The major antioxidant enzymes are catalase, GPx, and the two SODs (Fig. 4). Mn-SOD is active in the mitochondria, and Cu/Zn-SOD is active in the cytosol. SOD catalyzes the reaction of superoxides with hydrogen to form hydrogen peroxide. Catalase catalyzes dismutation of hydrogen peroxide to water and molecular oxygen. In mammals, at least four species of GPx exist that catalyze the reduction of hydrogen peroxide by GSH. GPx can also reduce lipid peroxides to alcohols, which catalase cannot do. GCL, formerly termed glutamylcysteine synthetase, is a holoenzyme made up of a catalytic (heavy) and catalytic (light) subunit. GCL catalyzes the cysteine substrate–limiting reaction that forms γ-glutamyl cysteine, the substrate for the second enzyme regulating GSH synthesis, GSH synthetase. GSH is regenerated for future use from its oxidized form, GSSG, through a reaction involving GSH reductase and NADPH. To protect itself from the highly toxic hydroxyl radical, the β-cell must metabolize hydrogen peroxide via catalase and GPx. However, a potentially major problem for the β-cell is its unusually low complement of SOD, catalase, and GPx. This unusual situation sets up the β-cell as an easy target for ROS, whether generated by interactions with cytokines or too much glucose.