The role of exposure to bioaccumulative organochlorine compounds on the occurrenc

描述(申请人提供)：肥胖症和2型糖尿病的患病率正在以惊人的速度增长，这给美国的医疗保健系统带来了越来越大的负担。2型糖尿病占所有确诊糖尿病病例的90%至95%，其特征是发生胰岛素抵抗和随后的高血糖。直到最近，环境因素对2型糖尿病的影响还没有被推测出来。然而，对1999年至2001年国家健康和营养检查调查(NHANES)收集的数据进行的回顾分析最近的研究表明，血清中某些持久性有机污染物的高浓度，包括有机氯化合物DDE和氧氯丹，与胰岛素抵抗和糖尿病患病率的增加显著相关。目前的初步数据表明，暴露于DDE改变了脂肪的生成，促进了成熟脂肪细胞释放IL-6和瘦素，并阻止了胰岛素刺激的葡萄糖转运蛋白4在骨骼肌肌小管中的转位。因此，下面的建议试图确定暴露于有机氯化合物DDE和氧氯丹是否通过改变脂肪细胞成熟和诱导脂肪组织和骨骼肌中的胰岛素抵抗而促进胰岛素抵抗和2型糖尿病的发生。为了研究DDE导致脂肪细胞成熟度下降的分子机制，NIH3T3-L1细胞在分化为成熟脂肪细胞之前和过程中暴露于DDE，并将评估成脂转录因子的表达和DNA结合。成年NIH3T3-L1脂肪细胞和L6大鼠骨骼肌肌小管可分别作为脂肪组织和骨骼肌细胞的体外细胞培养模型。为了确定暴露于DDE是否会促进整个动物中2型糖尿病的发生，将采用高脂肪喂养的2型糖尿病动物模型。雄性C57BL/6J小鼠在食用正常或高脂肪饲料之前和期间每周暴露于DDE，为期16周。体重增加和胰岛素抵抗将在饮食方案的整个过程中进行监测，以确定暴露于DDE是否会促进高胰岛素血症和高血糖的发生。综上所述，目前的建议试图从经验上确定，暴露于DDE或氧氯丹这两种普遍存在的生物累积性环境污染物是否会促进2型糖尿病的发生。鉴于胰岛素抵抗的起源仍然是一个谜，这一研究路线特别重要。 公共卫生相关性：目前的提案旨在研究接触绝大多数美国人血清中存在的生物累积性有机氯化合物对胰岛素抵抗和2型糖尿病发展的影响。这项研究将利用脂肪组织和骨骼肌的细胞培养模型以及2型糖尿病的动物模型来确定暴露在这些持久性化合物中是否会促进胰岛素抵抗的形成。如果是这样的话，本研究将提供这些化合物促进这种疾病的机制，并将某些有机氯化合物的暴露确定为发展为2型糖尿病的风险因素。

DESCRIPTION (provided by applicant): The prevalence of obesity and type 2 diabetes is increasing at alarming rate and represents a growing burden on the health care system of the United States. Type 2 diabetes accounts for 90 to 95% of all diagnosed cases of diabetes mellitus and is characterized by the occurrence of insulin resistance and subsequent hyperglycemia. Until recently, an environmental mediator of type 2 diabetes had not been postulated. However, recent studies from retrospective analysis of data gathered by the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2001 have suggested that high serum concentrations of certain persistent organic pollutants, including the organochlorine compounds DDE and oxychlordane, are significantly correlated with increased prevalence of insulin resistance and diabetes. The current preliminary data suggest that exposure to DDE alters adipogenesis, promotes the release of both IL-6 and leptin from mature adipocytes, and prevents insulin-stimulated glucose transporter 4 translocation in skeletal muscle myotubules. Thus the following proposal seeks to determine if exposure to the organochlorine compounds DDE and oxychlordane promotes the occurrence of insulin resistance and type 2 diabetes through altering adipocyte maturation and inducing insulin resistance in the adipose tissue and skeletal muscle. To examine the molecular mechanisms involved in DDE-mediated decreases in adipocyte maturation, NIH3T3-L1 cells will be exposed to DDE prior to and during differentiation into mature adipocytes and the expression and DNA binding of adipogenic transcription factors will be assessed. Insulin stimulated glucose uptake following exposure to DDE or oxychlordane in mature NIH3T3-L1 adipocytes and L6 rat skeletal muscle myotubules will be used as in vitro cell culture models for the adipose tissue and skeletal muscle, respectively. In order to determine if exposure to DDE promotes the occurrence of type 2 diabetes in the whole animal, a high fat fed animal model of type 2 diabetes will be employed. Male C57BL/6J mice will be exposed to DDE weekly prior to and during consumption of either a normal or high fat diet for 16 weeks. Weight gain and insulin resistance will be monitored over the course of the dietary regimen to determine if exposure to DDE promotes the occurrence of hyperinsulinemia and hyperglycemia. Taken together, the current proposal seeks to empirically determine whether exposure to either DDE or oxychlordane, two prevalent bioaccumulative environmental contaminants, promotes the occurrence of type 2 diabetes. This line of investigation is of particular importance given that the origins of insulin resistance remain an enigma. PUBLIC HEALTH RELEVANCE: The presently proposal seeks to examine the effect of exposure to bioaccumulative organochlorine compounds that are present in the serum of a vast majority of the United States population on the development of insulin resistance and type 2 diabetes. This research will utilize cell culture models of adipose tissue and skeletal muscle as well as an animal model of type 2 diabetes to determine if exposure to these persistent compounds promotes the formation of insulin resistance. If so, the present study will provide mechanisms through which these compounds promote this disease and will establish exposure to certain organochlorine compounds as a risk factor for the development of type 2 diabetes.