AIMS/HYPOTHESIS This study aimed to: (1) identify metabolite patterns during late childhood that differ with respect to exposure to maternal gestational diabetes mellitus (GDM); (2) examine the persistence of GDM/metabolite associations 5 years later, during adolescence; and (3) investigate the associations of metabolite patterns with adiposity and metabolic biomarkers from childhood through adolescence. METHODS This study included 592 mother-child pairs with information on GDM exposure (n = 92 exposed), untargeted metabolomics data at age 6-14 years (T1) and at 12-19 years (T2), and information on adiposity and metabolic risk biomarkers at T1 and T2. We first consolidated 767 metabolites at T1 into factors (metabolite patterns) via principal component analysis (PCA) and used multivariable regression to identify factors that differed by GDM exposure, at α = 0.05. We then examined associations of GDM with individual metabolites within factors of interest at T1 and T2, and investigated associations of GDM-related factors at T1 with adiposity and metabolic risk throughout T1 and T2 using mixed-effects linear regression models. RESULTS Of the six factors retained from PCA, GDM exposure was associated with greater odds of being in quartile (Q)4 (vs Q1-3) of 'Factor 4' at T1 after accounting for age, sex, race/ethnicity, maternal smoking habits during pregnancy, Tanner stage, physical activity and total energy intake, at α = 0.05 (OR 1.78 [95% CI 1.04, 3.04]; p = 0.04). This metabolite pattern comprised phosphatidylcholines, diacylglycerols and phosphatidylethanolamines. GDM was consistently associated with elevations in a subset of individual compounds within this pattern at T1 and T2. While this metabolite pattern was not related to the health outcomes in boys, it corresponded with greater adiposity and a worse metabolic profile among girls throughout the follow-up period. Each 1-unit increment in Factor 4 corresponded with 0.17 (0.08, 0.25) units higher BMI z score, 8.83 (5.07, 12.59) pmol/l higher fasting insulin, 0.28 (0.13, 0.43) units higher HOMA-IR, and 4.73 (2.15, 7.31) nmol/l higher leptin. CONCLUSIONS/INTERPRETATION Exposure to maternal GDM was nominally associated with a metabolite pattern characterised by elevated serum phospholipids in late childhood and adolescence at α = 0.05. This metabolite pattern was associated with greater adiposity and metabolic risk among female offspring throughout the late childhood-to-adolescence transition. Future studies are warranted to confirm our findings.

中文翻译：

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一项关于子宫内妊娠糖尿病暴露与儿童晚期和青春期代谢组学特征之间关联的前瞻性研究。

目的/假设 本研究旨在：(1) 确定儿童晚期的代谢物模式，这些模式与母体妊娠糖尿病 (GDM) 的暴露有关；(2) 检查 5 年后青春期期间 GDM/代谢物关联的持续性；(3) 研究代谢物模式与从儿童期到青春期的肥胖和代谢生物标志物的关联。方法 本研究包括 592 对母子对，其中包含 GDM 暴露信息（n = 92 暴露）、6-14 岁 (T1) 和 12-19 岁 (T2) 的非靶向代谢组学数据，以及肥胖和代谢风险信息T1 和 T2 的生物标志物。我们首先通过主成分分析 (PCA) 将 T1 的 767 种代谢物合并为因子（代谢物模式），并使用多变量回归来识别因 GDM 暴露而不同的因子，α = 0.05。然后，我们检查了 GDM 与 T1 和 T2 时感兴趣的因素内单个代谢物的关联，并使用混合效应线性回归模型研究了 T1 时 GDM 相关因素与整个 T1 和 T2 肥胖和代谢风险的关联。结果 在 PCA 保留的六个因素中，在考虑年龄、性别、种族/民族、母亲吸烟后，GDM 暴露与在 T1 时处于“因素 4”的四分位数 (Q)4（相对于 Q1-3）的更大几率相关怀孕期间的习惯、Tanner 阶段、体力活动和总能量摄入，α = 0.05（OR 1.78 [95% CI 1.04, 3.04]；p = 0.04）。这种代谢物模式包括磷脂酰胆碱、二酰基甘油和磷脂酰乙醇胺。GDM 始终与 T1 和 T2 时此模式内的单个化合物子集的升高相关。虽然这种代谢物模式与男孩的健康结果无关，但在整个随访期间，女孩的肥胖程度更高，代谢情况更差。因子 4 中每增加 1 个单位对应 0.17 (0.08, 0.25) 个单位的 BMI z 评分，8.83 (5.07, 12.59) pmol/l 更高的空腹胰岛素，0.28 (0.13, 0.43) 个单位的 HOMA-IR 和 4.73 (4.73) 2.15, 7.31) nmol/l 更高的瘦素。结论/解释 母体 GDM 暴露在名义上与代谢模式相关，其特征是在 α = 0.05 的儿童晚期和青春期血清磷脂升高。在整个儿童后期到青春期的过渡期间，这种代谢物模式与女性后代的肥胖和代谢风险更大有关。未来的研究有必要证实我们的发现。