Decio L. Eizirik: BETA CELL APOPTOSIS IN TYPE 1 DIABETES
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 βeta-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 βeta-cell level. Recent studies by our group indicate that important genetically regulated pathways in βeta-cells include innate immunity and antiviral activity, involving RIG-like receptors (particularly MDA5) and regulators of type I IFNs (i.e. PTPN2, USP18 and TYK2), and genes related to βeta-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 dialog between the immune system and pancreatic βeta-cells. This dialog is probably influenced by polymorphisms in genes expressed at the βeta-cell and/or immune system level, leading to inadequate responses to environmental cues such as viral infections. Our ongoing work aims to clarify how these disease-associated variants affect pancreatic βeta-cell responses to inflammation and the subsequent triggering of autoimmune responses and the specific and progressive βeta-cell loss by apoptosis.
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2. Nogueira TC, Paula FV, Villate O, Colli ML, Moura RF, Cunha DA, Marselli L, Marchetti P, Cnop M, Julier C, Eizirik DL GLIS3, a susceptibility gene for type 1 and 2 diabetes mellitus, modulates pancreatic beta cell apoptosis via regulation of a splice variant of the BH3-only protein Bim. PLoS Genet, 9: e1003532, 2013.
3. Santin I, Eizirik DL Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and beta-cell apoptosis. Diabetes Obes Metab 15 (Suppl. 3): 71-81, 2013
4. Marroqui L, Lopes M, Santos RSD, Roivainen M, Richardson S, Morgan N, Op de Beeck A, Eizirik DL Differential cell autonomous immune responses determine the outcome of coxsackievirus infections in pancreatic α and β cells. eLife, 4: e06990, 2015.