title: Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans.
abstract: OBJECTIVE
  The Gq-coupled 5-hydroxytryptamine 2B (5-HT2B) receptor is known to regulate the proliferation of islet beta cells during pregnancy. However, the role of serotonin in the control of insulin release is still controversial. The aim of the present study was to explore the role of the 5-HT2B receptor in the regulation of insulin secretion in mouse and human islets, as well as in clonal INS-1(832/13) cells.
  
  
  METHODS
  Expression of HTR2B mRNA and 5-HT2B protein was examined with quantitative real-time PCR, RNA sequencing and immunohistochemistry. α-Methyl serotonin maleate salt (AMS), a serotonin receptor agonist, was employed for robust 5-HT2B receptor activation. Htr2b was silenced with small interfering RNA in INS-1(832/13) cells. Insulin secretion, Ca(2+) response and oxygen consumption rate were determined.
  
  
  RESULTS
  Immunohistochemistry revealed that 5-HT2B is expressed in human and mouse islet beta cells. Activation of 5-HT2B receptors by AMS enhanced glucose-stimulated insulin secretion (GSIS) in human and mouse islets as well as in INS-1(832/13) cells. Silencing Htr2b in INS-1(832/13) cells led to a 30% reduction in GSIS. 5-HT2B receptor activation produced robust, regular and sustained Ca(2+) oscillations in mouse islets with an increase in both peak distance (period) and time in the active phase as compared with control. Enhanced insulin secretion and Ca(2+) changes induced by AMS coincided with an increase in oxygen consumption in INS-1(832/13) cells.
  
  
  CONCLUSIONS
  Activation of 5-HT2B receptors stimulates GSIS in beta cells by triggering downstream changes in cellular Ca(2+) flux that enhance mitochondrial metabolism. Our findings suggest that serotonin and the 5-HT2B receptor stimulate insulin release.
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Unit of Diabetes and Celiac disease, Clinical Research Centre, Jan Waldenströms gata 35, Clinical Research Centre House 91:10, Skåne University Hospital Malmö, SE-20502, Malmö, Sweden. hedvig.bennet@med.lu.se.
authors.forename: Hedvig
authors.initials: H
authors.lastname: Bennet
authors.affiliation: Lund University Diabetes Centre, Islet Cell Exocytosis, Malmö, Sweden.
authors.forename: Inês G
authors.initials: IG
authors.lastname: Mollet
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Unit of Diabetes and Celiac disease, Clinical Research Centre, Jan Waldenströms gata 35, Clinical Research Centre House 91:10, Skåne University Hospital Malmö, SE-20502, Malmö, Sweden.
authors.forename: Alexander
authors.initials: A
authors.lastname: Balhuizen
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Unit of Diabetes and Celiac disease, Clinical Research Centre, Jan Waldenströms gata 35, Clinical Research Centre House 91:10, Skåne University Hospital Malmö, SE-20502, Malmö, Sweden.
authors.forename: Anya
authors.initials: A
authors.lastname: Medina
authors.affiliation: Lund University Diabetes Centre, Molecular Metabolism, Malmö, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nagorny
authors.affiliation: Lund University Diabetes Centre, Molecular Metabolism, Malmö, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Bagge
authors.affiliation: Lund University Diabetes Centre, Diabetes and Endocrinology, Malmö, Sweden.
authors.forename: Joao
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Lund University Diabetes Centre, Diabetes and Endocrinology, Malmö, Sweden.
authors.forename: Emilia
authors.initials: E
authors.lastname: Ottosson-Laakso
authors.affiliation: Lund University Diabetes Centre, Diabetes and Endocrinology, Malmö, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Vikman
authors.affiliation: Lund University Diabetes Centre, Diabetes and Endocrinology, Malmö, Sweden.|Royal Brisbane Clinical School, UQ Centre for Clinical Research, The University of Queensland, Herston, QLD, Australia.
authors.forename: Marloes
authors.initials: M
authors.lastname: Dekker-Nitert
authors.affiliation: Lund University Diabetes Centre, Islet Cell Exocytosis, Malmö, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.affiliation: Lund University Diabetes Centre, Neuroendocrine Cell Biology, Malmö, Sweden.
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.affiliation: Lund University Diabetes Centre, Stem Cell Center, Biomedical Centre (BMC), Lund, Sweden.
authors.forename: Isabella
authors.initials: I
authors.lastname: Artner
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Unit of Diabetes and Celiac disease, Clinical Research Centre, Jan Waldenströms gata 35, Clinical Research Centre House 91:10, Skåne University Hospital Malmö, SE-20502, Malmö, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000378:metabolism*
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D005947:Glucose
keywords: Beta cell; Ca2+ oscillations; G protein-coupled receptor; Human islets of Langerhans; Insulin secretion; Mitochondrial respiration