title: Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose.
abstract: The arrangement of β cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual β cells in orchestrating these responses has long been suspected, but not directly demonstrated. We show here that the β cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns. Hubs were metabolically adapted and targeted by both pro-inflammatory and glucolipotoxic insults to induce widespread β cell dysfunction. Thus, the islet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus.
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Johnston
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Mitchell
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Haythorne
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Maria Paiva
authors.initials: MP
authors.lastname: Pessoa
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Semplici
authors.affiliation: Beta Cell Genome Regulation Lab, Department of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.affiliation: Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.affiliation: Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bugliani
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, 1205 Geneva, Switzerland.
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, 1205 Geneva, Switzerland.
authors.forename: Ekaterine
authors.initials: E
authors.lastname: Berishvili
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Duncanson
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Watkinson
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Broichhagen
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, UK. Electronic address: g.rutter@imperial.ac.uk.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, UK; Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, UK. Electronic address: d.hodson@bham.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hodson
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000528:radiation effects; D002454:Cell Differentiation / Q000187:drug effects; D003199:Computer Systems; D003920:Diabetes Mellitus / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D008027:Light; D008055:Lipids / Q000633:toxicity; D055442:Metabolome / Q000187:drug effects; D055432:Metabolomics; D051379:Mice; D055620:Optical Phenomena; D010641:Phenotype; D013045:Species Specificity
chemical_list: D007328:Insulin; D008055:Lipids; D005947:Glucose
keywords: diabetes; imaging; insulin; islets; optogenetics; β cells