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Metallothionein and Catalase Sensitize to Diabetes in Nonobese Diabetic Mice

Reactive Oxygen Species May Have a Protective Role in Pancreatic ß-Cells

¹ Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky
² Department of Pediatrics, University of Louisville, Louisville, Kentucky

Address correspondence and reprint requests to Paul N. Epstein, Department of Pediatrics, University of Louisville, 570 South Preston St., Baxter Research Building, Suite 304, Louisville, KY 40202. E-mail: paul.epstein{at}louisville.edu

Abbreviations: CM-H₂DCFDA, 5-(6)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate; CYP, cyclophosphamide; ER, endoplasmic reticulum; IL, interleukin; MnSOD, manganese SOD; MT, metallothionein; PDX-1, pancreatic duodenal homeobox-1; PTP, protein tyrosine phosphatase; ROS, reactive oxygen species; SOD, superoxide dismutase; STZ, streptozotocin; TNF, tumor necrosis factor

It is widely proposed that reactive oxygen species (ROS) contribute to ß-cell death in type 1 diabetes. We tested this in nonobese diabetic (NOD) mice using ß-cell–specific overexpression of three antioxidant proteins: metallothionein (MT), catalase (Cat), or manganese superoxide dismutase (MnSOD). Unexpectedly, the cytoplasmic antioxidants, MT and catalase, greatly accelerated diabetes after cyclophosphamide and accelerated spontaneous diabetes in male NOD mice. This occurred despite the fact that they reduced cytokine-induced ROS production and MT reduced streptozotocin diabetes in NOD mice. Accelerated diabetes onset coincided with increased ß-cell death but not with increased immune attack. Islets from MTNOD mice were more sensitive to cytokine injury. In vivo and in vitro studies indicated reduced activation of the Akt/pancreatic duodenal homeobox-1 survival pathway in MTNOD and CatNOD islets. Our study indicates that cytoplasmic ROS may have an important role for protecting the ß-cell from autoimmune destruction.

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