Model for the regulation of insulin secretion in the β-cell stimulated by glucose and amino acids. Model for the regulation of insulin secretion in the β-cell stimulated by glucose and amino acids. Glucose equilibrates across the plasma membrane and is metabolized via glycolysis yielding pyruvate (Pyr), which is then metabolized further by the TCA cycle. Mitochondrial metabolism is also activated by amino acids such as alanine, glutamine, or glutamate. The TCA cycle generates reducing equivalents, which are transferred to the electron transport chain, leading to generation of ATP. The rise in ATP levels leads to closure of KATP channels and depolarizes the cell membrane. This opens voltage-dependent Ca2+ channels, increasing intracellular Ca2+ concentration ([Ca2+]i), which triggers insulin exocytosis. Additional metabolic signals may be generated from TCA cycle intermediates, which “amplify” the initial Ca2+-dependent stimulation for the exocytosis of insulin. Philip Newsholme et al. Diabetes 2006;55:S39-S47 ©2006 by American Diabetes Association