Serum biomarkers from cell-based assays for AhRL and MIS strongly predicted the future development of diabetes in a large community-based prospective study in Korea

Hong Kyu Lee, Wook Ha Park, Young Cheol Kang, Sora Kang, Suyeol Im, Sol Park, Jin Taek Kim, Minhyeok Lee, Junhee Seok, Man Suk Oh, Hoon Sung Choi, Youngmi Kim Pak

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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.

Original languageEnglish
Article number6339
JournalScientific reports
Issue number1
Publication statusPublished - 2020 Dec 1

Bibliographical note

Funding Information:
Authors thank Dr. Nam H. Cho (Ajou University College of Medicine, Suwon, Korea), the principal investigator of the Ansung cohort of the KoGES study, for providing the serum samples for analysis. This research was supported by the Korean Health Technology R&D Project (HI14C2700) through the Korea Health Industry Development Institute (KHIDI) and by the Basic Science Research Program (2018R1A6A1A03025124) through the National Research Foundation of Korea (NRF) funded by the Korean government (to YKP). The funding source had no role in the collection of data or in the decision to submit the manuscript for publication.

Publisher Copyright:
© 2020, The Author(s).

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