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Antioxidant enzyme activity and mRNA expression in the islets of Langerhans from the BB/S rat model of type 1 diabetes and an insulin-producing cell line

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Abstract

It has been proposed that low activities of antioxidant enzymes in pancreatic beta cells may increase their susceptibility to autoimmune attack. We have therefore used the spontaneously diabetic BB/S rat model of type 1 diabetes to compare islet catalase and superoxide dismutase activities in diabetes-prone and diabetes-resistant animals. In parallel studies, we employed the RINm5F beta cell line as a model system (previously validated) to investigate whether regulation of antioxidant enzyme activity by inflammatory mediators (cytokines, nitric oxide) occurs at the gene or protein expression level. Diabetes-prone rat islets had high insulin content at the age used (58–65 days) but showed increased amounts of DNA damage when subjected to cytokine or hydrogen peroxide treatments. There was clear evidence of oxidative damage in freshly isolated rat islets from diabetes-prone animals and significantly lower catalase and superoxide dismutase activities than in islets from age-matched diabetes-resistant BB/S and control Wistar rats. The mRNA expression of antioxidant enzymes in islets from diabetes-prone and diabetes-resistant BB/S rats and in RINm5F cells, treated with a combination of cytokines or a nitric oxide donor, DETA-NO, was analysed semi-quantitatively by real time PCR. The mRNA expression of catalase was lower, whereas MnSOD expression was higher, in diabetes-prone compared to diabetes-resistant BB/S rat islets, suggesting regulation at the level of gene expression as well as of the activities of these enzymes in diabetes. The protein expression of catalase, CuZnSOD and MnSOD was assessed by Western blotting and found to be unchanged in DETA-NO treated cells. Protein expression of MnSOD was increased by cytokines in RINm5F cells whereas the expression of CuZnSOD was slightly decreased and the level of catalase protein was unchanged. We conclude that there are some changes, mostly upregulation, in protein expression but no decreases in the mRNA expression of catalase, CuZnSOD or MnSOD enzymes in beta cells treated with either cytokines or DETA-NO. The lower antioxidant enzyme activities observed in islets from diabetes-prone BB/S rats could be a factor in the development of disease and in susceptibility to DNA damage in vitro and could reflect islet alterations prior to immune attack or inherent differences in the islets of diabetes-prone animals, but are not likely to result from cytokine or nitric oxide exposure in vivo at that stage.

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Acknowledgements

Supported in part by the Concerted Action IREN in the BIOMED 2 programme of the European Union. We thank Mrs Jasmine Barley for her skilful management of the BB/S rat colony, Professor M.H.L.Green for advice on the comet assay and Dr Stephan Lortz and colleagues, Hannover Medical School, for advice on antibodies. The work formed part of the PhD of Louise Sigfrid, funded by the University of Brighton. A.L.R.H. was in receipt of a PhD studentship from the Consejo Nacional en Ciencia y Tecnologia of Mexico. The financial support of the Wellcome Trust (A.J.B., J.M.C.) is gratefully acknowledged.

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  1. Louise A. Sigfrid

    Present address: Biology and Environmental Science, University of Sussex, John Maynard Smith Building, Brighton , East Sussex, BN1 9QG, UK

  2. Alma L. Rosales Hernandez

    Present address: London Health Sciences Centre, MOTS, London , Ontario, N6A 5A5, Canada

Authors and Affiliations

  1. Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Brighton , BN2 4GJ, UK

    Louise A. Sigfrid, James M. Cunningham, Neil Beeharry, Alma L. Rosales Hernandez, Adrian J. Bone & Irene C. Green

  2. Department of Medical Cell Biology, University of Uppsala, Box 571, 751-23 , Uppsala, Sweden

    L. A. Håkan Borg & Carina Carlsson

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Sigfrid, L.A., Cunningham, J.M., Beeharry, N. et al. Antioxidant enzyme activity and mRNA expression in the islets of Langerhans from the BB/S rat model of type 1 diabetes and an insulin-producing cell line. J Mol Med 82, 325–335 (2004). https://doi.org/10.1007/s00109-004-0533-4

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