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Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

  • James Dooley
  • Lei Tian
  • Susann Schonefeldt
  • Viviane Delghingaro-Augusto
  • Josselyn E Garcia-Perez
  • Emanuela Pasciuto
  • Daniele Di Marino
  • Edward J Carr
  • Nikolay Oskolkov
  • Valeriya Lyssenko
  • Dean Franckaert
  • Vasiliki Lagou
  • Lut Overbergh
  • Jonathan Vandenbussche
  • Joke Allemeersch
  • Genevieve Chabot-Roy
  • Jane E Dahlstrom
  • D Ross Laybutt
  • Nikolai Petrovsky
  • Luis Socha
  • Kris Gevaert
  • Anton M Jetten
  • Diether Lambrechts
  • Michelle A Linterman
  • Chris C Goodnow
  • Christopher J Nolan
  • Sylvie Lesage
  • Susan M Schlenner
  • Adrian Liston
Publishing year: 2016
Language: English
Pages: 519-527
Publication/Series: Nature Genetics
Volume: 48
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.


  • Endocrinology and Diabetes


  • Genomics, Diabetes and Endocrinology
  • ISSN: 1546-1718
Nikolay Oskolkov
E-mail: nikolay [dot] oskolkov [at] biol [dot] lu [dot] se

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Molecular Cell Biology

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Microbial Ecology