Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants
| Autor: | Fiona M. Gribble, Andrei I. Tarasov, Merewyn K. Loder, Tarvinder K. Taneja, Helen E. Parker, Nadeeja Wijesekara, Jocelyn M. Baldwin, Myriam Masseboeuf, Raphael Scharfmann, Philippe Froguel, Katrin Kronenberger, Gabriela da Silva Xavier, Volodymir Stetsyuk, Vasilij Koshkin, Frank Reimann, Paul Johnson, Guy A. Rutter, Peter Arvan, Armen V. Gyulkhandanyan, Robert Sladek, Stephen J. Hughes, Sarah Libert, Rémy Burcelin, Ming Liu, Tamara J. Nicolson, Elisa A. Bellomo, Fabrice Chimienti, Philippe Ravassard, Raffaella Carzaniga, Frans Schuit, Stephen A. Baldwin, Michael B. Wheeler, Roberto Lara-Lemus |
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| Přispěvatelé: | Section of Cell Biology, Division of Medicine, Imperial College London, Department of Physiology, University of Toronto, Institute of Membrane and Systems Biology, University of Leeds, Electron Microscopy Centre, Mellitech, Section of Genomic Medicine, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Nuffield Department of Surgery, University of Oxford [Oxford], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Metabolism, Endocrinology & Diabetes, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Gene Expression Unit, Université Catholique de Louvain = Catholic University of Louvain (UCL), Institut de biologie de Lille - IBL ( IBLI ), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs ( LGMNPN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Cambridge Institute for Medical Research, ( CIMR ), University of Cambridge [UK] ( CAM ), Department of Human Genetics, McGill University, Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Catholique de Louvain ( UCL ), University of Oxford, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Blood Glucose
Male Endocrinology Diabetes and Metabolism medicine.medical_treatment Gene Expression Type 2 diabetes [ SDV.CAN ] Life Sciences [q-bio]/Cancer Mice 0302 clinical medicine Risk Factors Insulin-Secreting Cells Insulin Secretion Glucose homeostasis Homeostasis Insulin Cation Transport Proteins Mice Knockout 0303 health sciences SLC30A8 biology Zinc Zinc Transporter 8 Female Original Article Insulin processing medicine.medical_specialty 030209 endocrinology & metabolism [SDV.CAN]Life Sciences [q-bio]/Cancer Cytoplasmic Granules Exocytosis 03 medical and health sciences [SDV.CAN] Life Sciences [q-bio]/Cancer Internal medicine Diabetes mellitus Internal Medicine medicine Animals Humans Pancreatic hormone 030304 developmental biology Polymorphism Genetic medicine.disease Mice Inbred C57BL Endocrinology Diabetes Mellitus Type 2 Islet Studies biology.protein HeLa Cells |
| Zdroj: | Diabetes Diabetes, American Diabetes Association, 2009, 58 (9), pp.2070-2083. ⟨10.2337/db09-0551⟩ Diabetes, American Diabetes Association, 2009, 58 (9), pp.2070-2083. 〈10.2337/db09-0551〉 Diabetes, 2009, 58 (9), pp.2070-2083. ⟨10.2337/db09-0551⟩ |
| ISSN: | 0012-1797 1939-327X |
| DOI: | 10.2337/db09-0551⟩ |
| Popis: | OBJECTIVE Zinc ions are essential for the formation of hexameric insulin and hormone crystallization. A nonsynonymous single nucleotide polymorphism rs13266634 in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8, is associated with type 2 diabetes. We describe the effects of deleting the ZnT8 gene in mice and explore the action of the at-risk allele. RESEARCH DESIGN AND METHODS Slc30a8 null mice were generated and backcrossed at least twice onto a C57BL/6J background. Glucose and insulin tolerance were measured by intraperitoneal injection or euglycemic clamp, respectively. Insulin secretion, electrophysiology, imaging, and the generation of adenoviruses encoding the low- (W325) or elevated- (R325) risk ZnT8 alleles were undertaken using standard protocols. RESULTS ZnT8−/− mice displayed age-, sex-, and diet-dependent abnormalities in glucose tolerance, insulin secretion, and body weight. Islets isolated from null mice had reduced granule zinc content and showed age-dependent changes in granule morphology, with markedly fewer dense cores but more rod-like crystals. Glucose-stimulated insulin secretion, granule fusion, and insulin crystal dissolution, assessed by total internal reflection fluorescence microscopy, were unchanged or enhanced in ZnT8−/− islets. Insulin processing was normal. Molecular modeling revealed that residue-325 was located at the interface between ZnT8 monomers. Correspondingly, the R325 variant displayed lower apparent Zn2+ transport activity than W325 ZnT8 by fluorescence-based assay. CONCLUSIONS ZnT8 is required for normal insulin crystallization and insulin release in vivo but not, remarkably, in vitro. Defects in the former processes in carriers of the R allele may increase type 2 diabetes risks. |
| Databáze: | OpenAIRE |
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