Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet

Acetylcholine regulates hormone secretion from the pancreatic islet and is thus crucial for glucose homeostasis. Little is known, however, about acetylcholine (cholinergic) signaling in the human islet. We recently reported that in the human islet, acetylcholine is primarily a paracrine signal released from alpha-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 complex than expected from studies conducted on cell lines and rodent islets. We found that endogenous acetylcholine not only stimulates the insulin-secreting beta-cell via the muscarinic acetylcholine receptors M3 and M5, but also the somatostatin-secreting delta-cell via M1 receptors. Because somatostatin is a strong inhibitor of insulin secretion, we hypothesized that cholinergic input to the d-cell indirectly regulates beta-cell function. Indeed, when all muscarinic signaling was blocked, somatostatin secretion decreased and insulin secretion unexpectedly increased, suggesting a reduced inhibitory input to beta-cells. Endogenous cholinergic signaling therefore provides direct stimulatory and indirect inhibitory input to beta-cells to regulate insulin secretion from the human islet.