title: Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans.
abstract: Acetylcholine is a neurotransmitter that has a major role in the function of the insulin-secreting pancreatic beta cell. Parasympathetic innervation of the endocrine pancreas, the islets of Langerhans, has been shown to provide cholinergic input to the beta cell in several species, 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 diabetes, highlighting the relevance of this advance to future drug development.
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Rayner
authors.initials: R
authors.lastname: Rodriguez-Diaz
authors.forename: Robin
authors.initials: R
authors.lastname: Dando
authors.forename: M Caroline
authors.initials: MC
authors.lastname: Jacques-Silva
authors.forename: Alberto
authors.initials: A
authors.lastname: Fachado
authors.forename: Judith
authors.initials: J
authors.lastname: Molina
authors.forename: Midhat H
authors.initials: MH
authors.lastname: Abdulreda
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Roper
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Alejandro
authors.initials: A
authors.lastname: Caicedo
mesh_terms: D000109:Acetylcholine / Q000378:metabolism* / Q000502:physiology; D000475:Alkenes / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D010830:Physostigmine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000502:physiology; D022142:Secretory Vesicles / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D050494:Vesicular Acetylcholine Transport Proteins / Q000502:physiology
chemical_list: D000475:Alkenes; D007328:Insulin; C121300:J 104129; D010880:Piperidines; D011950:Receptors, Cholinergic; D050494:Vesicular Acetylcholine Transport Proteins; C006189:vesamicol; D010830:Physostigmine; D005947:Glucose; D000109:Acetylcholine