Two tales of antioxidant enzymes on β cells and diabetes.

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 beta 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 beta 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 beta 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 beta 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. Antioxid. Redox Signal. 14, 489-503.