Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China; Center for Diabetes and Metabolism Research, Division of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China.
Animal Center, West China Hospital, Sichuan University, Chengdu, China.
Biochem Biophys Res Commun. 2021 Dec 3;581:110-117. doi: 10.1016/j.bbrc.2021.10.019. Epub 2021 Oct 9.
Type 2 diabetes (T2D) is a multifactorial and polygenetic disease, although its exact etiology remains poorly understood. The objective of this study was to identify key biomarkers and potential molecular mechanisms in the development of T2D. Human RNA-Seq datasets across different tissues (GSE18732, GSE41762, and GSE78721) were collected from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) between T2D and controls were identified using differential analysis. A total of 90 overlapping DEGs were identified, among which YTHDF2, DDX21, and MDM2 were considered as key genes due to their central positions in the PPI network and the same regulatory pattern in T2D. Logistic regression analysis showed that low expression of the key genes increased the risk of T2D. Enrichment analysis revealed that the key genes are involved in various important biological functions and signaling pathways including Notch, Fork head box O (FOXO), and phosphoinositide 3-kinase (PI3K)-Akt. RT-qPCR and Western blot analysis showed that all three key genes were down-regulated in pancreatic islets of both prediabetic and diabetic mouse models. Finally, the insulin-sensitizer, pioglitazone was used to treat db/db mice and immunofluorescence analysis showed that the expression of all three key genes was significantly down-regulated in db/db islets, an effect that was overcome by pioglitazone treatment. Together, these results suggest that the identified key genes could be involved in the development of T2D and serve as potential biomarkers and therapeutic targets for this disease.
2 型糖尿病（T2D）是一种多因素和多基因疾病，尽管其确切病因仍知之甚少。本研究旨在确定 T2D 发生发展中的关键生物标志物和潜在分子机制。从基因表达综合数据库（GEO）中收集了不同组织的人类 RNA-Seq 数据集（GSE18732、GSE41762 和 GSE78721），并使用差异分析鉴定 T2D 与对照组之间的差异表达基因（DEGs）。共鉴定出 90 个重叠的 DEGs，其中 YTHDF2、DDX21 和 MDM2 由于它们在 PPI 网络中的中心位置和在 T2D 中的相同调节模式而被认为是关键基因。逻辑回归分析显示，关键基因的低表达增加了 T2D 的风险。富集分析显示，关键基因参与了各种重要的生物学功能和信号通路，包括 Notch、Fork head box O（FOXO）和磷酸肌醇 3-激酶（PI3K）-Akt。RT-qPCR 和 Western blot 分析显示，在糖尿病前期和糖尿病小鼠模型的胰岛中，这三个关键基因均下调。最后，使用胰岛素增敏剂吡格列酮治疗 db/db 小鼠，免疫荧光分析显示，所有三个关键基因在 db/db 胰岛中的表达均显著下调，吡格列酮治疗可克服这种下调。综上所述，这些结果表明，所鉴定的关键基因可能参与了 T2D 的发生发展，可以作为该疾病的潜在生物标志物和治疗靶点。
