Model of glucose-stimulated insulin secretion in the pancreatic β cell. Following phosphorylation by glucokinase (GK), glucose is converted to pyruvate by glycolysis. Pyruvate enters the mitochondria and fuels the TCA cycle, resulting in the transfer of reducing equivalents to the respiratory chain, hyperpolarization of the mitochondrial membrane, and ATP generation. Subsequent closure of KATP channels depolarizes the cell membrane, which opens voltage-gated calcium channels, increasing the concentration of cytosolic calcium ([Ca2+]c). This influx of calcium triggers insulin release from the cell. Figure modified with permission from Nature (17). Pyr, pyruvate; Δψm, mitochondrial membrane potential; Δψc, cell membrane potential.