Dietary Interventions, Metabolites, and Risk of Type 2 Diabetes

描述（申请人提供）：2型糖尿病（T2 D）已达到流行比例。健康饮食等生活方式因素对预防T2 D至关重要。最近，西班牙完成了PREDIMED（PREvencion con DIeta MEDIPEEA）试验。该试验是一项多中心随机对照试验，其中7，447名参与者被随机分配到富含特级初榨橄榄油或坚果的地中海饮食干预或对照饮食。 尽管该试验主要旨在评估干预措施对CVD的影响，但饮食干预也使T2 D的发病率降低了30%（95%CI 0.54-0.92）。本研究的目的是检查地中海饮食对代谢物变化和T2 D风险的影响。我们将采用病例队列研究设计，纳入273例T2 D事件病例和708例随机选择的基线无糖尿病的参与者（20%）。将使用最先进的LC-MS技术，测量基线和试验第1年采集的储存空腹血液标本中经过充分验证的约300种代谢产物。我们的具体目标是：1）使用病例队列设计检查基线代谢物浓度与T2 D风险之间的关联; 2）。使用病例队列设计检查饮食干预是否改变代谢物基线水平与随后的T2 D风险之间的关系; 3）。使用病例队列设计，检查代谢物的1年变化是否介导饮食干预对2 - 5年后续T2 D结局的影响;和4）。在708名随机选择的基线时无糖尿病的参与者中，研究代谢物的1年变化是否影响2 - 5年的胰岛素抵抗和β细胞功能。大型PREDIMED试验，存档的血浆样本和丰富的饮食，生活方式和生物标志物的重复测量，代表了一个前所未有的机会，以极其具有成本效益的方式解决我们的特定目标。该项目有很大的潜力，以促进我们的代谢途径的理解，通过饮食干预影响T2 D风险。它还具有重要的公共卫生和临床意义，因为这些代谢物及其相关途径中的许多可能适用于直接的饮食和生活方式干预。为了为该项目做准备，我们已经完成了初步研究，在干预一年后从每个饮食组中随机选择了20个样本，并在麻省理工学院和哈佛大学布罗德研究所使用LC-MS进行了代谢组学分析。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) has reached epidemic proportion. Lifestyle factors such as a healthy diet are crucial for T2D prevention. Recently, the PREDIMED (PREvencion con DIeta MEDiterranea) trial was completed in Spain. The trial was a multicenter, randomized controlled trial in which 7,447 participants were randomly allocated to Mediterranean dietary interventions enriched with extra virgin olive oil or nuts or a control diet. Although the trial was primarily designed to assess the effect of the interventions on CVD, the dietary interventions also reduced incidence of T2D by 30% (95% CI 0.54-0.92). The goal of the present study is to examine whether the effects of Mediterranean diet on changes in metabolites and T2D risk. We will employ a case-cohort study design with 273 incident cases of T2D and 708 randomly selected participants free of diabetes at baseline (20%). Stored fasting blood specimens collected at baseline and at year 1 of the trial will be measured for a well-validated panel of ~300 metabolites, using the state-of-the-art LC-MS technology. Our Specific Aims are: 1) To examine the association between the baseline metabolite concentrations and the risk of T2D using a case-cohort design; 2). To examine whether the dietary interventions modify the relationships between baseline levels of metabolites and subsequent T2D risk using a case- cohort design; 3). To examine whether 1-year changes in metabolites mediate the effect of the dietary interventions on subsequent T2D outcomes from years 2 to 5 using a case-cohort design; and 4). To examine whether 1-year changes in metabolites influence insulin resistance and �-cell function from years 2 to 5 among 708 randomly selected participants free of diabetes at baseline. The large PREDIMED trial, with archived plasma samples and rich repeated measurements of diet, lifestyle, and biomarkers, represents an unprecedented opportunity to address our specific aims in an extremely cost-effective manner. This project has great potential to advance our understanding of the metabolic pathways through which dietary interventions influence T2D risk. It also has important public health and clinical implications because many of these metabolites and their associated pathways may be suitable for direct diet and lifestyle interventions. To prepare for this project, we have already completed a preliminary study by randomly selecting 20 samples from each diet group at one year of intervention and conducted metabolomic analyses using LC-MS at the Broad Institute of MIT and Harvard.