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Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans
Rayner Rodriguez-Diaz1,2,7, Robin Dando3,7, M Caroline Jacques-Silva1, Alberto Fachado1, Judith Molina4, Midhat H Abdulreda1, Camillo Ricordi1,2, Stephen D Roper3,5, Per-Olof Berggren1,2,6 & Alejandro Caicedo1,35
2011 Nature America, Inc. All rights reserved.
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 roleof autonomic innervation in human beta cell function is at present unclear. Here we show that, in contrast to the casein 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.
Acetylcholine is crucial for pancreatic beta cell function. It stimulates insulin secretion by increasing the cytoplasmic free Ca2+ concentration, [Ca2+]i, via inositol phosphate production and enhancing the effects of Ca2+ on exocytosis via protein kinase C in beta cells1 (Supplementary Fig. 1). Muscarinic receptors found in pancreatic beta cells are essential for maintaining proper insulin secretion and glucose homeostasis in mice2. Cholinergic agonists have been reported to restore defective glucose-stimulated insulin secretion6,7.
In humans, variations in the gene that encodes the muscarinic receptor M3 are associated with increased risk for early-onset type 2 diabetes8. It is generally believed that acetylcholine is released during feeding from parasympathetic nerve endings in pancreatic islets1,3.
The consensus is that the endocrine pancreas is richly innervated by the autonomic nervous system1,3,4,9, with studies based on the
cholinesterase technique revealing dense parasympathetic inner-vation in cat, rat, rabbit and human islets1013....