FIG. 5.
A schematic representation of the main molecular events during incretin-induced insulin secretion from a β-cell. The binding of incretin ligands or agonists to the incretin receptors results in production of cAMP via adenylyl cyclase (AC) activation and subsequent activation of PKA and the Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs), which leads to elevation of intracellular Ca2+ levels via a depolarization of plasma membrane by inhibition of KATP and KV channels after ATP generation from glucose and consequent opening of voltage-gated L-type Ca2+ channels. Intracellular Ca2+ levels are further increased via stimulation of IP3R and RyR on the ER. Long-term GLP-1 treatment also stimulates the expression of GLUT2 transporter and glucokinase (the β-cell glucose sensor), which lead to increased mitochondrial ATP synthesis. In addition, L-type Ca2+ channels are phosphorylated by PKA, resulting in an increase of their open probability and thus facilitation of enhanced Ca2+ influx. The changes in intracellular Ca2+ concentrations lead to fusion of insulin-containing vesicles to the plasma membrane and subsequent rapid exocytosis of insulin from β cells. In addition, the exocytosis of insulin-containing vesicles is directly regulated by PKA and Epac2 via interaction with the regulators of exocytosis and ATP.