title: Two tales of antioxidant enzymes on β cells and diabetes.
abstract: Pancreatic islets contain low activities of catalase, selenium-dependent glutathione peroxidase 1 (GPX1), and Cu,Zn-superoxide dismutase 1 (SOD1). Thus, enhancing expression of these enzymes in islets has been unquestionably favored. However, such an attempt has produced variable metabolic outcomes. While β cell-specific overexpression of Sod1 enhanced mouse resistance to streptozotocin-induced diabetes, the same manipulation of catalase aggravated onset of type 1 diabetes in nonobese diabetic mice. Global overexpression of Gpx1 in mice induced type 2 diabetes-like phenotypes. Although knockouts of Gpx1 and Sod1 each alone or together decreased pancreatic β cell mass and plasma insulin concentrations, these knockouts improved body insulin sensitivity to different extents. Pancreatic duodenal homeobox 1, forkhead box A2, and uncoupling protein 2 are three key regulators of β cell mass, insulin synthesis, and glucose-stimulated insulin secretion. Phenotypes resulted from altering GPX1 and/or SOD1 were partly mediated through these factors, along with protein kinase B and c-jun terminal kinase. A shifted reactive oxygen species inhibition of protein tyrosine phosphatases in insulin signaling might be attributed to altered insulin sensitivity. Overall, metabolic roles of antioxidant enzymes in β cells and diabetes depend on body oxidative status and target functions. Revealing regulatory mechanisms for this type of dual role will help prevent potential pro-diabetic risk of antioxidant over-supplementation to humans.
authors.affiliation: Department of Animal Science, Cornell University, Ithaca, New York 14853, USA. XL20@cornell.edu
authors.forename: Xin Gen
authors.initials: XG
authors.lastname: Lei
authors.forename: Marko Z
authors.initials: MZ
authors.lastname: Vatamaniuk
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000201:enzymology*; D007473:Ion Channels / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D000071246:Uncoupling Protein 2; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D018398:Homeodomain Proteins; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D015534:Trans-Activators; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; C084010:pancreatic and duodenal homeobox 1 protein; D051542:Hepatocyte Nuclear Factor 3-beta; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005947:Glucose; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human