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  • Dwivedi, Om PrakashUniversity of Helsinki (author)

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

  • Article/chapterEnglish2019

Publisher, publication year, extent ...

  • 2019-11-01
  • Springer Science and Business Media LLC,2019

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:adea1fb6-d721-4e0f-b08b-85a37539134e
  • https://lup.lub.lu.se/record/adea1fb6-d721-4e0f-b08b-85a37539134eURI
  • https://doi.org/10.1038/s41588-019-0513-9DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • 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 β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β 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.

Subject headings and genre

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  • Lehtovirta, MikkoUniversity of Helsinki (author)
  • Hastoy, BenoitUniversity of Oxford (author)
  • Chandra, VikashUniversity of Helsinki (author)
  • Krentz, Nicole A. J.University of Oxford (author)
  • Kleiner, Sandra (author)
  • Jain, DeepakLund University,Lunds universitet,Antigen presentation,Forskargrupper vid Lunds universitet,Medicinsk proteinvetenskap,Antigen Presentation,Lund University Research Groups,Medical Protein Science(Swepub:lu)med-dji (author)
  • Richard, Ann-MariePfizer Inc. US (author)
  • Abaitua, FernandoUniversity of Oxford (author)
  • Beer, Nicola L.University of Oxford (author)
  • Grotz, Antje (author)
  • Prasad, Rashmi B.Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-rpa (author)
  • Hansson, OlaLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,Skåne University Hospital,University of Helsinki(Swepub:lu)medk-oha (author)
  • Ahlqvist, EmmaLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,Skåne University Hospital(Swepub:lu)infl-eah (author)
  • Krus, UlrikaLund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups(Swepub:lu)medk-ufr (author)
  • Artner, IsabellaLund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Endokrin Celldifferentiering,Forskargrupper vid Lunds universitet,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine,Endocrine Cell Differentiation and Function,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-iba (author)
  • Suoranta, Anu (author)
  • Gomez, Daniel (author)
  • Baras, Aris (author)
  • Champon, Benoite (author)
  • Payne, Anthony J. (author)
  • Moralli, Daniela (author)
  • Thomsen, Soren K. (author)
  • Kramer, Philipp (author)
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  • Ramracheya, Reshma (author)
  • Chabosseau, Pauline (author)
  • Theodoulou, Andria (author)
  • Cheung, Rebecca (author)
  • Van De Bunt, Martijn (author)
  • Flannick, JasonMassachusetts General Hospital,Broad Institute (author)
  • Trombetta, MaddalenaUniversity of Verona (author)
  • Bonora, Enzo (author)
  • Wolheim, Claes B.Lund University (author)
  • Sarelin, LeenaFolkhälsan Research Center (author)
  • Bonadonna, Riccardo C. (author)
  • Rorsman, PatrikUniversity of Oxford(Swepub:lu)mphy-pro (author)
  • Davies, Benjamin (author)
  • Brosnan, Julia (author)
  • Mccarthy, Mark I. (author)
  • Otonkoski, Timo (author)
  • Lagerstedt, Jens O.Lund University,Lunds universitet,Medicinsk proteinvetenskap,Forskargrupper vid Lunds universitet,Medical Protein Science,Lund University Research Groups(Swepub:lu)med-jls (author)
  • Rutter, Guy A. (author)
  • Gromada, Jesper (author)
  • Gloyn, Anna L. (author)
  • Tuomi, TiinamaijaLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups(Swepub:lu)ti8736tu (author)
  • Groop, LeifLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,University of Helsinki,Skåne University Hospital(Swepub:lu)endo-lgr (author)
  • University of HelsinkiUniversity of Oxford (creator_code:org_t)

Related titles

  • In:Nature Genetics: Springer Science and Business Media LLC, s. 1-221061-40361546-1718

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