Effect of hyperglycemia on mitochondrial electron-transport chain function in the pancreatic β cell. Hyperglycemia increases production of electron donors from the tricarboxylic acid (TCA) cycle (NADH and FADH₂). This increases the membrane potential (Δμ_H⁺), because protons are pumped across the mitochondrial inner membrane in proportion to electron flux through the electron-transport chain. Inhibition of electron transport at Complex III by increased Δμ_H⁺ increases the half-life of free radical intermediates of coenzyme Q, which reduce O₂ to superoxide. Krauss and colleagues (13) have demonstrated that hyperglycemia-induced mitochondrial superoxide activates UCP2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion. Figure modified with permission from Nature (15). P_i, inorganic phosphorus.