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

Dooley, James; Tian, Lei; Schonefeldt, Susann; Delghingaro-Augusto, Viviane; Garcia-Perez, Josselyn E; Pasciuto, Emanuela; Di Marino, Daniele; Carr, Edward J; Oskolkov, Nikolay LU and Lyssenko, Valeriya LU , et al. (2016) In Nature Genetics
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.

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@misc{3b3e9384-e452-4299-b17f-d84ba2d6531f,
  abstract     = {<p>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.</p>},
  author       = {Dooley, James and Tian, Lei and Schonefeldt, Susann and Delghingaro-Augusto, Viviane and Garcia-Perez, Josselyn E and Pasciuto, Emanuela and Di Marino, Daniele and Carr, Edward J and Oskolkov, Nikolay and Lyssenko, Valeriya and Franckaert, Dean and Lagou, Vasiliki and Overbergh, Lut and Vandenbussche, Jonathan and Allemeersch, Joke and Chabot-Roy, Genevieve and Dahlstrom, Jane E and Laybutt, D Ross and Petrovsky, Nikolai and Socha, Luis and Gevaert, Kris and Jetten, Anton M and Lambrechts, Diether and Linterman, Michelle A and Goodnow, Chris C and Nolan, Christopher J and Lesage, Sylvie and Schlenner, Susan M and Liston, Adrian},
  issn         = {1546-1718},
  language     = {eng},
  month        = {03},
  publisher    = {ARRAY(0xc428b10)},
  series       = {Nature Genetics},
  title        = {Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes},
  url          = {http://dx.doi.org/10.1038/ng.3531},
  year         = {2016},
}