Dooley James, Tian Lei, Schonefeldt Susann, Delghingaro-Augusto Viviane, Garcia-Perez Josselyn E, Pasciuto Emanuela, Di Marino Daniele, Carr Edward J, Oskolkov Nikolay, Lyssenko Valeriya, Franckaert Dean, Lagou Vasiliki, Overbergh Lut, Vandenbussche Jonathan, Allemeersch Joke, Chabot-Roy Genevieve, Dahlstrom Jane E, Laybutt D Ross, Petrovsky Nikolai, Socha Luis, Gevaert Kris, Jetten Anton M, Lambrechts Diether, Linterman Michelle A, Goodnow Chris C, Nolan Christopher J, Lesage Sylvie, Schlenner Susan M, Liston Adrian
Center for the Biology of Disease, VIB, Leuven, Belgium.
Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
Nat Genet. 2016 May;48(5):519-27. doi: 10.1038/ng.3531. Epub 2016 Mar 21.
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.
1型糖尿病(T1D)和2型糖尿病(T2D)具有共同的病理生理特征,但两者之间的机制联系仍不清楚。T1D是由胰腺β细胞的自身免疫性破坏引起的,而T2D中的β细胞功能衰竭则是延迟且渐进性的。我们在此发现了T1D非肥胖糖尿病(NOD)小鼠中糖尿病易感性的一个新的遗传成分,确定了与免疫无关的β细胞脆弱性。Xrcc4和Glis3的基因变异改变了NODβ细胞对未折叠蛋白应激的反应,增强了细胞凋亡和衰老的命运。在人类胰岛中也观察到了相同的转录关系,证明了β细胞脆弱性在糖尿病遗传易感性中的作用。