DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway

Diabetologia. 2019 Mar;62(3):459-472. doi: 10.1007/s00125-018-4782-0. Epub 2018 Nov 26.


Aims/hypothesis: The initial stages of type 1 diabetes are characterised by an aberrant islet inflammation that is in part regulated by the interaction between type 1 diabetes susceptibility genes and environmental factors. Chromosome 16p13 is associated with type 1 diabetes and CLEC16A is thought to be the aetiological gene in the region. Recent gene expression analysis has, however, indicated that SNPs in CLEC16A modulate the expression of a neighbouring gene with unknown function named DEXI, encoding dexamethasone-induced protein (DEXI). We therefore evaluated the role of DEXI in beta cell responses to 'danger signals' and determined the mechanisms involved.

Methods: Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays.

Results: DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNβ levels. Exposure to PIC increased chromatin-bound DEXI and IFNβ promoter activity. This effect on IFNβ promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of IFNβ transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines.

Conclusions/interpretation: These observations support DEXI as the aetiological gene in the type 1 diabetes-associated 16p13 genomic region, and provide the first indication of a link between this candidate gene and the regulation of local antiviral immune responses in beta cells. Moreover, our results provide initial information on the function of DEXI.

Keywords: DEXI; Inflammation; Pancreatic beta cell; Susceptibility gene; Type 1 diabetes; Type I IFNs; Viral infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Interferon Type I / metabolism*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Polymorphism, Single Nucleotide
  • RNA, Double-Stranded
  • Rats
  • STAT Transcription Factors / metabolism*
  • Signal Transduction / genetics*


  • DEXI protein, human
  • DNA-Binding Proteins
  • Interferon Type I
  • Membrane Proteins
  • RNA, Double-Stranded
  • STAT Transcription Factors