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Nature Research, Nature Genetics, 5(48), p. 519-527, 2016

DOI: 10.1038/ng.3531

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

Journal article published in 2016 by James Dooley, Lei Tian, Susann Schonefeldt, Viviane Delghingaro-Augusto, Josselyn E. Garcia Perez ORCID, Emanuela Pasciuto ORCID, Daniele Di Marino, Edward J. Carr, Nikolay Oskolkov, Valeriya Lyssenko, Dean Franckaert, Vasiliki Lagou, Lut Overbergh, Jonathan Vandenbussche, Joke Allemeersch and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.