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Exposure to inorganic arsenic and its methylated metabolites alters metabolomics profiles in INS-1 832/13 insulinoma cells and isolated pancreatic islets

  • Inorganic Compounds
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Abstract

Inorganic arsenic (iAs) is an environmental diabetogen, but mechanisms underlying its diabetogenic effects are poorly understood. Exposures to arsenite (iAsIII) and its methylated metabolites, methylarsonite (MAsIII) and dimethylarsinite (DMAsIII), have been shown to inhibit glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells and isolated pancreatic islets. GSIS is regulated by complex mechanisms. Increase in ATP production through metabolism of glucose and other substrates is the ultimate trigger for GSIS in β-cells. In the present study, we used metabolomics to identify metabolites and pathways perturbed in cultured INS-1 832/13 rat insulinoma cells and isolated murine pancreatic islets by exposures to iAsIII, MAsIII and DMAsIII. We found that the exposures perturbed multiple metabolites, which were enriched primarily in the pathways of amino acid, carbohydrate, phospholipid and carnitine metabolism. However, the effects of arsenicals in INS-1 832/13 cells differed from those in the islets and were exposure specific with very few overlaps between the three arsenicals. In INS-1 832/13 cells, all three arsenicals decreased succinate, a metabolite of Krebs cycle, which provides substrates for ATP synthesis in mitochondria. Acetylcarnitine was decreased consistently by exposures to arsenicals in both the cells and the islets. Acetylcarnitine is usually found in equilibrium with acetyl-CoA, which is the central metabolite in the catabolism of macronutrients and the key substrate for Krebs cycle. It is also thought to play an antioxidant function in mitochondria. Thus, while each of the three trivalent arsenicals perturbed specific metabolic pathways, which may or may not be associated with GSIS, all three arsenicals appeared to impair mechanisms that support ATP production or antioxidant defense in mitochondria. These results suggest that impaired ATP production and/or mitochondrial dysfunction caused by oxidative stress may be the mechanisms underlying the inhibition of GSIS in β-cells exposed to trivalent arsenicals.

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Acknowledgements

This study was supported by the NIEHS grant R01ES022697 (PI, Styblo), the UNC Nutrition Obesity Research Center grant DK056350 from NIDDK (PI, Zeisel), and the NIH Common Fund Grant 1U24DK097193 (PI, Sumner). All raw and normalized analytical data and associated metadata have been uploaded in the publicly accessible NIH Common Fund Metabolomics Data Repository (doi: 0.21228/M8PH4S; Project ID: PR000851). We thank Dr. Wimal Pathmasiri for assistance with the pathway analysis.

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  1. Madelyn Huang

    Present address: National Toxicology Program, National Institute of Environmental Health Science, Research Triangle Park, NC, USA

Authors and Affiliations

  1. Department of Nutrition, Nutrition Research Institute, CB# 74612, University of North Carolina at Chapel Hill School of Public Health, Chapel Hill, NC, 27599-7461, USA

    Yuan-Yuan Li & Susan Jenkins Sumner

  2. Department of Nutrition, CB# 74612, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, 27599-7461, USA

    Yuan-Yuan Li, Christelle Douillet, Susan Jenkins Sumner & Miroslav Styblo

  3. Curriculum in Toxicology and Environmental Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA

    Madelyn Huang & Miroslav Styblo

  4. Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA

    Rowan Beck

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Li, YY., Douillet, C., Huang, M. et al. Exposure to inorganic arsenic and its methylated metabolites alters metabolomics profiles in INS-1 832/13 insulinoma cells and isolated pancreatic islets. Arch Toxicol 94, 1955–1972 (2020). https://doi.org/10.1007/s00204-020-02729-y

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