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.
Because of the increasing prevalence of type 2 diabetes and metabolic syndrome, the proposed research will examine the possible etiologic role of environmental chemicals that appear to be diabetogenic in experimental studies and epidemiological studies, most of which are cross-sectional. We will extend up to age 27 years our follow-up of a Faroese birth cohort with unusually wide ranges of exposures to suspected chemicals and link prenatal and postnatal exposures to glucose metabolism, metabolic flexibility, and body composition as indicators of early development of type 2 diabetes and metabolic syndrome.
|Audouze, Karine; Brunak, Soren; Grandjean, Philippe (2013) A computational approach to chemical etiologies of diabetes. Sci Rep 3:2712|