Incretins, such as GIP and GLP-1 enhance insulin secretion from pancreatic β cells in a glucose dependent manner. Incretins potentiate adenylate cyclase activity trough their G-protein coupled receptors and then increase intracellular cAMP level. Intracellular cAMP modulates insulin secretion by both PKA-dependent and PKA-independent pathways. PKA potentiates intracellular Ca+ influx via phosphorylation of voltage dependent calcium channel (VDCC), which increases insulin exocyosis. PKA also phosphorylates KATP channel and facilitates insulin release. In contrast, Epac2 potentiates insulin secretion by cAMP in a PKA–independent pathway. The small G-protein Rap1, which is activated specifically through Epac2, contributes the first phase of insulin secretion possibly by control of insulin granules fusion to plasma membrane.
