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

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

Author information

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.

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.

PMID:
26998692
PMCID:
PMC5584070
DOI:
10.1038/ng.3531
[Indexed for MEDLINE]
Free PMC Article

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