Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM

Abstract

T1DM (type 1 diabetes mellitus), which results from the irreversible elimination of beta-cells mediated by autoreactive T cells, is defined as an autoimmune disease. It is widely accepted that T1DM is caused by a combination of genetic and environmental factors, but the precise underlying molecular mechanisms are still unknown. To date, more than 50 genetic risk regions contributing to the pathogenesis of T1DM have been identified by GWAS (genome-wide association studies). Notably, more than 60% of the identified candidate genes are expressed in islets and beta-cells, which makes it plausible that these genes act at the beta-cell level and play a key role in the pathogenesis of T1DM. In this review, we focus on the current status of candidate genes that act at the beta-cell level by regulating the innate immune response and antiviral activity, affecting susceptibility to proapoptotic stimuli and influencing the pancreatic beta-cell phenotype.

Keywords: GWAS; T1DM; apoptosis; beta-cell phenotype; candidate gene; innate immunity; pancreatic beta-cell.

Figure 1

T1DM candidate genes acting at the beta-cell level mainly play a role in three pathways (11): (1) Regulate the innate immune response and pathways important for antiviral activity, such as the type 1 IFN signaling pathway (IFIH1, TYK2, PTPN2). (2) Modulate susceptibility to proapoptotic stimuli (BACH2, TNFAIP3, ERBB3, HIP14, STX4, CTSH, PTPN2). (3) Affect beta-cell phenotypes, primarily insulin production (GLIS3). Candidate genes in green and red represent protective and predisposing candidates, respectively. Some candidate genes clearly participate in more than one pathway.

Figure 2

Innate immunity (especially the type 1 IFN signaling pathway) and cytokine-induced apoptosis together contribute to beta-cell death. (1) When PAMPs are bound by PRRs, including the cytosolic receptors RIG-1 and MDA5 and endosomal TLRs, the interactions can promote the synthesis and secretion of type 1 IFNs. IFN-α/β bind their receptor IFNAR and induce the production of cytokines and chemokines that can cause and worsen insulitis and apoptosis. (2) The signaling pathways underlying cytokine-induced apoptosis mainly include (i) JAK/STAT signaling induced by IFN-γ binding to its receptor IFNGR and (ii) NF-κB and MAPK signaling induced by IL-β/IL-R and TNF-α/TNFR.