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β-Cell-Specific Overexpression of Glutathione Peroxidase Preserves Intranuclear MafA and Reverses Diabetes in db/db Mice

Pacific Northwest Diabetes Research Institute (J.S.H., M.B., S.D.P., S.S.M.M., E.A.O., R.P.R.) Seattle, Washington 98122; Diabetes Research Center (M.B.), Brussels Free University, B-1090 Brussels, Belgium; and Departments of Medicine (R.C.L.) and Pharmacology (R.P.R.), University of Washington, Seattle, Washington 98195

Address all correspondence and requests for reprints to: R. Paul Robertson, Pacific Northwest Diabetes Research Institute, 720 Broadway, Seattle, Washington 98122. E-mail: rpr{at}pnri.org.

Chronic hyperglycemia causes oxidative stress, which contributes to damage in various tissues and cells, including pancreatic β-cells. The expression levels of antioxidant enzymes in the islet are low compared with other tissues, rendering the β-cell more susceptible to damage caused by hyperglycemia. The aim of this study was to investigate whether increasing levels of endogenous glutathione peroxidase-1 (GPx-1), specifically in β-cells, can protect them against the adverse effects of chronic hyperglycemia and assess mechanisms that may be involved. C57BLKS/J mice overexpressing the antioxidant enzyme GPx-1 only in pancreatic β-cells were generated. The biological effectiveness of the overexpressed GPx-1 transgene was documented when β-cells of transgenic mice were protected from streptozotocin. The transgene was then introgressed into the β-cells of db/db mice. Without use of hypoglycemic agents, hyperglycemia in db/db-GPx(+) mice was initially ameliorated compared with db/db-GPx(–) animals and then substantially reversed by 20 wk of age. β-Cell volume and insulin granulation and immunostaining were greater in db/db-GPx(+) animals compared with db/db-GPx(–) animals. Importantly, the loss of intranuclear musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) that was observed in nontransgenic db/db mice was prevented by GPx-1 overexpression, making this a likely mechanism for the improved glycemic control. These studies demonstrate that enhancement of intrinsic antioxidant defenses of the β-cell protects it against deterioration during hyperglycemia.