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

James Dooley; Lei Tian; Susann Schonefeldt; Viviane Delghingaro-Augusto; Josselyn E Garcia-Perez; Emanuela Pasciuto; Daniele Di Marino; Edward J Carr; Nikolay Oskolkov; Valeriya Lyssenko; Dean Franckaert; Vasiliki Lagou; Lut Overbergh; Jonathan Vandenbussche; Joke Allemeersch; Genevieve Chabot-Roy; Jane E Dahlstrom; D Ross Laybutt; Nikolai Petrovsky; Luis Socha; Kris Gevaert; Anton M Jetten; Diether Lambrechts; Michelle A Linterman; Chris C Goodnow; Christopher J Nolan; Sylvie Lesage; Susan M Schlenner; Adrian Liston

doi:10.1038/ng.3531

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

Nat Genet. 2016 May;48(5):519-27. doi: 10.1038/ng.3531. Epub 2016 Mar 21.

Authors

James Dooley^{1

2}, Lei Tian^{1

2}, Susann Schonefeldt^{1

2}, Viviane Delghingaro-Augusto³, Josselyn E Garcia-Perez^{1

2}, Emanuela Pasciuto^{1

2}, Daniele Di Marino⁴, Edward J Carr⁵, Nikolay Oskolkov⁶, Valeriya Lyssenko^{6

7}, Dean Franckaert^{1

2}, Vasiliki Lagou^{1

2

8}, Lut Overbergh⁹, Jonathan Vandenbussche^{10

11}, Joke Allemeersch¹², Genevieve Chabot-Roy^{13

14}, Jane E Dahlstrom^{3

15}, D Ross Laybutt¹⁶, Nikolai Petrovsky¹⁷, Luis Socha¹⁸, Kris Gevaert^{10

11}, Anton M Jetten¹⁹, Diether Lambrechts^{20

21}, Michelle A Linterman⁵, Chris C Goodnow¹⁶, Christopher J Nolan^{3

22}, Sylvie Lesage^{13

14}, Susan M Schlenner^{1

2}, Adrian Liston^{1

2}

Affiliations

¹ Center for the Biology of Disease, VIB, Leuven, Belgium.
² Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
³ Australian National University Medical School, Canberra, Australian Capital Territory, Australia.
⁴ Department of Informatics, Università della Svizzera Italiana, Lugano, Switzerland.
⁵ Lymphocyte Signaling and Development Institute Strategic Programme, Babraham Institute, Cambridge, UK.
⁶ Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.
⁷ Department of Translational Pathophysiology, Steno Diabetes Center, Gentofte, Denmark.
⁸ Department of Neurosciences, University of Leuven, Leuven, Belgium.
⁹ Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium.
¹⁰ Department of Medical Protein Research, VIB, Ghent, Belgium.
¹¹ Department of Biochemistry, Ghent University, Ghent, Belgium.
¹² VIB Nucleomics Core, University of Leuven, Leuven, Belgium.
¹³ Immunology-Oncology Section, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
¹⁴ Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.
¹⁵ Department of Anatomical Pathology, Canberra Hospital, Garran, Australian Capital Territory, Australia.
¹⁶ Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia.
¹⁷ Department of Endocrinology, Flinders University, Adelaide, South Australia, Australia.
¹⁸ John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
¹⁹ Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
²⁰ Vesalius Research Center, VIB, Leuven, Belgium.
²¹ Department of Oncology, University of Leuven, Leuven, Belgium.
²² Department of Endocrinology, Canberra Hospital, Garran, Australian Capital Territory, Australia.

PMID: 26998692
PMCID: PMC5584070
DOI: 10.1038/ng.3531

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Cellular Senescence
DNA-Binding Proteins / genetics
Diabetes Mellitus, Type 1 / genetics*
Diabetes Mellitus, Type 1 / pathology
Diabetes Mellitus, Type 2 / genetics*
Diabetes Mellitus, Type 2 / pathology
Diet
Female
Gene Expression Regulation
Genetic Predisposition to Disease*
Humans
Insulin-Secreting Cells / pathology*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Transgenic
Protein Folding
Repressor Proteins / genetics
Sex Factors
Stress, Physiological
Trans-Activators / genetics

Substances

DNA-Binding Proteins
Glis3 protein, mouse
Repressor Proteins
Trans-Activators
XRCC4 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding