Knockouts of SOD1 and GPX1 Exert Different Impacts on Murine Islet Function and Pancreatic Integrity

Abstract

Metabolic subtlety and clinical relevance of different forms of reactive oxygen species in diabetes remain unclear. Using single knockout of Cu,Zn-superoxide dismutase (SOD1(-/-)) or Se-glutathione peroxidase-1 (GPX1(-/-)) and their double-knockout (DKO) mouse models, we determined if elevating endogenously-derived superoxide and hydroperoxide exerted distinct impacts and mechanisms on body glucose homeostasis. Whereas the three knockout groups displayed decreased plasma insulin concentrations and islet β-cells mass, only SOD1(-/-) showed decreased body weight, increased blood glucose, and blocked glucose-stimulated insulin secretion. Null of SOD1 and GPX1 elevated respective islet superoxide and hydroperoxide production, and upregulated p53 phosphorylation. Knockout of SOD1 downregulated the foxhead box A2/pancreatic and duodenal homeobox 1 pathway in a superoxide-dependent fashion at epigenetic, mRNA, and protein levels in islets, but improved insulin signaling in liver and muscle. The SOD1(-/-) mice showed more apparent pancreatitis than the GPX1(-/-) mice that were more susceptible to the cerulein-induced amylase increase. Knockout of SOD1 impaired islet function, pancreas integrity, and body glucose homeostasis more than that of GPX1. Simultaneous ablation of both enzymes did not result in additive or aggravated metabolic outcomes.

Selenium and diabetes - evidence from animal studies

“…However, GPx1 overproduction had no significant effect on islet FOXA2 mRNA levels. Unlike the GPx1 overproduction, the GPx1 knockout did not affect islet PDX1 mRNA and H3 and H4 acetylation [24]. GPx1 overproduction down-regulated islet UCP2 protein and elevated mitochondrial membrane potential, contributing to the accelerated GSIS and hyperinsulinemia [55].…”

“…Mice-The GPx1 overexpressing (OE) mice became obese at 6 months of age, and developed hyperglycemia, hyperinsulinemia, hyperlipidemia, and insulin resistance, along with elevated pancreatic β cell mass, islet insulin secretion, plasma leptin concentration, and hepatic lipogenesis [22][23][24]. Diet restriction (3 vs. 5 g of feed/day) of OE mice from 2 to 6 months of age [55] prevented all their phenotypes except for fasting hyperinsulinemia and hyper-secretion of insulin after glucose stimulation [55].…”

“…Overexpression or knockout of GPx1 altered intracellular ROS status and subsequent redox regulation of key events in insulin synthesis, secretion, and function, resulting in dysregulated glucose and lipid metabolism [22,24]. More specifically, GPx1 overproduction up-regulated PDX1 mRNA and protein levels and attenuated degradation of PDX1 protein in islets [55].…”

“…An elevated functional PDX1 protein in islets resulted in hypertrophy of β cell mass, and subsequent increased pancreatic and plasma insulin concentrations [88][89][90]. In contrast, the reverse was induced by the GPx1 knockout [24]. Furthermore, GPx1 overexpression resulted in hyperacetylation of histone 3 and 4 (H3 and H4) in the PDX1 gene promoter [55] that may help explain in part the increased islet PDX1 mRNA levels.…”

“…While there was a high hope for using antioxidants including Se to prevent and treat diabetes and its complications, a number of recent human trials have actually shown an alarming correlation between high Se intake or body Se status and diabetic risks [15][16][17][18][19][20][21]. Before this revealing, overexpression of GPx1, the "oldest" and most abundant Se-dependent protein, was shown to induce type 2 diabeteslike phenotypes in mice [22][23][24]. After this initial linking of selenoprotein to glucose and lipid metabolism, several new animal studies have provided compelling evidence and mechanism for the pro-diabetic potential of prolonged high Se intakes in different species.…”