Two Tales of Antioxidant Enzymes onβCells 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.

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

“…Furthermore, JNK phosphorylation is increased in the skeletal muscle of PRDX6 2/2 mice, and augmented JNK activation can lead to the deregulation of IRS1, as has already been reported in insulin-resistant nonobese subjects (32). Our results, in agreement with those of previous studies (33,34), support the hypothesis that antioxidant enzymes can reduce insulin-signaling activation and decrease glucose uptake.…”

Localization and regulation of pancreatic selenoprotein P

“…Thus, proper regulation of the cellular redox balance is of prime importance to maintain and adapt pancreatic insulin production and secretion. Low expression and activity of major antioxidant enzymes such as catalase, SOD, and GPx may render b-cells particularly sensitive to signaling as well as to cytotoxic actions of ROS (Tiedge et al 1997, Pi et al 2007, Lei & Vatamaniuk 2011. In this study, we demonstrate that b-cells express an additional antioxidant protein, Sepp1.…”

Selenium and diabetes - evidence from animal studies

“…Data from earlier epidemiologic investigations showed correlations between abnormal glucose or lipid metabolism and decreased plasma Se concentrations or selenoperoxidase activity in diabetic subjects [41][42][43][44][45][46][47][48]. Likewise, there were also similar correlations or associations in animals.…”

“…It seems that the role of catalase in glucose metabolism is similar to that of GPx1, but different from that of SOD1. A comprehensive review of this topic can be found elsewhere [48].…”

“…High Se intake may affect expression and(or) function of the key regulators for glycolysis, gluconeogenesis, and lipogenesis. These pathways might contribute to the pro-diabetic potential of high Se intake cooperatively or independently [40,48,[125][126][127]. Although expression and activity of many selenoproteins are saturated at the adequate Se intake, several selenoproteins or their mRNA levels are affected by higher Se intake [128][129][130].…”