹的代谢谱中急性和长期变化的详细特征。

结果

通过使用基于GC-MS的非靶向代谢组学方法，代谢指纹图谱可鉴定70种血清代谢物，包括氨基酸（46％），有机酸（21％）碳水化合物（16％），脂肪酸（14％）和嘌呤碱（3％）。游离脂肪酸（FFA）和氨基酸在比较的代谢曲线中显示出最大的变化，表明rhIGF1治疗对PAPP-A2缺陷受试者的脂质和蛋白质代谢途径的影响最大。

结论

rhIGF1的使用导致与关键代谢途径（包括脂质和蛋白质代谢）相关的变化，这可能与先前报道的治疗引起的轻度基础高胰岛素血症的改善有关。