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Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.
Dwivedi, Om Prakash; Lehtovirta, Mikko; Hastoy, Benoit; Chandra, Vikash; Krentz, Nicole A J; Kleiner, Sandra; Jain, Deepak; Richard, Ann-Marie; Abaitua, Fernando; Beer, Nicola L; Grotz, Antje; Prasad, Rashmi B; Hansson, Ola; Ahlqvist, Emma; Krus, Ulrika; Artner, Isabella; Suoranta, Anu; Gomez, Daniel; Baras, Aris; Champon, Benoite; Payne, Anthony J; Moralli, Daniela; Thomsen, Soren K; Kramer, Philipp; Spiliotis, Ioannis; Ramracheya, Reshma; Chabosseau, Pauline; Theodoulou, Andria; Cheung, Rebecca; van de Bunt, Martijn; Flannick, Jason; Trombetta, Maddalena; Bonora, Enzo; Wolheim, Claes B; Sarelin, Leena; Bonadonna, Riccardo C; Rorsman, Patrik; Davies, Benjamin; Brosnan, Julia; McCarthy, Mark I; Otonkoski, Timo; Lagerstedt, Jens O; Rutter, Guy A; Gromada, Jesper; Gloyn, Anna L; Tuomi, Tiinamaija; Groop, Leif.
Afiliação
  • Dwivedi OP; Institute for Molecular Medicine Finland, Helsinki University, Helsinki, Finland.
  • Lehtovirta M; Institute for Molecular Medicine Finland, Helsinki University, Helsinki, Finland.
  • Hastoy B; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Chandra V; Stem Cells and Metabolism Research Program and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Krentz NAJ; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Kleiner S; Regeneron Pharmaceuticals, Tarrytown, NY, USA.
  • Jain D; Department of Experimental Medical Science, Lund University, Lund, Sweden.
  • Richard AM; Pfizer Inc., Cambridge, MA, USA.
  • Abaitua F; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Beer NL; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Grotz A; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Prasad RB; Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
  • Hansson O; Institute for Molecular Medicine Finland, Helsinki University, Helsinki, Finland.
  • Ahlqvist E; Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
  • Krus U; Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
  • Artner I; Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
  • Suoranta A; Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
  • Gomez D; Institute for Molecular Medicine Finland, Helsinki University, Helsinki, Finland.
  • Baras A; Regeneron Pharmaceuticals, Tarrytown, NY, USA.
  • Champon B; Regeneron Pharmaceuticals, Tarrytown, NY, USA.
  • Payne AJ; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Moralli D; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Thomsen SK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Kramer P; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Spiliotis I; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Ramracheya R; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Chabosseau P; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Theodoulou A; Section of Cell Biology, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith, Hospital, London, UK.
  • Cheung R; Section of Cell Biology, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith, Hospital, London, UK.
  • van de Bunt M; Section of Cell Biology, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith, Hospital, London, UK.
  • Flannick J; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Trombetta M; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Bonora E; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
  • Wolheim CB; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
  • Sarelin L; Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
  • Bonadonna RC; Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
  • Rorsman P; Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
  • Davies B; Folkhälsan Research Center, Helsinki, Finland.
  • Brosnan J; Department of Medicine and Surgery, University of Parma School of Medicine and Azienda Ospedaliera Universitaria of Parma, Parma, Italy.
  • McCarthy MI; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Otonkoski T; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Lagerstedt JO; Pfizer Inc., Cambridge, MA, USA.
  • Rutter GA; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Gromada J; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Gloyn AL; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
  • Tuomi T; Stem Cells and Metabolism Research Program and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Groop L; Department of Experimental Medical Science, Lund University, Lund, Sweden.
Nat Genet ; 51(11): 1596-1606, 2019 11.
Article em En | MEDLINE | ID: mdl-31676859
ABSTRACT
A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived ß-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human ß cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ilhotas Pancreáticas / Diabetes Mellitus Tipo 2 / Células-Tronco Pluripotentes Induzidas / Transportador 8 de Zinco / Secreção de Insulina / Glucose Limite: Adolescent / Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Finlândia
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ilhotas Pancreáticas / Diabetes Mellitus Tipo 2 / Células-Tronco Pluripotentes Induzidas / Transportador 8 de Zinco / Secreção de Insulina / Glucose Limite: Adolescent / Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Finlândia