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.

FIG. 1.

Overview of endocrine cell types and functions, main forms of ROS and RNS, and antioxidant defense systems in pancreatic islets. The tilted balance scale symbolizes a perceived susceptibility of β cells to ROS or oxidative stress due to relatively low activity of antioxidant enzymes. RNS, reactive nitrogen species; ROS, reactive oxygen species.

FIG. 2.

Scheme of Gpx1 overexpression leading to chronic hyperinsulinemia. ↑, Activation or increase; ↓, inhibition or decrease; ⊥, decrease; P, phosphorylation. AKT, protein kinase B; FOXA2, forkhead box A2; GPX1, glutathione peroxidase 1; GSIS, glucose-stimulated insulin secretion; PDX1, pancreatic duodenal homeobox 1; PTP, protein tyrosine phosphatase; PTP-1B, protein tyrosine phosphatase-1B; UCP2, uncoupling protein 2.

FIG. 3.

Comparative impacts of Gpx1 and Sod1 knockouts on regulation of pancreatic islet FOXA2, PDX1, and β cell mass and function. ↓, Inhibition; SOD1^−/−, superoxide dismutase 1 knockout mice.

FIG. 4.

Symmetric phenotypes of pancreatic islet β cells and body insulin produced by overexpression of Gpx1 and knockout of Gpx1 and Sod1 each alone or together. The three inside circles represent different status of oxidants/antioxidants: balanced in wild type; reductive stress in the transgenic model; oxidative stress in the knockout models.

FIG. 5.

Metabolic role, physiological importance, and molecular mechanism of antioxidant enzymes for different target functions under various ROS status. +, Protection or positive role; −, negative role; ?, questionable role. PTEN, phosphatidylinositol 3-kinase–phosphatase with tensin homology.