Abstract
Exposure to environment-polluting chemicals (EPC) is associated with the development of diabetes. Many EPCs exert toxic effects via aryl hydrocarbon receptor (AhR) and/or mitochondrial inhibition. Here we investigated if the levels of human exposure to a mixture of EPC and/or mitochondrial inhibitors could predict the development of diabetes in a prospective study, the Korean Genome and Epidemiological Study (KoGES). We analysed AhR ligands (AhRL) and mitochondria-inhibiting substances (MIS) in serum samples (n = 1,537), collected during the 2008 Ansung KoGES survey with a 4-year-follow-up. Serum AhRL, determined by the AhR-dependent luciferase reporter assay, represents the contamination level of AhR ligand mixture in serum. Serum levels of MIS, analysed indirectly by MIS-ATP or MIS-ROS, are the serum MIS-induced mitochondria inhibiting effects on ATP content or reactive oxygen species (ROS) production in the cultured cells. Among 919 normal subjects at baseline, 7.1% developed impaired glucose tolerance (IGT) and 1.6% diabetes after 4 years. At the baseline, diabetic and IGT sera displayed higher AhRL and MIS than normal sera, which correlated with indices of insulin resistance. When the subjects were classified according to ROC cut-off values, fully adjusted relative risks of diabetes development within 4 years were 7.60 (95% CI, 4.23–13.64), 4.27 (95% CI, 2.38–7.64), and 21.11 (95% CI, 8.46–52.67) for AhRL ≥ 2.70 pM, MIS-ATP ≤ 88.1%, and both, respectively. Gender analysis revealed that male subjects with AhRL ≥ 2.70 pM or MIS-ATP ≤ 88.1% showed higher risk than female subjects. High serum levels of AhRL and/or MIS strongly predict the future development of diabetes, suggesting that the accumulation of AhR ligands and/or mitochondrial inhibitors in body may play an important role in the pathogenesis of diabetes.
Highlights
Exposure to multiple environment-polluting chemicals (EPC) is becoming increasingly important to understand the pathogenesis of metabolic disease and diabetes epidemics[1,2,3]
Our previous studies showed that serum AhR ligand (AhRL), which was linearly correlated with the toxic equivalency (TEQ) value of the tested persistent organic pollutant (POP) mixtures, was higher in Koreans with impaired glucose tolerance (IGT) and diabetes than those with normal glucose tolerance (NGT)[13], and was associated with components of metabolic syndrome and insulin resistance[15]
Human exposure to EPC mixture of aryl hydrocarbon receptor (AhR) ligands (AhRL) and mitochondria-inhibiting substances (MIS) (MIS-ATP or MIS-reactive oxygen species (ROS)) was measured using serum samples obtained from Korean Genome and Epidemiology Study (KoGES) study to see if it could be used as a predictor of the incidence of diabetes
Summary
Exposure to multiple environment-polluting chemicals (EPC) is becoming increasingly important to understand the pathogenesis of metabolic disease and diabetes epidemics[1,2,3]. Many of those with high AhRL and MIS-ROS with low MIS-ATP (possibly belong to black cluster) in the NGT or IGT group in 2008 progressed to diabetes in 2012. In logistic regression analyses for diabetes development among the 1,163 subjects that did not have diabetes at baseline (NGT [919] + IGT [244]), AhRL, MIS-ATP, and MIS-ROS had significant odds ratios of 2.28 (1.91–2.72), 1.09 (1.05–1.11), and 1.04 (1.02–1.05), respectively.
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