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

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 SochaKris Gevaert, Anton M. Jetten, Diether Lambrechts, Michelle A. Linterman, Chris C. Goodnow, Christopher J. Nolan, Sylvie Lesage, Susan M. Schlenner, Adrian Liston^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

101 Citations (Scopus)

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.

Original language	English
Pages (from-to)	519-527
Number of pages	9
Journal	Nature Genetics
Volume	48
Issue number	5
DOIs	https://doi.org/10.1038/ng.3531
Publication status	Published - 1 May 2016

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Dooley, J., Tian, L., Schonefeldt, S., Delghingaro-Augusto, V., Garcia-Perez, J. E., Pasciuto, E., Di Marino, D., Carr, E. J., Oskolkov, N., Lyssenko, V., Franckaert, D., Lagou, V., Overbergh, L., Vandenbussche, J., Allemeersch, J., Chabot-Roy, G., Dahlstrom, J. E., Laybutt, D. R., Petrovsky, N., ... Liston, A. (2016). Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes. Nature Genetics, 48(5), 519-527. https://doi.org/10.1038/ng.3531

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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.",

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

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year = "2016",

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doi = "10.1038/ng.3531",

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Dooley, J, Tian, L, Schonefeldt, S, Delghingaro-Augusto, V, Garcia-Perez, JE, Pasciuto, E, Di Marino, D, Carr, EJ, Oskolkov, N, Lyssenko, V, Franckaert, D, Lagou, V, Overbergh, L, Vandenbussche, J, Allemeersch, J, Chabot-Roy, G, Dahlstrom, JE, Laybutt, DR, Petrovsky, N, Socha, L, Gevaert, K, Jetten, AM, Lambrechts, D, Linterman, MA, Goodnow, CC, Nolan, CJ, Lesage, S, Schlenner, SM & Liston, A 2016, 'Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes', Nature Genetics, vol. 48, no. 5, pp. 519-527. https://doi.org/10.1038/ng.3531

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AU - Tian, Lei

AU - Schonefeldt, Susann

AU - Delghingaro-Augusto, Viviane

AU - Garcia-Perez, Josselyn E.

AU - Pasciuto, Emanuela

AU - Di Marino, Daniele

AU - Carr, Edward J.

AU - Oskolkov, Nikolay

AU - Lyssenko, Valeriya

AU - Franckaert, Dean

AU - Lagou, Vasiliki

AU - Overbergh, Lut

AU - Vandenbussche, Jonathan

AU - Allemeersch, Joke

AU - Chabot-Roy, Genevieve

AU - Dahlstrom, Jane E.

AU - Laybutt, D. Ross

AU - Petrovsky, Nikolai

AU - Socha, Luis

AU - Gevaert, Kris

AU - Jetten, Anton M.

AU - Lambrechts, Diether

AU - Linterman, Michelle A.

AU - Goodnow, Chris C.

AU - Nolan, Christopher J.

AU - Lesage, Sylvie

AU - Schlenner, Susan M.

AU - Liston, Adrian

PY - 2016/5/1

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N2 - 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.

AB - 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.

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DO - 10.1038/ng.3531

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SN - 1061-4036

VL - 48

SP - 519

EP - 527

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

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

Abstract

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