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The transcription factor STAT6 plays a critical role in promoting beta cell viability and is depleted in islets of individuals with type 1 diabetes.

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.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Leslie KA,Russell MA,Taniguchi K,Richardson SJ,Morgan NG

doi

10.1007/s00125-018-4750-8

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

87-98

issue

1

eissn

0012-186X

issn

1432-0428

pii

10.1007/s00125-018-4750-8

journal_volume

62

pub_type

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