Metallothionein and catalase sensitize to diabetes in nonobese diabetic mice: reactive oxygen species may have a protective role in pancreatic beta-cells.
It is widely proposed that reactive oxygen species (ROS) contribute to beta-cell death in type 1 diabetes. We tested this in nonobese diabetic (NOD) mice using beta-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 beta-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 beta-cell from autoimmune destruction.
Li
Xiaoyan
X
Department of Pharmacology and Toxicology, University of Louisville, 570 South Preston St., Baxter Research Building, Suite 304, Louisville, KY 40202, USA.
Chen
Hainan
H
Epstein
Paul N
PN
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D003520:Cyclophosphamide / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005979:Glutathione Peroxidase / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D016207:Cytokines; D007328:Insulin; D017382:Reactive Oxygen Species; D003520:Cyclophosphamide; D008668:Metallothionein; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase