Pollutant-related diabetes in the Nurses' Health Study II

描述（由申请人提供）：过去二十年来，肥胖患病率急剧上升，2型糖尿病（T2 D）患病率出现平行飞跃。虽然这两种情况都有明确的遗传决定因素，但有确凿的证据证明，这两种情况也可以通过对可改变的风险因素进行生活方式和饮食干预来预防。与此同时，现在有证据表明，一些环境污染物，特别是持久性有机污染物（POP），也可能导致肥胖和T2 D的风险增加。从动物研究中积累的数据表明，一些持久性有机污染物，如多氯联苯（PCB）和p，p '-二氯二苯乙炔（p，p'-DDE），与体重增加和胰岛素抵抗有关。该领域的人体研究很少，大多数现有研究采用横断面设计，无法确定暴露与结局之间的因果关系或时间轴。此外，我们从流行病学观察和系统生物学模拟的初步数据表明，六氯苯（HCB），持久性有机污染物主要被认为是仅仅是一个长期的总持久性有机污染物暴露的标志物，可能与糖尿病的风险有因果关系。此外，进入环境的新持久性有机污染物，如全氟化合物（PFCs），在其对肥胖和T2 D的影响方面很少受到关注。为了缩小这方面的科学差距差距，我们的目的是评估多氯联苯、DDE、六氯苯和全氟化碳与1）随后的体重增加，2）新诊断的2型糖尿病的发展，3）胰岛素抵抗/葡萄糖代谢异常的标志物，包括空腹胰岛素、血红蛋白-A1 c和总脂联素的关系，这些都是在参加一个充分表征的前瞻性队列的年轻和中年妇女中进行的：护士健康研究（NHS）II。我们还将探讨生活方式和饮食的持久性有机污染物的决定因素，以及持久性有机污染物和其他风险因素之间的潜在相互作用对肥胖和糖尿病在这个队列。NHS II为我们提供了一个独特而理想的机会来研究目标。自1991年研究基线以来，每2至4年重复收集一次关于生活方式、饮食、病史的极其丰富的数据。此外，在1994-1995年，约30，000名NHS II参与者提供了血液样本，他们构成了当前调查的研究人群。在这些参与者中，我们将进行一项2型糖尿病的巢式病例对照研究，预计将包括1，050例45岁或以上的2型糖尿病病例和相同数量的匹配对照。严格的质量控制方案和流程已经并将继续应用于NHS II队列，以确保最高质量的研究数据。此外，我们还组建了一支优秀的研究团队，由环境健康、营养等多学科领域的知名研究人员组成， 生物统计学将确保项目的成功实施。总之，目前的研究将提供新的和关键的证据，不仅将大大扩大我们对持久性有机污染物致糖尿病影响的认识，而且还将为公共卫生政策制定提供信息，以帮助预防肥胖和2型糖尿病。

DESCRIPTION (provided by applicant): The past two decades have witnessed a dramatic rise of obesity prevalence and a parallel leap of type 2 diabetes (T2D) prevalence. Although there are clear genetic determinants for both conditions, solid evidence proves that both conditions can also be prevented through lifestyle and dietary intervention on modifiable risk factors. Meanwhile, evidence now suggests that some environmental pollutants, especially the persistent organic pollutants (POPs), may also lead to increased risk of both obesity and T2D. Accumulating data from animal studies have linked a few POPs, such as polychlorinated biphenyls (PCBs) and p,p'- dichlorodiphenyldichloethylene (p,p'-DDE), with weight gain and insulin resistance. Human studies are rare in this field and most of the existing studies used a cross-sectional design, which cannot establish causal relationship or timeline between exposures and outcomes. Moreover, our preliminary data from epidemiologic observation and system biology simulation have suggested that hexachlorobenzene (HCB), a POP primarily deemed to be merely a marker of long-term total POP exposure, may be causally associated with risk of diabetes. In addition, new POPs that have entered the environment, such as the perfluorinated compounds (PFCs), have received little attention with respect to their effects on obesity and T2D. To narrow the gap in science in this regard, we aim to evaluate PCBs, DDE, HCB, and PFCs in relation to 1) subsequent weight gain, 2) development of newly diagnosed type 2 diabetes, and 3) markers of insulin resistance/glucose metabolism abnormalities, including fasting insulin, hemoglobin-A1c, and total adiponectin, in young and middle-aged women who participated in a well-characterized prospective cohort: The Nurses' Health Study (NHS) II. We will also explore lifestyle and dietary determinants of the POPs and potential interactions between POPs and other risk factors on obesity and diabetes in this cohort. The NHS II provides a unique and ideal opportunity for us to examine the aims. Since the study baseline in 1991, extremely rich data on lifestyle, diet, medical history have been repeatedly collected every 2 to 4 years. Moreover, in 1994-1995, blood samples were provided by approximately 30,000 NHS II participants, who comprised the study population for the current investigation. Among these participants, we will conduct a nested case-control study of type 2 diabetes, which is expected to include 1,050 incident type 2 diabetes cases at age 45 or older and the equal number of matched controls. Rigorous quality control protocol and processes have been and will be continuously applied in the NHS II cohort to ensure the highest quality of research data. In addition, we have assembled an outstanding research team comprised of well-established researchers in multi-disciplinary fields including environmental health, nutrition, and biostatistics that will ensure the successful implementation of the project. In summary, the current investigation will provide novel and critical evidence that will not only greatly expand ou knowledge of the diabetogenic effects of POPs, but also inform public health policy-making to help prevent obesity and T2D.