Objective: The pancreatic endocrinal system dominates the regulation of blood glucose levels in vivo, and the dysfunction of pancreatic endocrine β-cells is a major cause of the occurrence and development of Type 2 diabetes (T2D). Although microRNA (miRNA) have been found to be key regulators of pancreatic β-cells proliferation, differentiation and apoptosis, the underlying mechanism remains enigmatic. The aim of this study was to identify several novel miRNAs which might be involved in the etiopathogenesis of diabetic β-cells dysfunction./nMethods: The miRNA expression profiles in the pancreas of high-fat diet (HFD) fed Zucker diabetic fatty (ZDF) rats and Zucker lean (ZL) rats feed with normal-fat diet (NFD) were detected by using miRNA microarray chip, and individually verified the most significant factors by quantitative real-time polymerase chain reaction (qRT-PCR) assay. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to predict the target genes related to each of the identified miRNAs and the functions of these target genes in different metabolic signaling pathways./nResults: Compared with the ZL rats, a total of 24 differentially expressed miRNAs were detected in ZDF rats. Among which miR-34a-5p and miR-452-5p were the most significantly up-regulated and down-regulated respectively. These miRNAs have not been reported in rats' pancreas before. By GO and KEGG enrichment analyses, we found that miR-34a-5p could negatively regulate pancreatic β-cell proliferation through the involvement of Wnt signaling pathway. In addition, it was also found to regulate insulin secretion through the insulin signaling pathway to modulate blood glucose levels. At the same time, miR-452-5p was found to positively regulate the activity of the key rate-limiting enzyme branched-chain α-keto acid dehydrogenase-β (BCKDHB) in the catabolism of branched chain amino acids (BCAA), leading to mitochondrial dysfunction in pancreatic β-cells./nConclusions: miR-34a-5p and miR-452-5p were identified as the novel regulators of pancreatic endocrine dysfunction. These miRNAs might have the potential to be utilized as the new predictive biomarkers for the diagnosis of the occurrence and development of T2D, as well as the therapeutic targets for T2D treatment.

中文翻译：

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MiR-34a-5p 和 miR-452-5p：糖尿病 Zucker 大鼠胰腺内分泌功能障碍的新型调节剂？

目的：胰腺内分泌系统主导体内血糖水平的调节，胰腺内分泌β细胞功能障碍是2型糖尿病（T2D）发生发展的主要原因。尽管已发现 microRNA (miRNA) 是胰腺 β 细胞增殖、分化和凋亡的关键调节因子，但其潜在机制仍然是个谜。本研究的目的是鉴定几种可能与糖尿病 β 细胞功能障碍的发病机制有关的新型 miRNA。/n方法：采用miRNA微阵列芯片检测高脂饮食（HFD）喂养的Zucker糖尿病脂肪（ZDF）大鼠和Zucker瘦（ZL）大鼠正常脂肪饮食（NFD）的胰腺中miRNA表达谱，并分别进行验证通过定量实时聚合酶链反应 (qRT-PCR) 测定最重要的因素。基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析用于预测与每个鉴定的miRNA相关的靶基因以及这些靶基因在不同代谢信号通路中的功能。/n结果：与ZL大鼠相比，ZDF大鼠共检测到24个差异表达的miRNA。其中 miR-34a-5p 和 miR-452-5p 分别是最显着的上调和下调。这些 miRNA 以前在大鼠的胰腺中没有报道过。通过GO和KEGG富集分析，我们发现miR-34a-5p可以通过参与Wnt信号通路负调控胰腺β细胞增殖。此外，还发现通过胰岛素信号通路调节胰岛素分泌，从而调节血糖水平。同时，发现miR-452-5p正向调节支链氨基酸（BCAA）分解代谢中的关键限速酶支链α-酮酸脱氢酶-β（BCKDHB）的活性，导致胰腺β细胞线粒体功能障碍。/n结论： miR-34a-5p 和 miR-452-5p 被确定为胰腺内分泌功能障碍的新调节因子。这些 miRNA 有可能被用作新的预测性生物标志物，用于诊断 T2D 的发生和发展，以及 T2D 治疗的治疗靶点。