Overview of glucose stimulus-secretion coupling in the pancreatic δ-cell. Glucose enters the δ-cell and subsequent metabolism generates ATP at the expense of ADP. This change in energy status has several important effects. As depicted at the top, the increase in ATP (combined with reduced ADP) closes K_ATP channels, which cause the membrane potential (V_m) to become less negative and voltage-dependent Ca²⁺ channels (VDCC) to open. The resulting influx of Ca²⁺ triggers exocytosis of somatostatin-containing secretory granules. The Ca²⁺ signal is amplified by Ca²⁺ mobilization from the ER mediated by RYR3 and such CICR contributes to additional exocytosis. ATP generated by glucose metabolism amplifies the CICR process by fuelling the SERCA to sequester Ca²⁺ into the ER store, making it available for release when the RYR channels open. The principal novelty in the study by Denwood et al. (2019) is that glucose metabolism amplifies somatostatin secretion by promoting the generation of cAMP from ATP via adenylyl cyclases (AC). A main action of cAMP is to trigger CICR via Epac2, which somehow activates RYRs. cAMP concomitantly activates PKA, which exerts a potent stimulatory action directly on the exocytosis process.