title: 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.
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: James
authors.initials: J
authors.lastname: Dooley
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Susann
authors.initials: S
authors.lastname: Schonefeldt
authors.affiliation: Australian National University Medical School, Canberra, Australian Capital Territory, Australia.
authors.forename: Viviane
authors.initials: V
authors.lastname: Delghingaro-Augusto
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Josselyn E
authors.identifier: 0000-0003-2369-532X
authors.initials: JE
authors.lastname: Garcia-Perez
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pasciuto
authors.affiliation: Department of Informatics, Università della Svizzera Italiana, Lugano, Switzerland.
authors.forename: Daniele
authors.initials: D
authors.lastname: Di Marino
authors.affiliation: Lymphocyte Signaling and Development Institute Strategic Programme, Babraham Institute, Cambridge, UK.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Carr
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Oskolkov
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.|Department of Translational Pathophysiology, Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Dean
authors.initials: D
authors.lastname: Franckaert
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.|Department of Neurosciences, University of Leuven, Leuven, Belgium.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Lagou
authors.affiliation: Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Lut
authors.initials: L
authors.lastname: Overbergh
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, Belgium.|Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vandenbussche
authors.affiliation: VIB Nucleomics Core, University of Leuven, Leuven, Belgium.
authors.forename: Joke
authors.initials: J
authors.lastname: Allemeersch
authors.affiliation: Immunology-Oncology Section, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Chabot-Roy
authors.affiliation: Australian National University Medical School, Canberra, Australian Capital Territory, Australia.|Department of Anatomical Pathology, Canberra Hospital, Garran, Australian Capital Territory, Australia.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Dahlstrom
authors.affiliation: Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: D Ross
authors.initials: DR
authors.lastname: Laybutt
authors.affiliation: Department of Endocrinology, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Petrovsky
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
authors.forename: Luis
authors.initials: L
authors.lastname: Socha
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, Belgium.|Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.affiliation: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Department of Oncology, University of Leuven, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Lymphocyte Signaling and Development Institute Strategic Programme, Babraham Institute, Cambridge, UK.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Linterman
authors.affiliation: Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Chris C
authors.initials: CC
authors.lastname: Goodnow
authors.affiliation: Australian National University Medical School, Canberra, Australian Capital Territory, Australia.|Department of Endocrinology, Canberra Hospital, Garran, Australian Capital Territory, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nolan
authors.affiliation: Immunology-Oncology Section, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Sylvie
authors.identifier: 0000-0002-0968-2795
authors.initials: S
authors.lastname: Lesage
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Schlenner
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
mesh_terms: D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D004032:Diet; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D017510:Protein Folding; D012097:Repressor Proteins / Q000235:genetics; D012737:Sex Factors; D013312:Stress, Physiological; D015534:Trans-Activators / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C478000:Glis3 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; C511788:XRCC4 protein, mouse