Chronic oxidative stress resulting from hyperlipidemia is thought to be a key pathogenic driver of pancreatic β-cell dysfunction in leading to the onset of type 2 diabetes mellitus (T2DM). Long non-coding RNAs (lncRNAs) have been increasingly recognized to regulate dysfunction within pancreatic β-cells in the context of T2DM. In the present study, we sought to comprehensively analyze the roles of lncRNAs in dysfunctional β-cells and mouse islets. Analyses of INS-1E cells were performed by RNA-seq and qRT-PCR after treating with or without 0.5 mM palmitate for 4 days, leading us to identify the novel lncRNA Eif4g2 (lncEif4g2) as a functional regulator within these cells. When we overexpressed lncEif4g2 in INS-1E β-cells and mouse islets, this was sufficient for the reversal of palmitate-mediated reductions in cell viability, insulin production, ATP production by mitochondria, and creation of intracellular reactive oxygen species (ROS) and the dysfunction of mouse islets, with nuclear factor erythroid 2 related factor 2 (Nrf2) activation also being observed. In contrast, when lncEif4g2 was knocked down this led INS-1E cells and mouse islets to become more sensitive to palmitate-induced dysfunction, with reduced Nrf2 nuclear translocation also being detected. When antioxidants were used to treat INS-1E cells and mouse islets, however, these negative effects were reversed. Additional functional analyses revealed lncEif4g2 to be capable of directly binding to miR-3074–5p in β-cells, with the expression of lncEif4g2 and miR-3074–5p being negatively correlated with one another. We further found that cAMP-responsive element binding-protein (CREB) was a miR-3074–5p target gene in these cells, thus at least in part serving as a functional mediator of the lncEif4g2/miR-3074–5p axis within dysfunctional β-cells. In summary, our results thus reveal that lncEif4g2 is able to indirectly regulate the expression of CREB via targeting miR-3074–5p in INS-1E cells and mouse islets, thereby leading to enhanced Nrf2 activation.

高脂血症引起的慢性氧化应激被认为是导致2型糖尿病（T2DM）发作的胰腺β细胞功能异常的关键病原体。在T2DM的背景下，人们越来越多地认识到长非编码RNA（lncRNA）可调节胰腺β细胞内的功能障碍。在本研究中，我们试图全面分析lncRNA在功能异常的β细胞和小鼠胰岛中的作用。在用或不用0.5 mM棕榈酸酯处理4天后，通过RNA-seq和qRT-PCR对INS-1E细胞进行了分析，这使我们确定了新的lncRNA Eif4g2（lncEif4g2）作为这些细胞中的功能调节剂。当我们在INS-1Eβ细胞和小鼠胰岛中过表达lncEif4g2时，这足以逆转棕榈酸酯介导的细胞活力，胰岛素产生，还观察到线粒体的ATP产生，细胞内活性氧（ROS）的产生和小鼠胰岛功能障碍，以及核因子红系2相关因子2（Nrf2）的激活。相反，当敲低lncEif4g2时，这导致INS-1E细胞和小鼠胰岛对棕榈酸酯诱导的功能障碍变得更加敏感，同时还检测到Nrf2核易位减少。但是，当使用抗氧化剂治疗INS-1E细胞和小鼠胰岛时，这些负面影响被逆转了。进一步的功能分析表明，lncEif4g2能够直接与β细胞中的miR-3074-5p结合，而lncEif4g2和miR-3074-5p的表达则彼此负相关。我们进一步发现，cAMP反应元件结合蛋白（CREB）是这些细胞中的miR-3074-5p靶基因，因此，至少部分地在功能异常的β细胞中充当了lncEif4g2 / miR-3074-5p轴的功能介体。总之，我们的结果因此表明，lncEif4g2能够通过靶向miR-3074-5p在INS-1E细胞和小鼠胰岛中间接调节CREB的表达，从而增强Nrf2的激活。