Biochemical and Genetic Markers of Type 2 Diabetes Risk

描述(申请人提供)：2型糖尿病(T2D)已成为世界范围内的主要公共卫生问题。在环境因素中，饮食结构和体力活动的改变无疑是关键的原因。与此同时，越来越多的证据表明，接触工业产品中广泛存在的内分泌干扰物(EDCs)，包括双酚A(BPA)和邻苯二甲酸盐，也可能在疾病的发展中发挥作用。已提出的调节后者的机制包括对脂肪形成、炎症、氧化应激、类固醇信号以及肝和胰腺功能的影响。在这次竞争性更新中，我们将在护士健康研究(NHS)中检查尿BPA和邻苯二甲酸酯代谢物与T2D风险的关系。在1999至2001年间，对18,743名NHS参与者进行了第一次晨间现场尿样采集。在这些参与者中，我们将进行嵌套病例对照研究，包括850个T2D事件病例和850个匹配对照。其具体目的是：1.检验尿BPA和邻苯二甲酸盐代谢产物水平较高与T2D风险增加相关的假设，独立于糖尿病危险因素，包括饮食和生活方式。一组113名妇女的样本在3年内提供了3份晨间现场尿样。我们将使用这些重复测量来评估长期变化，并使用我们小组以前开发的方法来修正随机测量误差的观察到的相对风险估计。2.验证肝酶(胎球蛋白-A、GGT、ALT)水平升高与T2D风险增加相关的假设，该假设与肥胖、酒精摄入量和炎症标志物无关。3.研究肝酶和双酚A/邻苯二甲酸盐之间的相互作用与T2D风险的关系。我们将调查BPA和邻苯二甲酸盐与T2D风险之间的关联是否由GGT、ALT和Fetuin-A活性介导。此外，我们将测试假设，即双酚A或邻苯二甲酸盐对T2D的有害影响在那些肝功能障碍的人中更强，反映在肝酶的增加上。大量明确的预期队列，可获得关于饮食和生活方式的详细信息，结合尿样和EDC暴露的敏感措施，为识别影响T2D发展的新风险因素提供了一个独特且具有成本效益的机会。这些研究的结果可以用来激励更安全的食品和产品制造实践，为预防T2D做出贡献。 公共卫生相关性： 越来越多的证据表明，接触工业产品中广泛存在的内分泌干扰物(EDCs)，包括双酚A(BPA)和邻苯二甲酸酯，可能在糖尿病的发展中发挥作用。在这项研究中，我们将在一项大型队列研究中检验尿BPA和邻苯二甲酸盐代谢物水平较高是否与糖尿病风险增加有关。此外，我们将测试假设，即双酚A或邻苯二甲酸盐对糖尿病的有害影响在那些肝功能障碍的人中更强，反映在肝酶的增加上。这项研究的发现可以用来激励更安全的食品和产品制造实践，为预防糖尿病做出贡献。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) has become a major public health problem worldwide. Among the contributing environmental factors, changes in dietary patterns and physical activity are undoubtedly key causal factors. At the same time, there is growing evidence that exposure to endocrine disrupting chemicals (EDCs) widely existing in industrial products, including bisphenol A (BPA) and phthalates, might also play a role in the development of the disease. Proposed mechanisms mediating the latter include influences on adipogenesis, inflammation, oxidative stress, steroid-signaling, and hepatic and pancreatic function. In this competing renewal, we will examine the relationship between urinary BPA and phthalate metabolites and risk of T2D in the Nurses' Health Study (NHS). First morning spot urine samples were collected in 18,743 NHS participants between 1999 and 2001. Among these participants, we will conduct a nested case-control study including 850 incident T2D cases and 850 matched controls. The specific aims are: 1. To test the hypothesis that higher levels of urinary BPA and phthalate metabolites are associated with increased risk of T2D, independent of diabetes risk factors, including diet and lifestyle. A subsample of 113 women provided 3 morning spot urine samples over 3 years. We will use these repeated measures to assess the long-term variation and correct the observed relative risk estimates for random measurement error using methods previously developed by our group. 2. To test the hypothesis that increased levels of liver enzymes (fetuin-A, GGT, ALT) are associated with increased risk of T2D, independent of obesity, alcohol intake, and markers of inflammation. 3. To examine the interplay between liver enzymes and BPA/phthalates in relation to T2D risk. We will investigate whether the association between BPA and phthalates and T2D risk is mediated by GGT, ALT and fetuin-A activity. In addition, we will test the hypothesis that the detrimental effects of BPA or phthalates on T2D are stronger among those with liver dysfunction, as reflected by increased liver enzymes. The large well-defined prospective cohort with availability of detailed information on diet and lifestyle in combination with urine samples and sensitive measures of EDC exposure provides a unique and cost-effective opportunity to identify novel risk factors affecting the development of T2D. Findings from these studies can be used to motivate safer food and product manufacturing practices to contribute to the prevention of T2D. PUBLIC HEALTH RELEVANCE: There is growing evidence that exposure to endocrine disrupting chemicals (EDCs) widely existing in industrial products, including bisphenol A (BPA) and phthalates, may play a role in the development of diabetes. In this study, we will examine whether higher levels of urinary BPA and phthalate metabolites are associated with increased risk of diabetes in a large cohort study. In addition, we will test the hypothesis that the detrimental effects of BPA or phthalates on diabetes are stronger among those with liver dysfunction, as reflected by increased liver enzymes. Findings from this study can be used to motivate safer food and product manufacturing practices to contribute to the prevention of diabetes.