Department of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain.
Department of Pediatrics, Universidad Autónoma de Madrid, CIBEROBN, Instituto de Salud Carlos III, Madrid, Spain.
Int J Obes (Lond). 2017 Oct;41(10):1473-1480. doi: 10.1038/ijo.2017.137. Epub 2017 Jun 7.
BACKGROUND/OBJECTIVES: Insulin resistance (IR) is the cornerstone of the obesity-associated metabolic derangements observed in obese children. Targeted metabolomics was employed to explore the pathophysiological relevance of hyperinsulinemia in childhood obesity in order to identify biomarkers of IR with potential clinical application.
SUBJECTS/METHODS: One hundred prepubertal obese children (50 girls/50 boys, 50% IR and 50% non-IR in each group), underwent an oral glucose tolerance test for usual carbohydrate and lipid metabolism determinations. Fasting serum leptin, total and high molecular weight-adiponectin and high-sensitivity C-reactive protein (CRP) levels were measured and the metabolites showing significant differences between IR and non-IR groups in a previous metabolomics study were quantified. Enrichment of metabolic pathways (quantitative enrichment analysis) and the correlations between lipid and carbohydrate metabolism parameters, adipokines and serum metabolites were investigated, with their discriminatory capacity being evaluated by receiver operating characteristic (ROC) analysis.
Twenty-three metabolite sets were enriched in the serum metabolome of IR obese children (P<0.05, false discovery rate (FDR)<5%). The urea cycle, alanine metabolism and glucose-alanine cycle were the most significantly enriched pathways (P<0.00005). The high correlation between metabolites related to fatty acid oxidation and amino acids (mainly branched chain and aromatic amino acids) pointed to the possible contribution of mitochondrial dysfunction in IR. The degree of body mass index-standard deviation score (BMI-SDS) excess did not correlate with any of the metabolomic components studied. In the ROC analysis, the combination of leptin and alanine showed a high IR discrimination value in the whole cohort (area under curve, AUC=0.87), as well as in boys (AUC0.84) and girls (AUC=0.91) when considered separately. However, the specific metabolite/adipokine combinations with highest sensitivity were different between the sexes.
Combined sets of metabolic, adipokine and metabolomic parameters can identify pathophysiological relevant IR in a single fasting sample, suggesting a potential application of metabolomic analysis in clinical practice to better identify children at risk without using invasive protocols.
背景/目的：胰岛素抵抗（IR）是肥胖儿童中观察到的与肥胖相关的代谢紊乱的基石。采用靶向代谢组学方法探索儿童肥胖中高胰岛素血症的病理生理学相关性，以确定具有潜在临床应用的 IR 生物标志物。
受试者/方法：100 名青春期前肥胖儿童（50 名女孩/50 名男孩，每组 50%的 IR 和 50%的非 IR）接受口服葡萄糖耐量试验以测定常规碳水化合物和脂质代谢。测量空腹血清瘦素、总和高分子量脂联素和高敏 C 反应蛋白（CRP）水平，并对之前代谢组学研究中 IR 和非 IR 组之间存在显著差异的代谢物进行定量。研究代谢途径的富集（定量富集分析）以及脂质和碳水化合物代谢参数、脂联素和血清代谢物之间的相关性，并通过接受者操作特征（ROC）分析评估其区分能力。
IR 肥胖儿童血清代谢组中 23 个代谢物集富集（P<0.05，错误发现率（FDR）<5%）。尿素循环、丙氨酸代谢和葡萄糖-丙氨酸循环是最显著富集的途径（P<0.00005）。与脂肪酸氧化和氨基酸（主要是支链和芳香族氨基酸）相关的代谢物之间的高度相关性表明，IR 中可能存在线粒体功能障碍。体重指数标准差评分（BMI-SDS）过量程度与所研究的代谢组学成分均无相关性。在 ROC 分析中，瘦素和丙氨酸的组合在整个队列中具有较高的 IR 区分值（曲线下面积，AUC=0.87），以及在男孩（AUC=0.84）和女孩（AUC=0.91）中分别考虑时。然而，在男女之间，具有最高敏感性的特定代谢物/脂联素组合是不同的。
代谢、脂联素和代谢组学参数的组合可以在单个空腹样本中识别出具有病理生理学相关性的 IR，这表明代谢组学分析在临床实践中的潜在应用可以更好地识别无侵袭性方案的风险儿童。
