目的:目前尚不清楚孕早期和晚发型妊娠期糖尿病(GDM)患者的早期妊娠代谢组是否存在差异,并根据孕妇超重进行分层。这项研究的目的是分析早孕代谢产物与母体血糖和人体测量特征之间的相关性。并确定以瘦女性(BMI<25kg/m2)和超重女性(BMI≥25kg/m2)为特征的早发性GDM(E-GDM)或晚发性GDM(L-GDM)的早孕代谢组学改变。
方法:我们在基于人群的妊娠糖尿病前瞻性早期诊断队列中进行了一项巢式病例对照研究,包括210名GDM参与者(126名早发,84晚发)和209名正常血糖控制参与者根据产妇年龄相匹配,BMI类和初值。产妇体重,在妊娠8-14周测量身高和腰围。在妊娠12-16周(OGTT1)进行2小时75gOGTT,结果正常的女性在妊娠24-28周(OGTT2)时接受重复检测。空腹血清样本的综合代谢组学分析,在OGTT1收集,通过非靶向超HPLC-MS进行。线性模型用于研究OGTT1、空腹胰岛素、HOMA-IR,BMI和腰围。使用线性和多变量模型研究了GDM亚型(根据孕妇超重和GDM发病时的妊娠时间点对参与者进行分层)的早期妊娠代谢组学特征。使用Benjamini-Hochberg方法控制错误发现率。
结果:在总队列中(n=419),(1)母体葡萄糖浓度与长链脂肪酸和中长链酰基肉碱之间最明显的相关模式;(2)母体BMI和/或腰围与长链脂肪酸之间,中链和长链酰基肉碱,磷脂,和芳香和支链氨基酸;和(3)HOMA-IR和/或空腹胰岛素和L-酪氨酸,某些长链脂肪酸和磷脂(q<0.001)。GDM亚型的单变量分析显示,与对照组参与者相比,仅在超重的E-GDM女性中,七种非葡萄糖代谢物存在显着差异(q<0.05):亚麻酸,油酸,二十二碳五烯酸,二十二碳四烯酸和溶血磷脂酰胆碱20:4/0:0丰度较高,而特定磷脂酰胆碱(P-16:0/18:2和15:0/18:2)的水平较低。然而,研究GDM亚型妊娠早期代谢组的多变量分析显示,在体重正常和超重的E-和L-GDM女性中,酰基肉碱和长链脂肪酸的聚集差异。
结论:GDM亚型显示出与母体血糖和人体测量特征相关的独特的早孕代谢组学特征。确定的模式表明母亲脂质代谢的妊娠早期紊乱,在E-GDM超重女性中观察到大多数改变。我们的发现强调了产妇肥胖作为预防和治疗的主要目标的重要性。
OBJECTIVE: It is not known whether the early-pregnancy metabolome differs in patients with early- vs late-onset gestational diabetes mellitus (GDM) stratified by maternal overweight. The aims of this study were to analyse correlations between early-pregnancy metabolites and maternal glycaemic and anthropometric characteristics, and to identify early-pregnancy metabolomic alterations that characterise lean women (BMI <25 kg/m2) and women with overweight (BMI ≥25 kg/m2) with early-onset GDM (E-GDM) or late-onset GDM (L-GDM).
METHODS: We performed a nested case-control study within the population-based prospective Early Diagnosis of Diabetes in Pregnancy cohort, comprising 210 participants with GDM (126 early-onset, 84 late-onset) and 209 normoglycaemic control participants matched according to maternal age, BMI class and primiparity. Maternal weight, height and waist circumference were measured at 8-14 weeks\' gestation. A 2 h 75 g OGTT was performed at 12-16 weeks\' gestation (OGTT1), and women with normal results underwent repeat testing at 24-28 weeks\' gestation (OGTT2). Comprehensive metabolomic profiling of fasting serum samples, collected at OGTT1, was performed by untargeted ultra-HPLC-MS. Linear models were applied to study correlations between early-pregnancy metabolites and maternal glucose concentrations during OGTT1, fasting insulin, HOMA-IR, BMI and waist circumference. Early-pregnancy metabolomic features for GDM subtypes (participants stratified by maternal overweight and gestational timepoint at GDM onset) were studied using linear and multivariate models. The false discovery rate was controlled using the Benjamini-Hochberg method.
RESULTS: In the total cohort (n=419), the clearest correlation patterns were observed between (1) maternal glucose concentrations and long-chain fatty acids and medium- and long-chain acylcarnitines; (2) maternal BMI and/or waist circumference and long-chain fatty acids, medium- and long-chain acylcarnitines, phospholipids, and aromatic and branched-chain amino acids; and (3) HOMA-IR and/or fasting insulin and L-tyrosine, certain long-chain fatty acids and phospholipids (q<0.001). Univariate analyses of GDM subtypes revealed significant differences (q<0.05) for seven non-glucose metabolites only in overweight women with E-GDM compared with control participants: linolenic acid, oleic acid, docosapentaenoic acid, docosatetraenoic acid and lysophosphatidylcholine 20:4/0:0 abundances were higher, whereas levels of specific phosphatidylcholines (P-16:0/18:2 and 15:0/18:2) were lower. However, multivariate analyses exploring the early-pregnancy metabolome of GDM subtypes showed differential clustering of acylcarnitines and long-chain fatty acids between normal-weight and overweight women with E- and L-GDM.
CONCLUSIONS: GDM subtypes show distinct early-pregnancy metabolomic features that correlate with maternal glycaemic and anthropometric characteristics. The patterns identified suggest early-pregnancy disturbances of maternal lipid metabolism, with most alterations observed in overweight women with E-GDM. Our findings highlight the importance of maternal adiposity as the primary target for prevention and treatment.