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

被引：98

作者：

Dooley, James ^{[1
,2
]}

Tian, Lei ^{[1
,2
]}

Schonefeldt, Susann ^{[1
,2
]}

Delghingaro-Augusto, Viviane ^{[3
]}

Garcia-Perez, Josselyn E. ^{[1
,2
]}

Pasciuto, Emanuela ^{[1
,2
]}

Di Marino, Daniele ^{[4
]}

Carr, Edward J. ^{[5
]}

Oskolkov, Nikolay ^{[6
]}

Lyssenko, Valeriya ^{[6
,7
]}

Franckaert, Dean ^{[1
,2
]}

Lagou, Vasiliki ^{[1
,2
,8
]}

Overbergh, Lut ^{[9
]}

Vandenbussche, Jonathan ^{[10
,11
]}

Allemeersch, Joke ^{[12
]}

Chabot-Roy, Genevieve ^{[13
,14
]}

Dahlstrom, Jane E. ^{[3
,15
]}

Laybutt, D. Ross ^{[16
]}

Petrovsky, Nikolai ^{[17
]}

Socha, Luis ^{[18
]}

Gevaert, Kris ^{[10
,11
]}

Jetten, Anton M. ^{[19
]}

Lambrechts, Diether ^{[20
,21
]}

Linterman, Michelle A. ^{[5
]}

Goodnow, Chris C. ^{[16
]}

Nolan, Christopher J. ^{[3
,22
]}

Lesage, Sylvie ^{[13
,14
]}

Schlenner, Susan M. ^{[1
,2
]}

Liston, Adrian ^{[1
,2
]}

机构：

[1] VIB, Ctr Biol Dis, Leuven, Belgium

[2] Univ Leuven, Dept Microbiol & Immunol, Leuven, Belgium

[3] Australian Natl Univ, Sch Med, Canberra, ACT, Australia

[4] Univ Svizzera Italiana, Dept Informat, Lugano, Switzerland

[5] Babraham Inst, Lymphocyte Signaling & Dev Inst Strateg Programme, Cambridge, England

[6] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

[7] Steno Diabet Ctr, Dept Translat Pathophysiol, DK-2820 Gentofte, Denmark

[8] Univ Leuven, Dept Neurosci, Leuven, Belgium

[9] Univ Leuven, Dept Clin & Expt Med, Leuven, Belgium

[10] VIB, Dept Med Prot Res, Ghent, Belgium

[11] Univ Ghent, Dept Biochem, B-9000 Ghent, Belgium

[12] Univ Leuven, VIB Nucle Core, Leuven, Belgium

[13] Hop Maison Neuve Rosemont, Immunol Oncol Sect, Montreal, PQ H1T 2M4, Canada

[14] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada

[15] Canberra Hosp, Dept Anat Pathol, Garran, ACT, Australia

[16] Univ New S Wales, Garvan Inst Med Res, Sydney, NSW, Australia

[17] Flinders Univ S Australia, Dept Endocrinol, Adelaide, SA 5001, Australia

[18] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 2601, Australia

[19] NIEHS, Immun Inflammat & Dis Lab, US Natl Inst Hlth, POB 12233, Res Triangle Pk, NC 27709 USA

[20] VIB, Vesalius Res Ctr, Leuven, Belgium

[21] Univ Leuven, Dept Oncol, Leuven, Belgium

[22] Canberra Hosp, Dept Endocrinol, Garran, ACT, Australia

来源：

NATURE GENETICS | 2016年 / 48卷 / 05期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会; 欧洲研究理事会; 瑞典研究理事会;

关键词：

ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; TRANSGENIC MOUSE MODEL; MOLECULAR-DYNAMICS; DNA; EXPRESSION; ORGAN; MICE; RNA; INSULITIS;

D O I：

10.1038/ng.3531

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：519 / +

页数：12

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