β-cell-specific overexpression of glutathione peroxidase preserves intranuclear MafA and reverses diabetes in db/db Mice

Jamie S. Harmon, Marika Bogdani, Susan D. Parazzoli, Sabrina S.M. Mak, Elizabeth A. Oseid, Marleen Berghmans, Renée C. LeBoeuf, R. Paul Robertson

Research output: Contribution to journalArticle

106 Scopus citations

Abstract

Chronic hyperglycemia causes oxidative stress, which contributes todamagein 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-1transgenewasdocumentedwhen β- cellsoftransgenicmicewereprotectedfromstreptozotocin. 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.

Original languageEnglish (US)
Pages (from-to)4855-4862
Number of pages8
JournalEndocrinology
Volume150
Issue number11
DOIs
StatePublished - Nov 2009

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