Dietary Interventions, Metabolites, and Risk of Type 2 Diabetes

描述(申请人提供)：2型糖尿病(T2D)已达到流行比例。健康饮食等生活方式因素对T2D的预防至关重要。最近，PREDIMED(Prevencion con Dieta地中海)试验在西班牙完成。这项试验是一项多中心的随机对照试验，其中7,447名参与者被随机分配到地中海饮食干预组，其中富含特级初榨橄榄油或坚果或对照饮食。 虽然这项试验的主要目的是评估干预措施对心血管疾病的影响，但饮食干预也将T2D的发生率降低了30%(95%可信区间0.54-0.92)。本研究的目的是检查地中海饮食是否对代谢物的变化和T2D风险的影响。我们将采用病例队列研究设计，包括273例T2D事件病例和708名随机选择的无糖尿病参与者(20%)。将使用最先进的LC-MS技术，对在试验基线和试验第一年收集的存储的空腹血液样本进行测量，以获得由约300种代谢物组成的经过充分验证的小组。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T2D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了代谢物基线水平和随后的T2D风险之间的关系；3)采用病例队列设计，检验1年代谢物的变化是否在饮食干预对随后第2至第5年的T2D结果的影响中起中介作用；在随机选择的708名基线无糖尿病的受试者中，检测代谢产物1年的变化是否会影响2-5年的胰岛素抵抗和�细胞功能。大规模的PREDIMED试验拥有存档的血浆样本和丰富的饮食、生活方式和生物标记物的重复测量，这是一个前所未有的机会，以极具成本效益的方式满足我们的特定目标。这个项目有很大的潜力来促进我们对饮食干预影响T2D风险的代谢途径的理解。它还具有重要的公共卫生和临床意义，因为许多这些代谢物及其相关途径可能适合于直接的饮食和生活方式干预。为了为这个项目做准备，我们已经完成了一项初步研究，在干预一年的时候从每一组饮食中随机选择20个样本，并在麻省理工学院和哈佛大学使用LC-MS进行代谢分析。

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.