Department of Biomedical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
Mol Cell Endocrinol. 2019 Oct 1;496:110524. doi: 10.1016/j.mce.2019.110524. Epub 2019 Jul 27.
Decreased insulin secretory capacity in Type 2 diabetes mellitus is associated with beta-cell dedifferentiation and inflammation. We hypothesize that prolonged exposure of beta-cells to low concentrations of IL-1β induce beta-cell dedifferentiation characterized by impaired glucose-stimulated insulin secretion, reduced expression of key beta-cell genes and changes in histone modifications at gene loci known to affect beta-cell function. Ten days exposure to IL-1β at non-cytotoxic concentrations reduced insulin secretion and beta-cell proliferation and decreased expression of key beta-cell identity genes, including MafA and Ucn3 and decreased H3K27ac at the gene loci, suggesting that inflammatory cytokines directly affects the epigenome. Following removal of IL-1β, beta-cell function was normalized and mRNA expression of beta-cell identity genes, such as insulin and Ucn3 returned to pre-stimulation levels. Our findings indicate that prolonged exposure to low concentrations of IL-1β induces epigenetic changes associated with loss of beta-cell identity as observed in Type 2 diabetes.
2 型糖尿病患者的胰岛素分泌能力下降与β细胞去分化和炎症有关。我们假设，β细胞长期暴露于低浓度的 IL-1β 会诱导β细胞去分化，表现为葡萄糖刺激的胰岛素分泌受损、关键β细胞基因表达减少以及已知影响β细胞功能的基因位点上组蛋白修饰的改变。10 天暴露于非细胞毒性浓度的 IL-1β 会降低胰岛素分泌和β细胞增殖，并降低关键β细胞特征基因，包括 MafA 和 Ucn3 的表达，并降低基因位点的 H3K27ac，表明炎症细胞因子直接影响表观基因组。去除 IL-1β 后，β细胞功能恢复正常，β细胞特征基因，如胰岛素和 Ucn3 的 mRNA 表达恢复到刺激前的水平。我们的研究结果表明，长期暴露于低浓度的 IL-1β 会诱导与 2 型糖尿病中观察到的β细胞特征丧失相关的表观遗传改变。
