Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans

Abstract

Acetylcholine signaling by the parasympathetic nervous system is crucial for proper insulin release. Alejandro Caicedo and his colleagues now show that such cholinergic signaling in human pancreatic islets is instead locally derived by pancreatic alpha cells—a finding that may have an impact on future drug development to treat diabetes. Acetylcholine is a neurotransmitter that has a major role in the function of the insulin-secreting pancreatic beta cell1,2. Parasympathetic innervation of the endocrine pancreas, the islets of Langerhans, has been shown to provide cholinergic input to the beta cell in several species1,3,4, but the role of autonomic innervation in human beta cell function is at present unclear. Here we show that, in contrast to the case in mouse islets, cholinergic innervation of human islets is sparse. Instead, we find that the alpha cells of human islets provide paracrine cholinergic input to surrounding endocrine cells. Human alpha cells express the vesicular acetylcholine transporter and release acetylcholine when stimulated with kainate or a lowering in glucose concentration. Acetylcholine secretion by alpha cells in turn sensitizes the beta cell response to increases in glucose concentration. Our results demonstrate that in human islets acetylcholine is a paracrine signal that primes the beta cell to respond optimally to subsequent increases in glucose concentration. Cholinergic signaling within islets represents a potential therapeutic target in diabetes5, highlighting the relevance of this advance to future drug development.