Metabolite profiles and the risk of diabetes in Asians

 描述(申请人提供)：2型糖尿病(DM)是世界范围内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。人们越来越认识到，在糖尿病患者中存在表型的异质性。近年来引起特别关注的一个亚组是“瘦身糖尿病”组，即没有肥胖的糖尿病患者。与肥胖的糖尿病患者相比，患有糖尿病的瘦人死亡和其他并发症的风险要高得多。然而，对于在没有肥胖的情况下促进糖尿病的因素，或者在这一亚组中导致更差结果的机制，人们知之甚少。亚洲人特别容易患上精益DM。大约一半患有糖尿病的亚洲人被认为是正常体重(BMI低于25公斤/平方米)。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，亚裔美国人患糖尿病的比例很高。糖尿病的发病机制反映了遗传、饮食和环境暴露的复杂相互作用，影响了多个途径。一种同时了解许多代谢途径的活性的方法是代谢组学图谱。“代谢组学”是指对生物样本中的代谢物进行系统分析，如血浆。结合人类群体中的生物标志物和表型数据，为识别代谢性疾病的生化特征提供了丰富的机会，这可以加强生物学理解，并为疾病筛查提供有效的工具。来自非欧洲人群，尤其是亚洲人群的代谢组学数据很少。不同种族/民族的糖尿病流行病学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，中国妇女有一些不同于欧洲人群的糖尿病危险标记。因此，我们建议大幅扩展我们在欧洲人群中的工作和我们在SWHS中的试点研究，在2个中国队列中进行全面的代谢组学分析，以确定与糖尿病发病相关的代谢物。我们的目标是(1)在参加SWHS和上海男性健康研究(SMHS)的中国人中确定与糖尿病发病相关的代谢物；(2)在另一项病例队列研究中复制代谢物与糖尿病发病的相关性。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，以及代谢物预测因素是否与死亡率和心血管事件有关。考虑到我们在大规模队列中应用代谢组学的专业知识、我们能够获得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，我们的团队在进行这些研究方面具有得天独厚的优势。

 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.