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Inosine Protects Against the Development of Diabetes in Multiple-Low-Dose Streptozotocin and Nonobese Diabetic Mouse Models of Type 1 Diabetes

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Abstract

Inosine, a naturally occurring purine, was long considered to be an inactive metabolite of adenosine. However, recently inosine has been shown to be an immunomodulator and anti-inflammatory agent. The aim of this study was to determine whether inosine influences anti-inflammatory effects and affects the development of type 1 diabetes in murine models. Type 1 diabetes was induced either chemically by streptozotocin or genetically using the nonobese diabetic mouse (NOD) model. Mice were treated with inosine (100 or 200 mg kg−1d−1) and diabetes incidence was monitored. The effect of inosine on pancreas immune cell infiltration, oxidative stress, and cytokine profile also was determined. For the transplantation model islets were placed under the renal capsule of NOD mice and inosine (200 mg kg−1d−1) treatment started the day of islet transplantation. Graft rejection was diagnosed by return of hyperglycemia accompanied by glucosuria and ketonuria. Inosine reduced the incidence of diabetes in both streptozotocin-induced diabetes and spontaneous diabetes in NOD mice. Inosine decreased pancreatic leukocyte infiltration and oxidative stress in addition to switching the cytokine profile from a Th1 to a Th2 profile. Inosine prolonged pancreatic islet graft survival, increased the number of surviving β cells, and reduced the number of infiltrating leukocytes. Inosine protects against both the development of diabetes and against the rejection of transplanted islets. The purine exerts anti-inflammatory effects in the pancreas, which is its likely mode of action. The use of inosine should be considered as a potential preventative therapy in humans susceptible to developing Type 1 diabetes and as a possible antirejection therapy for islet transplant recipients.

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Acknowledgments

This study was supported by grants from the National Institutes of Health (1R43 DK59676 to GS) and the Canadian Institutes of Health Research (1-199-908 to AR).

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Authors and Affiliations

  1. Inotek Pharmaceuticals Corp, 100 Cummings Center, Suite 419E, Beverly, MA, 01915, USA

    Jon G Mabley, Pál Pacher, Gary Southan, Andrew Salzman & Csaba Szabó

  2. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Alex Rabinovitch & Wilma Suarez-Pinzon

  3. Department of Surgery, New Jersey Medical School, Newark, NJ, USA

    György Haskó & Csaba Szabó

  4. Department of Laboratory Medicine, University of Alberta, Edmonton, Alberta, Canada

    Robert Power

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  1. Jon G Mabley
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  2. Alex Rabinovitch
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Correspondence to Jon G Mabley.

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Mabley, J.G., Rabinovitch, A., Suarez-Pinzon, W. et al. Inosine Protects Against the Development of Diabetes in Multiple-Low-Dose Streptozotocin and Nonobese Diabetic Mouse Models of Type 1 Diabetes. Mol Med 9, 96–104 (2003). https://doi.org/10.2119/2003-00016.Mabley

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