Metabolite profiles and the risk of diabetes in Asians

 描述（由申请人提供）：2型糖尿病（DM）是全球发病率和死亡率的主要来源。预计到2025年，糖尿病病例将增加72%，影响所有国家和收入群体的3.25亿人。越来越多的人认识到，糖尿病患者的表型存在异质性。近年来引起特别关注的一个亚组是“瘦型糖尿病”组，例如患有DM但不肥胖的个体。与肥胖的糖尿病患者相比，消瘦的糖尿病患者的死亡率和其他并发症的风险明显更高。然而，很少有人知道的因素，促进糖尿病在没有肥胖，或机制的基础上，在这一子集的不良后果。亚洲人特别容易患瘦型糖尿病。大约一半的亚洲糖尿病患者被认为体重正常（BMI小于25 kg/m2）。这种倾向与居住国无关，例如，它影响居住在美国和亚洲国家的亚洲人。事实上，美国的研究表明，亚裔美国人的糖尿病发病率非常高。DM的发病机制反映了遗传、饮食和环境暴露的复杂相互作用，影响多个途径。一种同时了解许多代谢途径活性的方法是代谢组学分析。“代谢物组学”是指生物样品（例如血浆）中代谢物的系统分析。结合人群中的生物标志物和表型数据提供了丰富的机会来识别代谢疾病的生化特征，这可以增强生物学理解并产生疾病筛查的工具。来自非欧洲队列，特别是亚洲队列的代谢组学数据很少。不同种族/民族之间DM流行病学的差异表明可能存在病理生理学差异。最近，在上海妇女健康研究（SWHS）的一项初步研究中，我们发现有证据表明，中国妇女有一些糖尿病的风险标志物，这些标志物与欧洲人群中描述的不同。因此，我们建议通过在2个中国队列中进行全面的代谢组学分析，以确定与糖尿病相关的代谢物，从而大大扩展我们在欧洲人群中的工作和SWHS中的试点研究。我们的目的是（1）在参加SWHS和上海男性健康研究（SMHS）的中国个体中鉴定与DM事件相关的代谢物;（2）在单独的病例队列研究中复制代谢物与DM事件的相关性。我们还将评估与单独的风险因素相比，添加代谢物是否提高了预测亚洲人糖尿病风险的能力，以及代谢物预测因子是否与死亡率和心血管事件相关。我们的团队在开展这些研究方面具有独特的优势，因为我们在大型队列中应用代谢组学的专业知识，我们可以访问其他代谢组学数据集进行比较和验证，以及我们在中国慢性病流行病学方面的经验。

 DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (DM) is a major source of morbidity and mortality worldwide. Cases of DM are expected to rise by 72% through 2025, affecting 325 million people across all nations and income groups. It is increasingly recognized that there is phenotypic heterogeneity among individuals who develop DM. One subgroup that has attracted particular attention in recent years is the "lean diabetes" group, e.g. individuals with DM in the absence of obesity. Lean individuals with DM are at substantially higher risk of mortality and other complications than obese individuals with DM. However, little is known about the factors that promote DM in the absence of obesity, or the mechanisms underlying the worse outcomes in this subset. Asians are particularly susceptible to developing lean DM. Approximately half of Asians who develop DM are considered normal weight (BMI less than 25 kg/m2). This propensity is independent of country of residence, e.g. it affects Asians living in th U.S. as well as in Asian countries. Indeed, studies in the U.S. indicate very high rates of DM among Asian-Americans. The pathogenesis of DM reflects a complex interplay of genetic, dietary, and environmental exposures affecting multiple pathways. One approach to understanding the activity in many metabolic pathways at once is metabolomics profiling. "Metabolomics" refers to the systematic analysis of metabolites in a biological specimen, such as plasma. Combining biomarker and phenotypic data in human populations provides a rich opportunity to identify the biochemical signatures of metabolic diseases, which can enhance biological understanding as well as yield tools for disease screening. Metabolomics data from non-European cohorts, and particularly Asian cohorts, are sparse. The differences in the epidemiology of DM across racial/ethnic groups suggest the possibility of pathophysiological differences. Recently, in a preliminary study in the Shanghai Women's Health Study (SWHS), we found evidence that Chinese women had some risk markers for DM that were distinct from those described in European populations. Thus, we propose to expand considerably on our work in European populations and our pilot studies in the SWHS, by performing comprehensive metabolomics profiling in 2 Chinese cohorts to identify metabolites that are associated with incident DM. Our aims are (1) to identify metabolites that associate with incident DM in Chinese individuals enrolled in the SWHS and Shanghai Men's Health Study (SMHS); and (2) to replicate the association of metabolites with incident DM in a separate case-cohort study. We will also assess whether addition of metabolites improves the ability to predict risk of DM in Asians, compared with risk factors alone, and whether the metabolite predictors are associated with mortality and cardiovascular events. Our team is uniquely positioned to conduct these studies, given our expertise in applying metabolomics in large cohorts, our access to other metabolomics datasets for comparison and validation, and our experience with chronic disease epidemiology in China.