title: Altered serotonin (5-HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes.
abstract: Islet produced 5-hydroxy tryptamine (5-HT) is suggested to regulate islet hormone secretion in a paracrine and autocrine manner in rodents. Hitherto, no studies demonstrate a role for this amine in human islet function, nor is it known if 5-HT signaling is involved in the development of beta cell dysfunction in type 2 diabetes (T2D). To clarify this, we performed a complete transcriptional mapping of 5-HT receptors and processing enzymes in human islets and investigated differential expression of these genes in non-diabetic and T2D human islet donors. We show the expression of fourteen 5-HT receptors as well as processing enzymes involved in the biosynthesis of 5-HT at the mRNA level in human islets. Two 5-HT receptors (HTR1D and HTR2A) were over-expressed in T2D islet donors. Both receptors (5-HT1d and 5-HT2a) were localized to human alpha, beta and delta cells. 5-HT inhibited both insulin and glucagon secretion in non-diabetic islet donors. In islets isolated from T2D donors the amine significantly increased release of insulin in response to glucose. Our results suggest that 5-HT signaling participates in regulation of overall islet hormone secretion in non- diabetic individuals and over-expression of HTR1D and HTR2A may either contribute to islet dysfunction in T2D or arise as a consequence of an already dysfunctional islet.
authors.affiliation: Department of Clinical Science, Lund University Diabetes Centre, Scania University Hospital, Entrance 72, Clinical Research Centre House 91, Jan Waldenströmsgata 35, SE-20502, Malmö, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Bennet
authors.affiliation: Department of Clinical Science, Lund University Diabetes Centre, Scania University Hospital, Entrance 72, Clinical Research Centre House 91, Jan Waldenströmsgata 35, SE-20502, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Balhuizen
authors.affiliation: Department of Clinical Science, Lund University Diabetes Centre, Scania University Hospital, Entrance 72, Clinical Research Centre House 91, Jan Waldenströmsgata 35, SE-20502, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Medina
authors.affiliation: Department of Clinical Science, Lund University Diabetes Centre, Scania University Hospital, Entrance 72, Clinical Research Centre House 91, Jan Waldenströmsgata 35, SE-20502, Malmö, Sweden; Royal Brisbane Clinical School, UQ Centre for Clinical Research, The University of Queensland, Herston, QLD 4029, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Dekker Nitert
authors.affiliation: Department of Clinical Science, Lund University Diabetes Centre, Scania University Hospital, Entrance 72, Clinical Research Centre House 91, Jan Waldenströmsgata 35, SE-20502, Malmö, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Ottosson Laakso
authors.affiliation: The Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Getingevägen 60, SE-22241, Lund, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Essén
authors.affiliation: Department of Clinical Science, Lund University Diabetes Centre, Scania University Hospital, Entrance 72, Clinical Research Centre House 91, Jan Waldenströmsgata 35, SE-20502, Malmö, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Spégel
authors.affiliation: Department of Clinical Science, Lund University Diabetes Centre, Scania University Hospital, Entrance 72, Clinical Research Centre House 91, Jan Waldenströmsgata 35, SE-20502, Malmö, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Storm
authors.affiliation: Department of Clinical Science, Lund University Diabetes Centre, Scania University Hospital, Entrance 72, Clinical Research Centre House 91, Jan Waldenströmsgata 35, SE-20502, Malmö, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Krus
authors.affiliation: Department of Clinical Science, Lund University Diabetes Centre, Scania University Hospital, Entrance 72, Clinical Research Centre House 91, Jan Waldenströmsgata 35, SE-20502, Malmö, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Wierup
authors.affiliation: Department of Clinical Science, Lund University Diabetes Centre, Scania University Hospital, Entrance 72, Clinical Research Centre House 91, Jan Waldenströmsgata 35, SE-20502, Malmö, Sweden. Electronic address: malin.fex@med.lu.se.
authors.forename: M
authors.initials: M
authors.lastname: Fex
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005934:Glucagon / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D044346:Receptor, Serotonin, 5-HT1D / Q000096:biosynthesis*; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis*; D015398:Signal Transduction
chemical_list: D007328:Insulin; D044346:Receptor, Serotonin, 5-HT1D; D044402:Receptor, Serotonin, 5-HT2A; D005934:Glucagon
keywords: G-protein coupled receptors; Human islets; Serotonin; Type 2 diabetes