Premium
Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β ‐cell apoptosis
Author(s) -
Santin I.,
Eizirik D. L.
Publication year - 2013
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12162
Subject(s) - insulitis , biology , mda5 , innate immune system , pancreatic islets , candidate gene , inflammation , immune system , immunology , gene , genetics , genome wide association study , phenotype , autoimmunity , cell type , islet , cell , single nucleotide polymorphism , diabetes mellitus , rna interference , genotype , endocrinology , rna
Genome‐wide association studies ( GWAS ) have identified more than 50 loci associated with genetic risk of type 1 diabetes ( T1D ). Several T1D candidate genes have been suggested or identified within these regions, but the molecular mechanisms by which they contribute to insulitis and β‐cell destruction remain to be clarified. More than 60% of the T1D candidate genes are expressed in human pancreatic islets, suggesting that they contribute to T1D by regulating at least in part pathogenic mechanisms at the β‐cell level. Recent studies by our group indicate that important genetically regulated pathways in β‐cells include innate immunity and antiviral activity, involving RIG ‐like receptors (particularly MDA5 ) and regulators of type I IFNs (i.e. PTPN2 and USP18 ), and genes related to β‐cell phenotype and susceptibility to pro‐apoptotic stimuli (i.e. GLIS3 ). These observations reinforce the concept that the early pathogenesis of T1D is characterized by a dialogue between the immune system and pancreatic β‐cells. This dialogue is probably influenced by polymorphisms in genes expressed at the β‐cell and/or immune system level, leading to inadequate responses to environmental cues such as viral infections. Further studies are needed to clarify how these disease‐associated variants affect pancreatic β‐cell responses to inflammation and the subsequent triggering of autoimmune responses and progressive β‐cell loss.