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 Carr, Nikolay Oskolkov, Valeriya Lyssenko, Dean Franckaert, Vasiliki Lagou, Lut Overbergh, Jonathan Vandenbussche, Joke Allemeersch, Genevieve Chabot-Roy, Jane Esther Dahlstrom, David Laybutt, Nikolai Petrovsky, Luis A SochaKris Gevaert, Anton M Jetten, Diether Lambrechts, Michelle A Linterman, Christopher C Goodnow, Christopher J Nolan, Sylvie Lesage, Susan M Schlenner, Adrian Liston

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)519-527
Number of pages9
JournalNature Genetics
Volume48
Issue number5
DOIs
Publication statusPublished - 2016

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    Dooley, J., Tian, L., Schonefeldt, S., Delghingaro-Augusto, V., Garcia-Perez, J. E., Pasciuto, E., Di Marino, D., Carr, E., Oskolkov, N., Lyssenko, V., Franckaert, D., Lagou, V., Overbergh, L., Vandenbussche, J., Allemeersch, J., Chabot-Roy, G., Dahlstrom, J. E., Laybutt, D., Petrovsky, N., ... Liston, A. (2016). Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes. Nature Genetics, 48(5), 519-527. https://doi.org/10.1038/ng.3531