title: beta-Cell-specific overexpression of glutathione peroxidase preserves intranuclear MafA and reverses diabetes in db/db mice.
abstract: Chronic hyperglycemia causes oxidative stress, which contributes to damage in various tissues and cells, including pancreatic beta-cells. The expression levels of antioxidant enzymes in the islet are low compared with other tissues, rendering the beta-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 beta-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 beta-cells were generated. The biological effectiveness of the overexpressed GPx-1 transgene was documented when beta-cells of transgenic mice were protected from streptozotocin. The transgene was then introgressed into the beta-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. beta-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 beta-cell protects it against deterioration during hyperglycemia.
authors.affiliation: Pacific Northwest Diabetes Research Institute, 720 Broadway, Seattle, Washington 98122, USA.
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Harmon
authors.forename: Marika
authors.initials: M
authors.lastname: Bogdani
authors.forename: Susan D
authors.initials: SD
authors.lastname: Parazzoli
authors.forename: Sabrina S M
authors.initials: SS
authors.lastname: Mak
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Oseid
authors.forename: Marleen
authors.initials: M
authors.lastname: Berghmans
authors.forename: Renée C
authors.initials: RC
authors.lastname: Leboeuf
authors.forename: R Paul
authors.initials: RP
authors.lastname: Robertson
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003920:Diabetes Mellitus / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism; D042581:Intranuclear Space / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000094765:Glutathione Peroxidase GPX1
chemical_list: D001786:Blood Glucose; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1