Amino acid and lipid metabolism in post-gestational diabetes and progression to type 2 diabetes: A metabolic profiling study
Amino acid and lipid metabolism in post-gestational diabetes and progression to type 2 diabetes: A metabolic profiling study
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DOI：
10.1371/journal.pmed.1003112
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发表时间：
2020-05-01
期刊：
影响因子：
15.8
通讯作者：
Wheeler, Michael B.
中科院分区：
文献类型：
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作者：
Lai, Mi;Liu, Ying;Wheeler, Michael B.
背景有妊娠期糖尿病(GDM)病史的女性在中年患2型糖尿病(T2D)的风险增加7倍，患高血压和心血管疾病的风险增加。建议在分娩后对糖耐量进行重新分类，但只有不到40%的妊娠期糖尿病妇女进行了测试。因此，需要改进风险分层方法，以及更深入地了解从GDM向T2D转变的潜在病理。我们假设产后早期的代谢物准确地区分了从GDM发展到T2D的风险，代谢物的变化标志着未来疾病发展的潜在病理生理学。方法和发现本研究利用了从1,035名被诊断为GDM的妇女进行的具有良好特征的前瞻性研究中收集的空腹血浆样本。这一队列包括2008年至2011年在北加州凯撒永久医院分娩的不同种族/民族的孕妇(年龄20-45岁-33%初产，37%双产，30%经产)。参与者参加了面对面的研究访问，包括在研究基线(产后6-9周)和此后2年每年进行2小时75克口服葡萄糖耐量试验(OGTTS)，我们从电子医疗记录中检索了8年的糖尿病诊断。在嵌套式病例对照研究设计中，我们收集了基线(n=1,010)非糖尿病妇女的空腹血浆样本，以测量那些后来进展为T2D或未发展为T2D(非T2D)的妇女的代谢物。我们研究了173例T2D发病病例和485名对照(在体重指数、年龄和种族/民族方面配对)，以发现与新的T2D发病相关的代谢物。基线后两年，我们分析了98例T2D患者和239名对照的样本，以揭示T2D相关的代谢变化。纵向分析跟踪个体从基线到两年随访期间的代谢变化，作为T2D进展的轨迹。通过建立预测模型，我们在产后早期发现了一个明显的代谢特征，预测了未来的T2D，接收器操作特征曲线下的中位数分辨能力区域为0.883(95%CI 0.820-0.945，p<；0.001)。在基线时，最显著的发现是在发生T2D的女性中，氨基酸(AAs)和二酰基甘油磷脂总体增加，而神经鞘脂脂和酰基烷基甘油磷脂减少。通路分析显示，基线时AA代谢、精氨酸/脯氨酸代谢和支链AA(BCAA)代谢上调。在T2D开始后的随访中，AAs的上调和鞘磷脂和酰基烷基甘油磷脂的下调持续或加强。值得注意的是，纵向分析显示只有10种代谢物与进展到T2D有关，涉及AA和磷脂代谢。研究的局限性是所有的分析都是在相同的队列中进行的。在产后早期接受糖耐量测试的GDM妇女的独立纵向队列中验证我们的发现将是理想的。结论在这项研究中，我们发现了一个预测产后早期从GDM向T2D转变的代谢特征，该特征优于临床参数(空腹血糖、2小时血糖)。研究结果表明，代谢紊乱，特别是AA代谢异常，在糖尿病发病前几年就已经存在，并在妊娠期糖尿病妇女产后早期表现出来，在T2D进展之前。
BackgroundWomen with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D) during midlife and an elevated risk of developing hypertension and cardiovascular disease. Glucose tolerance reclassification after delivery is recommended, but fewer than 40% of women with GDM are tested. Thus, improved risk stratification methods are needed, as is a deeper understanding of the pathology underlying the transition from GDM to T2D. We hypothesize that metabolites during the early postpartum period accurately distinguish risk of progression from GDM to T2D and that metabolite changes signify underlying pathophysiology for future disease development.Methods and findingsThe study utilized fasting plasma samples collected from a well-characterized prospective research study of 1,035 women diagnosed with GDM. The cohort included racially/ethnically diverse pregnant women (aged 20-45 years-33% primiparous, 37% biparous, 30% multiparous) who delivered at Kaiser Permanente Northern California hospitals from 2008 to 2011. Participants attended in-person research visits including 2-hour 75-g oral glucose tolerance tests (OGTTs) at study baseline (6-9 weeks postpartum) and annually thereafter for 2 years, and we retrieved diabetes diagnoses from electronic medical records for 8 years. In a nested case-control study design, we collected fasting plasma samples among women without diabetes at baseline (n = 1,010) to measure metabolites among those who later progressed to incident T2D or did not develop T2D (non-T2D). We studied 173 incident T2D cases and 485 controls (pair-matched on BMI, age, and race/ethnicity) to discover metabolites associated with new onset of T2D. Up to 2 years post-baseline, we analyzed samples from 98 T2D cases with 239 controls to reveal T2D-associated metabolic changes. The longitudinal analysis tracked metabolic changes within individuals from baseline to 2 years of follow-up as the trajectory of T2D progression. By building prediction models, we discovered a distinct metabolic signature in the early postpartum period that predicted future T2D with a median discriminating power area under the receiver operating characteristic curve of 0.883 (95% CI 0.820-0.945, p < 0.001). At baseline, the most striking finding was an overall increase in amino acids (AAs) as well as diacyl-glycerophospholipids and a decrease in sphingolipids and acyl-alkyl-glycerophospholipids among women with incident T2D. Pathway analysis revealed up-regulated AA metabolism, arginine/proline metabolism, and branched-chain AA (BCAA) metabolism at baseline. At follow-up after the onset of T2D, upregulation of AAs and down-regulation of sphingolipids and acyl-alkyl-glycerophospholipids were sustained or strengthened. Notably, longitudinal analyses revealed only 10 metabolites associated with progression to T2D, implicating AA and phospholipid metabolism. A study limitation is that all of the analyses were performed with the same cohort. It would be ideal to validate our findings in an independent longitudinal cohort of women with GDM who had glucose tolerance tested during the early postpartum period.ConclusionsIn this study, we discovered a metabolic signature predicting the transition from GDM to T2D in the early postpartum period that was superior to clinical parameters (fasting plasma glucose, 2-hour plasma glucose). The findings suggest that metabolic dysregulation, particularly AA dysmetabolism, is present years prior to diabetes onset, and is revealed during the early postpartum period, preceding progression to T2D, among women with GDM.