Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell-mediated β cell destruction in the pancreas of genetically susceptible individuals. Extensive familial and population genetic studies uncovered the strong linkage and association between HLA gene variants and T1D. Non-HLA genes have also been associated with T1D, such as INS, CTLA4, and PTPN22. T1D is considered as one of the most heritable common diseases. However, evidence that monozygotic twins have incomplete concordance of disease susceptibility provides convincing proof that environmental factors also play important roles in the pathogenesis of the disease. Environmental factors can induce the alterations of gene expression via epigenetic mechanisms. Epigenetic modifications refer to the alterations in gene expression without changes of the DNA sequence, but instead occur as a result of DNA methylation, histone modifications, and miRNA regulation. Aberrant epigenetic modifications will cause the dysregulation of gene expression, thus leading to a variety of human diseases. There are significant differences in DNA methylation, histone modifications, and miRNA profiling found in T1D patients compared with healthy individuals. Epigenetic modifications contribute to the pathogenesis of T1D mainly by regulating the expression of susceptible genes in T1D. These susceptible genes are involved in antigen presentation (such as HLA), immune tolerance (such as FOXP3 and CTLA4), autoreactive T cell response (such as GAD65), and β cell functions (such as INS). A better understanding of epigenetic mechanisms for regulating susceptible genes of T1D will help identify candidates that target epigenetic pathways to control and/or prevent T1D. Knowledge of epigenetic changes in T1D also provides us with potential biomarkers for diagnosis, prognostication, personalized treatment, and prevention of the disease.

Inflammatory cytokines have a critical role in the progressive deterioration of pancreatic β-cell function and development of type 1 diabetes. Prolonged exposure of β-cells to inflammatory cytokines results in gene expression modifications, leading to loss of β-cell function. MicroRNAs (miRNAs) are small non-coding RNAs acting as key regulators of gene expression. Here, we demonstrate that miR-101a and miR-30b are key players in cytokine-mediated β-cell dysfunction. We found that IL-1β induces an increase in miR-101a and miR-30b in MIN6 cells, and that the two miRNAs participate in β-cell dysfunction, including decreased insulin content, gene expression, and increased β-cell death. miR-101a and miR-30b reduce proinsulin expression and insulin content by directly targeting the transcriptional factor Neurod1. In addition, β-cell apoptosis mediated by miR-101a and miR-30b is associated with diminished expression level of the antiapoptotic protein Bcl2. Moreover, we show that miR-101a causes an impairment in glucose-induced insulin secretion by decreasing the expression of the transcription factor Onecut2. Taken together, our findings suggest that changes in the levels of miR-101a and miR-30b contribute to cytokine-mediated β-cell dysfunction occurring during the development and progression of type 1 diabetes.

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