Per-Olof Berggren,2,3,4 and Alejandro Caicedo1,2,5,6 Control of Insulin Secretion by Cholinergic Signaling in the

Acetylcholine regulates hormone secretion from the pancreatic islet and is thus crucial for glucose homeo-stasis. Little is known, however, about acetylcholine (cholinergic) signaling in the human islet. We recently reported that in the human islet, acetylcholine is pri-marily a paracrine signal released from a-cells rather than primarily a neural signal as in rodent islets. In this study, we demonstrate that the effects acetylcholine produces in the human islet are different and more com-plex than expected from studies conducted on cell lines and rodent islets. We found that endogenous acetylcho-line not only stimulates the insulin-secreting b-cell via the muscarinic acetylcholine receptors M3 and M5, but also the somatostatin-secreting d-cell via M1 receptors. Because somatostatin is a strong inhibitor of insulin se