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Diabetes Obes Metab. 2013 Sep;15 Suppl 3:71-81. doi: 10.1111/dom.12162.

Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β-cell apoptosis.

Author information

1
Laboratory of Experimental Medicine, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium. izortze.santin@gmail.com

Abstract

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.

KEYWORDS:

apoptosis; candidate genes; cytokines; inflammation; pancreatic β-cells; type 1 diabetes

PMID:
24003923
DOI:
10.1111/dom.12162
[Indexed for MEDLINE]
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