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An interaction of inorganic arsenic exposure with body weight and composition on type 2 diabetes indicators in Diversity Outbred mice


Type 2 diabetes (T2D) is a complex metabolic disorder with no cure and high morbidity. Exposure to inorganic arsenic (iAs), a ubiquitous environmental contaminant, is associated with increased T2D risk. Despite growing evidence linking iAs exposure to T2D, the factors underlying inter-individual differences in susceptibility remain unclear. This study examined the interaction between chronic iAs exposure and body composition in a cohort of 75 Diversity Outbred mice. The study design mimics that of an exposed human population where the genetic diversity of the mice provides the variation in response, in contrast to a design that includes untreated mice. Male mice were exposed to iAs in drinking water (100 ppb) for 26 weeks. Metabolic indicators used as diabetes surrogates included fasting blood glucose and plasma insulin (FBG, FPI), blood glucose and plasma insulin 15 min after glucose challenge (BG15, PI15), homeostatic model assessment for \(\beta\)-cell function and insulin resistance (HOMA-B, HOMA-IR), and insulinogenic index. Body composition was determined using magnetic resonance imaging, and the concentrations of iAs and its methylated metabolites were measured in liver and urine. Associations between cumulative iAs consumption and FPI, PI15, HOMA-B, and HOMA-IR manifested as significant interactions between iAs and body weight/composition. Arsenic speciation analyses in liver and urine suggest little variation in the mice’s ability to metabolize iAs. The observed interactions accord with current research aiming to disentangle the effects of multiple complex factors on T2D risk, highlighting the need for further research on iAs metabolism and its consequences in genetically diverse mouse strains.

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All data from this study have been deposited in the Mouse Phenome Database (


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This study was funded by the National Institute of Environmental Health Sciences grants R01ES029925 to R.C.F., F.P.M.D.V., and M.S. and R01ES028721 to M.S. and R.C.F., and by the UNC Superfund Research Program Grant P42ES031007. Additional support was provided by the UNC Institute for Environmental Health Solutions and the UNC Nutrition Obesity Research Center grant DK056350 from National Institute of Diabetes and Digestive and Kidney Diseases. J.G.X. is funded by training grant T32ES007126.

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Correspondence to Rebecca C. Fry, Miroslav Stýblo or Fernando Pardo-Manuel de Villena.

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Xenakis, J.G., Douillet, C., Bell, T.A. et al. An interaction of inorganic arsenic exposure with body weight and composition on type 2 diabetes indicators in Diversity Outbred mice. Mamm Genome (2022).

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