The transcription factor STAT6 plays a critical role in promoting beta cell viability and is depleted in islets of individuals with type 1 diabetes
dc.contributor.author | Leslie, KA | |
dc.contributor.author | Russell, MA | |
dc.contributor.author | Taniguchi, K | |
dc.contributor.author | Richardson, SJ | |
dc.contributor.author | Morgan, NG | |
dc.date.accessioned | 2019-01-17T13:18:13Z | |
dc.date.issued | 2019-10-18 | |
dc.description.abstract | Aims/hypothesis: In type 1 diabetes, selective beta cell loss occurs within the inflamed milieu of insulitic islets. This milieu is generated via the enhanced secretion of proinflammatory cytokines and by the loss of anti-inflammatory molecules such as IL-4 and IL-13. While the actions of proinflammatory cytokines have been well-studied in beta cells, the effects of their anti-inflammatory counterparts have received relatively little attention and we have addressed this. Methods: Clonal beta cells, isolated human islets and pancreas sections from control individuals and those with type 1 diabetes were employed. Gene expression was measured using targeted gene arrays and by quantitative RT-PCR. Protein expression was monitored in cell extracts by western blotting and in tissue sections by immunocytochemistry. Target proteins were knocked down selectively with interference RNA. Results: Cytoprotection achieved with IL-4 and IL-13 is mediated by the early activation of signal transducer and activator of transcription 6 (STAT6) in beta cells, leading to the upregulation of anti-apoptotic proteins, including myeloid leukaemia-1 (MCL-1) and B cell lymphoma-extra large (BCLXL). We also report the induction of signal regulatory protein-α (SIRPα), and find that knockdown of SIRPα is associated with reduced beta cell viability. These anti-apoptotic proteins and their attendant cytoprotective effects are lost following siRNA-mediated knockdown of STAT6 in beta cells. Importantly, analysis of human pancreas sections revealed that STAT6 is markedly depleted in the beta cells of individuals with type 1 diabetes, implying the loss of cytoprotective responses. Conclusions/interpretation: Selective loss of STAT6 may contribute to beta cell demise during the progression of type 1 diabetes. | en_GB |
dc.description.sponsorship | Diabetes UK | en_GB |
dc.description.sponsorship | JDRF | en_GB |
dc.identifier.citation | Vol. 62 (1), pp. 87 - 98 | en_GB |
dc.identifier.doi | 10.1007/s00125-018-4750-8 | |
dc.identifier.grantnumber | 15/0005156 | en_GB |
dc.identifier.grantnumber | 25-2012-516 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/35506 | |
dc.language.iso | en | en_GB |
dc.publisher | Springer Verlag | en_GB |
dc.rights | © The Author(s) 2018. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. | en_GB |
dc.subject | Cytokine | en_GB |
dc.subject | Inflammation | en_GB |
dc.subject | Interleukin-4 | en_GB |
dc.subject | Interleukin-13 | en_GB |
dc.subject | Palmitate | en_GB |
dc.subject | SIRPα | en_GB |
dc.title | The transcription factor STAT6 plays a critical role in promoting beta cell viability and is depleted in islets of individuals with type 1 diabetes | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2019-01-17T13:18:13Z | |
dc.identifier.issn | 0012-186X | |
dc.description | This is the final version. Available on open access from Springer Verlag via the DOI in this record | en_GB |
dc.identifier.journal | Diabetologia | en_GB |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2018-09-14 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2018-09-14 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2019-01-17T13:15:05Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2019-01-17T13:18:19Z | |
refterms.panel | A | en_GB |
refterms.depositException | publishedGoldOA |
Files in this item
This item appears in the following Collection(s)
Except where otherwise noted, this item's licence is described as © The Author(s) 2018.
Open Access.
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.