A nested case-control study of exposure to toxic metals, essential metals and their interaction on the risk of type 2 diabetes

项目摘要 2型糖尿病（T2 D）是我们这个时代的流行病，全球有4亿多人受到影响。识别 新的可预防的风险因素是迫切的，因为既定的风险因素并不能完全解释快速的 T2 D发病率上升。重金属在T2 D风险中的病因学作用已经引起了相当大的关注 国际吧在美国，国家毒理学计划最近建议对此进行进一步的研究， 本课题是在全面回顾环境因素与T2 D之间关系的基础上提出的。最近 将重金属与T2 D风险联系起来的数据虽然诱人，但主要来自易受影响的横断面研究。 来反转因果关系此外，很少有研究调查暴露于多种金属对T2 D的作用。 风险，因此几乎没有证据表明多种金属的独立和联合影响。另外， 必需金属被推荐作为有益的补充剂以减轻有毒金属对糖尿病的影响， 但是对抗有毒金属效应所需的必需金属的最佳水平还没有很好地理解。 因此，迫切需要大规模和高质量的前瞻性研究，以进一步调查重金属作为风险 T2 D的因素，以及必需金属的可能缓解作用。我们的研究团队，在NIH的支持下， 建立了基于人群的前瞻性金昌金属队列研究。这项正在进行的研究包括- 2011-13年对42，122名参与者进行了访谈，2014-16年进行了第一次随访， 访问始于2017年。在基线和后续访视时，受试者完成1）体格检查; 2） 临床实验室测试; 3）亲自面谈;和4）血液和尿液样本的收集。广泛试点 已经在这一人群中开展了与金属暴露相关的T2 D风险研究。与这些 从这个庞大的前瞻性人群队列中获得的广泛数据，我们现在处于一个独特的位置 进行巢式病例对照研究，全面调查重金属暴露是否增加T2 D 风险将从2，200例T2 D事件中测量选定重金属的基线血清和尿液水平 病例及其年龄性别匹配的2，200名对照，当时无T2 D和前驱糖尿病 当相应的病例被诊断为T2 D时。本研究的具体目标包括：1）确定 基线有毒金属水平是否与T2 D风险独立或联合相关; 2）确定是否 基本金属的基线水平不平衡（缺乏或过量）是独立或共同的 与T2 D风险相关;以及3）确定是否可以通过以下方式减轻有毒金属对糖尿病的影响： 必需金属，如果是的话，必需金属的最佳身体水平可以降低T2 D风险， 金属.金昌金属队列研究是唯一一项专门设计的大型前瞻性研究， 调查金属暴露对心脏代谢疾病的影响。研究结果将阐明 金属暴露作为T2 D的一个可改变的风险因素，其水平与美国和中国相关，并将有助于 制定干预策略以改善人群的心脏代谢结果。

PROJECT SUMMARY Type 2 diabetes (T2D) is an epidemic of our time afflicting more than 400 million people globally. Identification of novel preventable risk factors is urgent because established risk factors do not fully account for the rapid increase in T2D rates. The etiologic role of heavy metals in T2D risk has gained considerable attention worldwide. In the U.S., the National Toxicological Program recently recommended further research on this topic following a comprehensively review of the relationship between environmental factors and T2D. Recent data linking heavy metals to T2D risk, while tantalizing, come mainly from cross-sectional studies susceptible to reverse causation. Moreover, few studies have investigated the role of exposures to multiple metals on T2D risk, such that there is little evidence of the independent and joint effects of multiple metals. Separately, essential metals are recommended as beneficial supplements to mitigate the diabetic effects of toxic metals, but the optimal levels of essential metals required to counteract the toxic metal effects are not well understood. Thus, large and high-quality prospective studies are urgently needed to further investigate heavy metals as risk factors for T2D, and the possible mitigating role of essential metals. Our research team, with support from NIH, has built the population-based prospective Jinchang Metal Cohort Study. This on-going study includes in- person interviews of 42,122 participants in 2011-13, a first follow-up visit in 2014-16, and a second follow-up visit started in 2017. At the baseline and subsequent visits, subjects completed 1) physical examinations; 2) clinical laboratory tests; 3) in-person interviews; and 4) collections of blood and urine samples. Extensive pilot work on T2D risk associated with metal exposure has already been conducted in this population. With such extensive data available from this large prospective population-based cohort, we are now in a unique position to conduct a nested case-control study to comprehensively investigate if heavy metal exposures increase T2D risk. Baseline serum and urine levels of selected heavy metals will be measured from 2,200 incident T2D cases and their individually age-sex-matched 2,200 controls who were T2D- and prediabetes-free at the time when the corresponding cases were diagnosed with T2D. The study specific aims include: 1) Determine whether baseline toxic metal levels are independently or jointly associated with T2D risk; 2) Determine whether imbalanced baseline levels (deficiency or overexposure) of essential metals are independently or jointly associated with T2D risk; and 3) Determine whether diabetic effects of toxic metals can be mitigated by essential metals and, if so, the optimal body levels of essential metals that could reduce T2D risk from toxic metals. The Jinchang Metal Cohort Study is the only large prospectively study specifically designed to investigate the impact of metal exposures on cardiometabolic diseases. The study results will clarify the role of metals exposure as a modifiable risk factor for T2D at levels relevant to both the US and China, and will help to establish intervention strategies to improve cardiometabolic outcomes in human populations.