Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden.
Islet Cell Exocytosis Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden.
Diabetes. 2019 Oct;68(10):1965-1974. doi: 10.2337/db18-0900. Epub 2019 Aug 16.
Type 2 diabetes (T2D) is characterized by insufficient insulin secretion and elevated glucose levels, often in combination with high levels of circulating fatty acids. Long-term exposure to high levels of glucose or fatty acids impair insulin secretion in pancreatic islets, which could partly be due to epigenetic alterations. We studied the effects of high concentrations of glucose and palmitate combined for 48 h (glucolipotoxicity) on the transcriptome, the epigenome, and cell function in human islets. Glucolipotoxicity impaired insulin secretion, increased apoptosis, and significantly (false discovery rate <5%) altered the expression of 1,855 genes, including 35 genes previously implicated in T2D by genome-wide association studies (e.g., and ). Additionally, metabolic pathways were enriched for downregulated genes. Of the differentially expressed genes, 1,469 also exhibited altered DNA methylation (e.g., , , , and ). A luciferase assay showed that increased methylation of directly reduces its transcription in pancreatic β-cells, supporting the idea that DNA methylation underlies altered expression after glucolipotoxicity. Follow-up experiments in clonal β-cells showed that knockdown of and alters insulin secretion. Together, our novel data demonstrate that glucolipotoxicity changes the epigenome in human islets, thereby altering gene expression and possibly exacerbating the secretory defect in T2D.
2 型糖尿病（T2D）的特征是胰岛素分泌不足和血糖水平升高，通常伴有循环脂肪酸水平升高。长期暴露于高浓度葡萄糖或脂肪酸会损害胰岛中的胰岛素分泌，这在一定程度上可能是由于表观遗传改变所致。我们研究了高浓度葡萄糖和棕榈酸联合作用 48 小时（糖脂毒性）对人胰岛转录组、表观基因组和细胞功能的影响。糖脂毒性损害了胰岛素分泌，增加了细胞凋亡，并显著（错误发现率<5%）改变了 1855 个基因的表达，包括 35 个先前通过全基因组关联研究（GWAS）与 T2D 相关的基因（例如，和）。此外，代谢途径富集了下调基因。在差异表达基因中，有 1469 个基因的 DNA 甲基化也发生了改变（例如，、、、和）。荧光素酶测定表明，基因的甲基化增加直接降低了其在胰岛β细胞中的转录，这支持了 DNA 甲基化是糖脂毒性后基因表达改变的基础的观点。在克隆β细胞中的后续实验表明，基因和基因的敲低改变了胰岛素的分泌。总之，我们的新数据表明，糖脂毒性改变了人胰岛的表观基因组，从而改变了基因表达，并可能加重 T2D 中的分泌缺陷。
