Biochemical and Genetic Markers of Type 2 Diabetes Risk

2 型糖尿病风险的生化和遗传标记

• 批准号: 8068430
• 负责人: Frank B Hu
• 金额: $ 9.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068430
• 关键词: Adverse effects; Affect; Alanine Transaminase; Alcohol consumption; Alcohols; Animals; Biochemical Genetics; Chemical Exposure; Chemicals; Chronic; Coffee; Cohort Studies; Consensus; Consumption; Coupled; Data; Development; Diabetes Mellitus; Diabetes prevention; Diet; Dietary Practices; Disease; Endocrine Disruptors; Environmental Risk Factor; Enzymes; Epidemiologic Methods; Exposure to; Fasting; Food; Gamma-glutamyl transferase; Genetic Markers; Grant; Health; Hepatic; High Pressure Liquid Chromatography; Human; Industrial Product; Inflammation; Insulin; Knowledge; Life Style; Liver; Liver Dysfunction; Measurement; Measures; Mediating; Methods; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Nurses' Health Study; Obesity; Oxidative Stress; Pancreas; Participant; Pathway interactions; Physical activity; Play; Prevention; Public Health; Relative Risks; Reporting; Risk; Risk Estimate; Risk Factors; Role; Sampling; Signal Transduction; Smoking; Spottings; Steroids; Testing; Time; Urine; Variant; Woman; adiponectin; alpha-Fetoproteins; bisphenol A; blood glucose regulation; cohort; cost; diabetes risk; enzyme activity; inflammatory marker; insulin sensitivity; interest; lifestyle factors; lipid biosynthesis; lipid metabolism; novel; phthalates; population health; prospective; public health relevance; reproductive; tandem mass spectrometry; urinary

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.

描述（由申请人提供）：2型糖尿病（T2D）已成为全球主要的公共卫生问题。在促成环境因素中，饮食模式和体育锻炼的变化无疑是关键因果因素。同时，越来越多的证据表明，在包括双酚A（BPA）和邻苯二甲酸酯在内的工业产品中，内分泌破坏化学物质（EDC）的暴露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生成，炎症，氧化应激，类固醇信号以及肝功能和胰腺功能的影响。在这种竞争的续约中，我们将研究尿BPA和邻苯二甲酸酯代谢产物与护士健康研究（NHS）中T2D风险之间的关系。在1999年至2001年之间，在18,743名NHS参与者中收集了第一个早晨的尿液样品。在这些参与者中，我们将进行一项嵌套的病例对照研究，包括850例事件T2D病例和850个匹配对照。具体目的是：1。检验以下假设：较高的尿液BPA和邻苯二甲酸酯代谢物与T2D风险增加有关，与糖尿病风险因素无关，包括饮食和生活方式。 113名妇女的子样本在3年内提供了3个早晨的尿液样本。我们将使用这些重复测量来评估长期变化并使用我们组先前开发的方法纠正随机测量误差的相对风险估计。 2。为了测试假设，即肝酶（Fetuin-A，GGT，ALT）的水平升高与T2D风险增加有关，与肥胖，酒精摄入量和炎症的标志无关。 3。检查肝酶与BPA/邻苯二甲酸盐之间的相互作用相对于T2D风险。我们将研究BPA和邻苯二甲酸酯与T2D风险之间的关联是否是由GGT，ALT和FETUIN-A活性介导的。此外，我们将检验以下假设：在肝功能障碍的患者中，BPA或邻苯二甲酸盐对T2D的有害作用更强，这是肝脏酶增加所反映的。明确定义的前瞻性队列，可提供有关饮食和生活方式的详细信息，并结合尿液样本和EDC暴露的敏感措施，为识别影响T2D发展的新型风险因素提供了独特且具有成本效益的机会。这些研究的发现可用于激励更安全的食品和产品制造实践，以预防T2D。 公共卫生相关性： 越来越多的证据表明，在包括双酚A（BPA）和邻苯二甲酸盐在内的工业产品中，内分泌破坏化学物质（EDC）的暴露可能在糖尿病的发展中起作用。在这项研究中，我们将研究一项大型队列研究中较高水平的尿液BPA和邻苯二甲酸酯代谢产物是否与糖尿病风险增加有关。此外，我们将检验以下假设：在肝功能障碍的患者中，BPA或邻苯二甲酸盐对糖尿病的有害作用更强，这是肝脏酶增加所反映的。这项研究的结果可用于激励更安全的食品和产品制造实践，以预防糖尿病。