Figure 1.

Graphical representation of oxidative stress mechanisms in β cells. The generation of Reactive Oxygen Species (ROS) could be caused by several conditions including hyperglycaemia, hyperlipidaemia, hypoxia, and Endoplasmic Reticulum (ER) stress (due to inflammation). Increased glucose concentration in β cells stimulates a rapid and proportional rise of glycolytic flux followed by a robust stimulation in the production of reducing equivalents, due to the channeling of glucose carbon into the Tricarboxylic Acid Cycle (TCA) cycle, which can lead to an enhancement of ROS production. However, further increases in intracellular Ca²⁺ can stimulate mitochondrial generation of ROS while Ca²⁺ via Protein Kinase C (PKC) activation, may enhance Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase-dependent generation of ROS and, thus, induce oxidative stress and/or apoptosis. The mechanism by which Free Fatty Acids (FFAs) promotes ROS generation in mitochondria could be explained by the activation of NADPH oxidase and another mechanism which contributes to lipid-induced oxidative stress in β cells is the modulation of respiratory chain. β cells are also prone to the stress caused by low oxygen levels which leads to ROS production and other signs of oxidative stress. Hypoxia or low oxygen tension can lead to increased ROS generation, mostly through the involvement of complexes I and III of the mitochondrial electron transport chain. In the ER, ROS are generated as a product of protein folding events; therefore, the increased accumulation of dysregulated formation or breakage of disulfide bonds result in an excessive amount of ROS which causes oxidative stress. In addition, the presence of Superoxide Dismutase (SOD), causes the abnormal accumulation of H₂O₂ and other ROS (green box inset) which may damage the cells at multiple levels.