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

Diabetologia. 2019 Jan;62(1):87-98. doi: 10.1007/s00125-018-4750-8. Epub 2018 Oct 18.


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.

Keywords: Cytokine; Inflammation; Interleukin-13; Interleukin-4; Palmitate; SIRPα.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Differentiation / metabolism
  • Apoptosis / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Diabetes Mellitus, Type 1 / metabolism*
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Interleukin-13 / pharmacology
  • Receptors, Immunologic / metabolism
  • STAT6 Transcription Factor / metabolism*


  • Antigens, Differentiation
  • Interleukin-13
  • Receptors, Immunologic
  • SIRPA protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human