title: Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells.
abstract: In the pancreatic islet, serotonin is an autocrine signal increasing beta cell mass during metabolic challenges such as those associated with pregnancy or high-fat diet. It is still unclear whether serotonin is relevant for regular islet physiology and hormone secretion. Here, we show that human beta cells produce and secrete serotonin when stimulated with increases in glucose concentration. Serotonin secretion from beta cells decreases cyclic AMP (cAMP) levels in neighboring alpha cells via 5-HT1Freceptors and inhibits glucagon secretion. Without serotonergic input, alpha cells lose their ability to regulate glucagon secretion in response to changes in glucose concentration, suggesting that diminished serotonergic control of alpha cells can cause glucose blindness and the uncontrolled glucagon secretion associated with diabetes. Supporting this model, pharmacological activation of 5-HT1Freceptors reduces glucagon secretion and has hypoglycemic effects in diabetic mice. Thus, modulation of serotonin signaling in the islet represents a drug intervention opportunity.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: jalmaca@med.miami.edu.
authors.forename: Joana
authors.initials: J
authors.lastname: Almaça
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Molina
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Danusa
authors.initials: D
authors.lastname: Menegaz
authors.affiliation: Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Alexey N
authors.initials: AN
authors.lastname: Pronin
authors.affiliation: Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Tamayo
authors.affiliation: Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Program in Neuroscience, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Vladlen
authors.initials: V
authors.lastname: Slepak
authors.affiliation: Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Rolf Luft Research Center for Diabetes & Endocrinology, Karolinska Institutet, Stockholm SE-17177, Sweden; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Program in Neuroscience, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Electronic address: acaicedo@med.miami.edu.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Caicedo
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D000096642:Receptor, Serotonin, 5-HT1F
chemical_list: D000242:Cyclic AMP; D005934:Glucagon; D005947:Glucose; D011985:Receptors, Serotonin; D012701:Serotonin; D000096642:Receptor, Serotonin, 5-HT1F
keywords: alpha cell; beta cell; diabetes; glucagon secretion; insulin secretion; pancreatic islet; paracrine signal; serotonin