Metabolite Profiles Preceding Progression to Diabetes Mellitus after Gestational Diabetes

项目总结/摘要 代谢组学已成为一种新的方法，以确定代谢物的改变，以提高预测 2型糖尿病（DM）的发病机制。妊娠期糖尿病（GDM）的女性有 产后5至10年内转化为糖尿病的几率极高。然而，模型 使用临床或代谢测量来预测DM对于该高危组是不可用的。口服葡萄糖 建议在产后4至12周进行耐受性试验（OGTT），但OGTT对新生儿来说是一个负担。 母亲和吸收率低。妊娠期糖尿病后母婴喂养与2型糖尿病关系的研究 R 01 HD 050625（Gunderson PI）在2008年至2011年入组了1，035例GDM女性，给药2小时 75 g研究OGTT和产后6-9周的综合评估（基线）， 每年一次，直到分娩后两年。这个前瞻性的、特征明确的GDM队列是唯一的 定位于解决我们在理解向DM转变的病理生理学和时间方面的主要差距 GDM妊娠后我们的研究小组进行了第一项研究， 方法来确定和验证代谢产物谱预测糖尿病的妇女与GDM。本研究 测量了182种以前与成人糖尿病相关的代谢物，以确定代谢物谱， 4种分析物同种型[支链氨基酸、己糖、PCaeC 40：5、SM（OH）C14：1]的预测能力（83%）超过 单独空腹血糖或负荷后2小时血糖（72-73%）。虽然前景看好，我们建议完善这一概况， 在整个队列中，大大扩展脂质代谢产物，并通过长期随访测试其预测能力。 总体研究目标是从产后早期血浆样品中鉴定代谢物谱， 是高度预测事件DM分娩后8年的妇女与GDM。SWIFT队列是 由于其种族/民族多样性（75%为少数民族）、大规模、来自多个国家的纵向生物样本库， 研究OGTT和产后早期至2年的详细评估，保持率高 (83%），以及在稳定的成员中通过电子健康记录（EHR）进行持续监测（84%） 5年后仍为会员）。时间是最佳的第四次亲自研究访问后约8年- 基线，以重新评估葡萄糖耐量和开发预测工具。具体目标是：目标1。到 在产后6-9周（基线）确定和改进代谢物谱，更好地预测糖尿病事件 我们假设在产后6-9周确定的代谢产物谱将是 在早期（2年）和后期（8年）随访期间，对DM具有高度预测性;目标2.表征 随访期间（基线、1 - 2年和8年）连续时间点的代谢特征，以及 评估它们与葡萄糖耐量转变的关系;我们假设不同的代谢产物谱 将与葡萄糖耐量随时间的稳定性或恶化密切相关。一个探索性的目标是 在特定人种/种族组中，开发不同的代谢物谱，高度预测DM事件。

PROJECT SUMMARY/ABSTRACT Metabolomics has emerged as a novel approach to identify alterations in metabolites to improve prediction of type 2 diabetes mellitus (DM) beyond blood glucose. Women with gestational diabetes mellitus (GDM) have an extremely high rate of conversion to diabetes within 5 to 10 years post-delivery. However, models for prediction of DM using clinical or metabolic measures are unavailable for this high-risk group. Oral glucose tolerance testing (OGTT) is recommended at 4 to 12 weeks postpartum, but the OGTT is burdensome for new mothers and uptake is low. The Study of Women Infant Feeding, and Type 2 Diabetes After GDM (SWIFT) R01HD050625 (Gunderson PI) enrolled 1,035 women with GDM in 2008 to 2011 and administered 2-hr 75 g research OGTTs and comprehensive assessments from 6-9 weeks postpartum (baseline) and annually through two years post-delivery. This prospective, well-characterized GDM cohort is uniquely positioned to address major gaps in our understanding of the pathophysiology and timing of transitions to DM following GDM pregnancy. Our research team conducted the first study to use a targeted metabolomics approach to identify and validate a metabolite profile predictive of DM among women with GDM. This study measured 182 metabolites previously linked with incident DM in adults to identify a metabolite profile consisting of 4 analyte isotypes [BCAAs, hexoses, PCaeC40:5, SM(OH)C14:1] with predictive ability (83%) that exceeded fasting glucose alone or 2-hr post-load glucose (72-73%). Although promising, we propose to refine this profile in the entire cohort, greatly expand the lipid metabolites and test its predictive ability with longer-term follow up. The overall study goal is to identify a metabolite profile from early postpartum plasma samples that is highly predictive of incident DM up to 8 years post-delivery in women with GDM. The SWIFT cohort is exceptional for its racial/ethnic diversity (75% minority), large size, longitudinal Biobank from multiple research OGTTs and detailed assessments from early through 2 years postpartum with high retention (83%), and ongoing surveillance via electronic health records (EHR) within a stable membership (84% remain members 5 years later). The timing is optimal for a 4th in-person research visit at ~8th year post- baseline to re-assess glucose tolerance and develop prediction tools. The specific aims are: Aim 1. To identify and refine metabolite profiles at 6-9 weeks postpartum (baseline) that better predict incident diabetes following GDM pregnancy; we hypothesize that metabolite profiles identified at 6-9 weeks postpartum will be highly predictive of DM during early (2-year) and later (8-year) follow up periods; Aim 2. To characterize the metabolic profiles at consecutive time points across follow up (baseline, 1 to 2 years, and 8 years) and evaluate their relationship to transitions in glucose tolerance; we hypothesize that distinct metabolite profiles will be strongly related to the stability or deterioration in glucose tolerance over time. An exploratory aim is to develop distinct metabolite profiles highly predictive of incident DM within specific race/ethnicity groups.