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

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.Exposure to multiple environment-polluting chemicals (EPC) is becoming increasingly important to understand the pathogenesis of metabolic disease and diabetes epidemics 1-3 . Many epidemiological studies have shown that high serum concentrations of EPCs are strongly associated with obesity 4 , diabetes 5 , and metabolic syndrome 6 . Many endocrine-disrupting chemicals (EDCs) 7,8 and metabolism-disrupting chemicals (MDCs) 2 are listed as causes of obesity and diabetes, and thus referred to as obesogens and diabetogens. However, establishing the cause-effect relationship between exposure to these chemicals and development of obesity or diabetes in humans have been inconsistent 9 . Among the many reasons behind this, the limitation of the methods estimating the exposure level to EPCs seems to be the most important 10,11 . Humans are exposed to an immense variety of

Aryl-hydrocarbon receptor binding and the incidence of type 2 diabetes: the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

“…This fact, coupled with the small size of our sample, limits the strength of our overall findings. Nonetheless, being prospective in nature and with findings similar to those recently reported in a Korean cohort [11], our study presents important evidence to support a causal role of these pollutants in the current diabetes pandemic.…”

“…Following this reasoning, the presence of POPs such as dioxins, not present during the evolution of these cellular mechanisms, may produce a pathological disruption of metabolism involving both insulin resistance and beta cell decline, apparently partially mediated by the AhR and at least partially the result of mitochondrial dysfunction. Our data, together with others [5,11,30], who have used the same cell-based assays here employed provide epidemiologic evidence produced in free-living populations which validates previous basic science and clinical research on the role of mitochondrial dysfunction in the pathophysiology of diabetes [5,7,25,26,29,30], especially in the presence of greater AhR activation, thus strengthening the contention that POPs cause diabetes and providing a causal pathway for their action.…”

“…Serum-induced AhR ligand-mediated luciferase activity, normalized to Renilla luciferase activity, referred to as AhRL, was quantified as fold induction (FI), compared to the activity induced in the 10% charcoal-stripped human serum (CSS)-treated cells, set as 1. When the fold induction of AhRL is converted to its TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) equivalent using the equation of the standard curve AhRL (FI) = 0.5279 x TCDD (pM) + 1.261 (r 2 = 0.9692, p < 0.0001) [11], the median value of 2.04 FI is equivalent to 1.48pM of TCDD.…”

“…In parallel with the AhRL assay, we also applied a similar cell-based assay to indirectly detect the presence in participant serum samples of mitochondrial inhibiting substances (MIS) by measuring intracellular ATP content in serumincubated cultured cells (MIS-ATP) [10]. Both AhRL and MIS-ATP, so measured, have recently been shown to be highly predictive of future diabetes [11].…”

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“…Interestingly, a meta-analysis showed that the antihyperglycemic drug metformin, which also displays antiinflammatory properties, has benefits in both prevention and treatment outcomes of TB patients with diabetes (Cameron et al, 2016;Zhang and He, 2020). Paradoxically, serum AhR ligand activity was higher in subjects with Type II diabetes, correlated with parameters of insulin resistance, and was a risk factor for diabetic nephropathy (Kim et al, 2013;Roh et al, 2015;Lee et al, 2020). The authors attributed AhR ligand activity to persistent organic pollutants such as tetrachlorodibenzo-para-dioxin, a dioxin with the highest known binding affinity to AhR (Mandal, 2005), although a causal relationship was not established.…”