Biochemical and Genetic Markers of Type 2 Diabetes Risk

描述（由申请人提供）：2型糖尿病（T2 D）已成为全球主要的公共卫生问题。在环境因素中，饮食模式和体育活动的变化无疑是关键的因果因素。与此同时，越来越多的证据表明，暴露于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，也可能在疾病的发展中发挥作用。提出的介导后者的机制包括对脂肪形成、炎症、氧化应激、类固醇信号传导以及肝脏和胰腺功能的影响。在这项竞争性更新中，我们将在护士健康研究（NHS）中研究尿BPA和邻苯二甲酸酯代谢物与T2 D风险之间的关系。在1999年至2001年期间，收集了18，743名NHS参与者的第一次晨尿样本。在这些参与者中，我们将进行一项巢式病例对照研究，包括850例新发T2 D病例和850例匹配对照。具体目标是：1.检验尿BPA和邻苯二甲酸酯代谢物水平较高与T2 D风险增加相关的假设，与糖尿病风险因素（包括饮食和生活方式）无关。113名女性的子样本在3年内提供了3份晨尿样本。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校正观察到的随机测量误差的相对风险估计。2.检验肝酶（胎球蛋白A、GGT、ALT）水平升高与T2 D风险升高相关的假设，与肥胖、酒精摄入和炎症标志物无关。3.检查肝酶和BPA/邻苯二甲酸酯与T2 D风险之间的相互作用。我们将研究BPA和邻苯二甲酸酯与T2 D风险之间的关联是否由GGT、ALT和胎球蛋白A活性介导。此外，我们将检验BPA或邻苯二甲酸酯对T2 D的不利影响在肝功能障碍患者中更强的假设，如肝酶增加所反映的。大型明确的前瞻性队列，结合尿液样本和EDC暴露的敏感指标，提供了关于饮食和生活方式的详细信息，为识别影响T2 D发展的新风险因素提供了独特且具有成本效益的机会。这些研究的结果可用于激励更安全的食品和产品生产实践，以促进预防T2 D。 公共卫生相关性： 越来越多的证据表明，暴露于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查尿BPA和邻苯二甲酸酯代谢物水平升高是否与糖尿病风险增加相关。此外，我们还将检验BPA或邻苯二甲酸酯对糖尿病的不利影响在肝功能障碍患者中更强的假设，如肝酶增加所反映的那样。这项研究的结果可用于激励更安全的食品和产品生产实践，以促进糖尿病的预防。

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.