Glucose Metabolism in Adults Prenatally Exposed to Diabetogenic Pollutants

描述(由申请人提供)：为了评估环境化学品在2型糖尿病病因学中的作用，我们将研究1986-1987年出生在法罗群岛的1022名受试者的出生队列，在法罗群岛，已有异常广泛的环境化学品暴露记录。队列成员现在将被邀请在27岁时进行临床检查，包括口服葡萄糖耐量试验，以评估葡萄糖代谢、肝脏胰岛素敏感性、代谢灵活性和代谢综合征的临床迹象。有关化学物质暴露、体重和其他协变量的数据是在出生时以及在7岁、14岁和22岁的先前临床检查中获得的。现有的暴露数据包括甲基汞、多氯联苯和DDE，现在将通过分析脐带血和出生后样本中的全氟化合物来补充这些数据。所有这些物质都被怀疑是导致糖尿病的，可能是通过葡萄糖代谢的发育编程。为了建立这些暴露的表观遗传学特征，我们将使用从队列成员的全血中提取的DNA进行全基因组表观遗传学图谱绘制。我们将研究CpG岛和海岸，岛外的CpG，在人类癌症干细胞中发现的非CpG甲基化位点，miRNA启动子区域和通过GWAS确定的疾病相关区域。总的和特定部位的DNA甲基化将与出生时和出生后暴露于环境化学物质，以及葡萄糖代谢和代谢灵活性的临床指标有关。我们将确定暴露在污染物中是否与2型糖尿病相关的亚临床变化有关，这些变化是否由DNA甲基化介导，以及它们是否受到体重变化的影响。因此，这些结果将有助于我们理解环境化学物质的发育编程效应，如DNA甲基化所示，以及它们在2型糖尿病发病机制中的作用。

DESCRIPTION (provided by applicant): To assess the role of environmental chemicals in the etiology of type 2 diabetes development, we will examine a birth cohort of 1022 subjects born in 1986-1987 at the Faroe Islands, where an unusually wide range of exposures to environmental chemicals has been documented. Cohort members will now be invited at age 27 years for clinical examination, including oral glucose tolerance test, to assess glucose metabolism, hepatic insulin sensitivity, metabolic flexibility, and clinical signs of metabolic syndrome development. Data on chemical exposures, body weight and other covariates were obtained at birth and at previous clinical examinations at ages 7, 14, and 22 years. Existing exposure data include methylmercury, PCB, and DDE, and they will now be complemented by analyses of perfluorinated compounds in cord blood and postnatal samples. All of these substances are suspected of being diabetogenic, possibly through developmental programming of glucose metabolism. To establish an epigenetic signature for these exposures we will conduct a genome-wide epigenetic mapping using DNA extracted from whole blood from cohort members. We will examine CpG islands and shores, CpG outside islands, non-CpG methylated sites identified in human cancer stem cells, miRNA promoter regions and disease-associated regions identified through GWAS. The total and site-specific DNA methylations will be linked to exposures to environmental chemicals at birth and postnatally and to clinical indicators of glucose metabolism and metabolic flexibility. We will determine if exposures to the pollutants are associated with subclinical changes related to type 2 diabetes, whether these changes are mediated by DNA methylation, and whether they are affected by changes in body weight. These results will therefore contribute to our understanding of developmental programming effects of environmental chemicals, as indicated by DNA methylation, and their role in type 2 diabetes pathogenesis.