Association of Persistent Organic Pollutants with Incident Diabetes in India

 描述（由申请人提供）：全世界3.82亿糖尿病成年人中有近20%生活在印度。在美国，亚裔印第安人的糖尿病患病率几乎是非西班牙裔白人的两倍。虽然对不健康饮食和缺乏身体活动等风险因素对糖尿病流行的影响进行了评估，但对持久性有机污染物等不太传统的接触仍未进行探讨。主要在高收入国家进行的流行病学研究表明，持久性有机污染物，特别是多氯联苯和有机氯农药，与糖尿病有关。在印度进行的为数不多的监测研究并未报告过去30年来人体血清中持久性有机污染物水平的下降;因此，印度被视为持久性有机污染物接触的“热点”。此外，亚洲印度人的糖尿病表型与其他种族不同：糖尿病发生在较低的BMI，β细胞功能下降在亚洲印度人胰岛素抵抗的早期阶段。这对持久性有机污染物的影响具有特别重要的意义，因为动物研究表明，这些污染物通过对β细胞的作用影响糖尿病风险。 CARRS（南亚心脏代谢风险降低中心）研究是埃默里大学、印度公共卫生基金会、马德拉斯糖尿病研究基金会和全印度医学科学研究所之间正在进行的合作，该研究跟踪了2010-2011年间从印度两个城市（德里和钦奈）招募的12，271名成年人（≥ 20岁）的代表性队列。参与者提供了用于糖尿病确定和生物库的血液样本。拟议的R21将在贾瓦哈拉尔·尼赫鲁大学（JNU）建立一个CDC标准化的实验室设施，用于测量人体血清中的持久性有机污染物，其中CARRS样本可以在一项嵌套的前瞻性病例对照研究中进行分析，该研究包括n=301例新发糖尿病病例和n=602例年龄和性别匹配的血糖正常对照。具体目标是：1）交叉验证Emory和JNU检测人血清（n=45例病例，n =45例对照）中4种最具生物相关性的PCBs（118，138，153，180）和7种OC农药（p，p '-DDT，o，p'-DDT，p，p '-DDE，o，p'-DDE，α-HCH，TNC，HCB）的气相色谱-质谱法。 2)采用巢式病例对照研究设计，在印度城市成人（n=301例，n=602例对照）的前瞻性队列中，估计这4种多氯联苯和7种有机氯农药与糖尿病事件的关联。然后我们将探索：2a）通过向心性肥胖（腰围）的作用修饰和2b）通过胰岛素抵抗（HOMA-IR）和β细胞功能（HOMA-B）的介导。 完成拟议的R21将在印度建立实验室能力，并使美国和印度的糖尿病和环境污染物专家小组能够对持久性有机污染物与糖尿病发病之间的关系进行最大规模的前瞻性分析，从而促进全世界对这些普遍接触在糖尿病流行中的作用的理解。

 DESCRIPTION (provided by applicant): Nearly 20% of the 382 million adults with diabetes in the world live in India. Within the United States, the prevalence of diabetes among Asian Indians is nearly twice that of non-Hispanic whites. While the contribution of risk factors such as unhealthy diets and physical inactivity to the diabetes epidemic has been evaluated, less traditional exposures such as persistent organic pollutants (POPs) remain unexplored. Epidemiological studies conducted largely in high-income countries have suggested an association of POPs, particularly polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides, with diabetes. The few surveillance studies available in India have not reported a decline in POPs levels in human serum over the past 30 years; thus, India is considered a "hot spot" for POPs exposure. Further, the phenotype of diabetes in Asian Indians differs from that of other ethnicities: diabetes occurs at a lower BMI and beta cell function declines at an earlier stage relative to insulin resistance in Asian Indians. This is of particular interest in considerin the effects of POPs because animal studies suggest that these pollutants affect diabetes risk via action on beta cells. The CARRS (Centre for cArdiometabolic Risk Reduction in South-Asia) Study, an ongoing collaboration between Emory University, the Public Health Foundation of India, the Madras Diabetes Research Foundation, and the All India Institute of Medical Sciences, follows a representative cohort of 12,271 adults (= 20 years old) enrolled between 2010-2011 from two urban sites in India (Delhi and Chennai). Participants provided blood samples for diabetes ascertainment and biobanking. The proposed R21 will establish a CDC-standardized laboratory facility at Jawaharlal Nehru University (JNU) for the measurement of POPs in human serum, where CARRS samples can be analyzed in a nested, prospective case-control study of n=301 incident diabetes cases and n=602 age- and sex-matched normoglycemic controls. The specific aims are: 1) To cross-validate gas chromatography-mass spectrometry methods for measuring the 4 most biologically relevant PCBs (118, 138, 153, 180) and 7 OC pesticides (p,p'-DDT, o,p'-DDT, p,p'-DDE, o,p'-DDE, ß-HCH, TNC, HCB) in human serum (n=45 cases, n=45 controls) between Emory and JNU. 2) To estimate the association of these 4 PCBs and 7 OC pesticides with incident diabetes using a nested case-control study design in a prospective cohort of adults (n=301 cases, n=602 controls) from urban India. We will then explore: 2a) effect modification by central obesity (waist circumference) and 2b) mediation by insulin resistance (HOMA-IR) and beta cell function (HOMA-B). Completion of the proposed R21 will build laboratory capacity in India and uniquely position a team of diabetes and environmental pollutant experts in the United States and India to conduct the largest prospective analysis of the association between POPs and incident diabetes, furthering the world's understanding of the role of these pervasive exposures in the diabetes epidemic.