Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Om Prakash Dwivedi
  • Mikko Lehtovirta
  • Benoit Hastoy
  • Vikash Chandra
  • Nicole A. J. Krentz
  • Sandra Kleiner
  • Deepak Jain
  • Ann-Marie Richard
  • Fernando Abaitua
  • Nicola L. Beer
  • Antje Grotz
  • Ulrika Krus
  • Anu Suoranta
  • Daniel Gomez
  • Aris Baras
  • Benoite Champon
  • Anthony J. Payne
  • Daniela Moralli
  • Soren K. Thomsen
  • Philipp Kramer
  • Ioannis Spiliotis
  • Reshma Ramracheya
  • Pauline Chabosseau
  • Andria Theodoulou
  • Rebecca Cheung
  • Martijn Van De Bunt
  • Jason Flannick
  • Maddalena Trombetta
  • Enzo Bonora
  • Claes B. Wolheim
  • Leena Sarelin
  • Riccardo C. Bonadonna
  • Patrik Rorsman
  • Benjamin Davies
  • Julia Brosnan
  • Mark I. Mccarthy
  • Timo Otonkoski
  • Guy A. Rutter
  • Jesper Gromada
  • Anna L. Gloyn
  • Tiinamaija Tuomi
Organisations
External organisations
  • University of Helsinki
  • University of Oxford
  • Pfizer Inc. US
  • Skåne University Hospital
  • Massachusetts General Hospital
  • Broad Institute
  • University of Verona
  • Lund University
  • Folkhälsan Research Center
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)1-22
JournalNature Genetics
Publication statusPublished - 2019 Nov 1
Publication categoryResearch
Peer-reviewedYes