On the Immense Variety and Complexity of Circumstances Conditioning Pancreatic β-Cell Apoptosis in Type 1 Diabetes

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FIG. 1.
FIG. 1.

A hypothetical model of the β-cell responses that contribute to insulitis and progressive loss of β-cell mass in type 1 diabetes. Locally produced cytokines (e.g., interleukin [IL]-1β, interferons -α, -β, and -γ, tumor necrosis factor-α, and IL-17) or “danger signals” provided by viruses or endogenous ligands of interferon-induced helicase 1/melanoma differentiation-associated gene 5 (IFIH1/MDA5) and other innate immune response sensors (e.g., retinoic acid–inducible gene I [RIG-I] and Toll-like receptor [TLR] 3) activate transcription factors including signal transducer and activator of transcription-1 (STAT-1) and nuclear factor-κB (NF-κB), miRNAs such as miRNA-29 a/b/c, and regulators of AS such as neuro-oncological ventral antigen 1 (Nova1). Downstream of these and other regulatory factors, there is triggering of endoplasmic reticulum (ER) stress and upregulation of the machinery for antigen presentation. This, together with changes in AS, may generate neoantigens that induce or augment β-cell recognition by the immune system. Additional signals provided by β-cells to the immune system include the production and release of chemokines and cytokines and cell death, which, in the context of local inflammation, may function as “danger signal” for the immune system. β-Cell apoptosis is regulated by key miRNAs and transcription factors and by endoplasmic reticulum stress, culminating in the activation of the intrinsic mitochondrial pathway of apoptosis. Type 1 diabetes candidate genes such as PTPN2 and MDA-5 regulate many of the different steps shown in the figure, besides their effects at the immune system level, providing a link between the genetics of type 1 diabetes and the mechanisms leading to β-cell loss. Activated immune cells, attracted by the local production of chemokines, will produce more cytokines and chemokines, perpetuating the local inflammatory response and changes in miRNAs, transcription factors, and AS. The figure was modified from ref. 5. Additional information, and supporting references, can be found in refs. 5 and 1416. CEBP-δ, CCAAT/enhancer binding protein-δ; IRF, interferon regulatory factor; JNK, c-Jun N-terminal kinase; Pdx-1, pancreatic and duodenal homeobox 1.

This Article

  1. Diabetes vol. 61 no. 7 1661-1663