Figure 4: Protective mechanism of β-cell-specific IGF-1 against oxidative stress in pancreatic β-cells Reactive oxygen species (ROS) generated from STZ exposure are metabolized and inactivated by superoxide dismutase (SOD) to produce H2O2. An imbalance in the coordinated expression/activity of glutathione peroxidase (GSHPx) and glutathione reductase (GR) can cause excessive generation of ROS, leading to oxidative stress. GSHPx converts H2O2 to water using glutathione (GSH) and produces oxidized glutathione (GSSG). Cellular maintenance of a balanced redox state is controlled by intracellular regulators such as reduced GSH and nicotinamide adenine dinucleotide phosphate (NADPH). Both GR and glucose-6-phosphate dehydrogenase (G6PD) are enzymes with expected protective activity against oxidative stress. 2-deoxy-glucose (2-DG, an inhibitor of the glycolytic pathway) and 6-aminonicotinamide (6-AN, an inhibitor of the pentose phosphate pathway) both decrease cellular levels of pyruvate and NADPH. This leads to an accumulation of H2O2, the buildup of which induces apoptosis. The protective action of β-cell-specific IGF-1 is exerted via an increase in two targets: increasing methionine synthase activity (MS), which enhances homocysteine metabolism (Figure 2); and enhancing the glycolytic pathway, leading to cellular elevation of pyruvate, which inhibitsof H2O2-induced cell death. Enhancement of the glycolytic pathway also leads to an intracellular environment favorable to cell growth. Arrows with (+) and (-) respectively represent stimulation and suppression.