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

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.

Type Journal
ISBN 1546-1718 (Electronic) 1061-4036 (Linking)
Authors Dooley, J.; Tian, L.; Schonefeldt, S.; Delghingaro-Augusto, V.; Garcia-Perez, J. E.; Pasciuto, E.; Di Marino, D.; Carr, E. J.; Oskolkov, N.; Lyssenko, V.; Franckaert, D.; Lagou, V.; Overbergh, L.; Vandenbussche, J.; Allemeersch, J.; Chabot-Roy, G.; Dahlstrom, J. E.; Laybutt, D. R.; Petrovsky, N.; Socha, L.; Gevaert, K.; Jetten, A. M.; Lambrechts, D.; Linterman, M. A.; Goodnow, C. C.; Nolan, C. J.; Lesage, S.; Schlenner, S. M.; Liston, A.;
Publisher Name NATURE GENETICS
Published Date 2016-05-01 00:00:00
Published Volume 48
Published Issue 5
Published Pages 519-27
Status Published in-print
URL link to publisher's version http://www.ncbi.nlm.nih.gov/pubmed/26998692
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/13621