Lu Ya-Ke, Chu Xi, Wang Shuo, Sun Yue, Zhang Jie, Dong Jing, Yan Yu-Xiang
Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing 100069, China.
Health Management Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
J Clin Endocrinol Metab. 2021 Jun 16;106(7):e2688-e2699. doi: 10.1210/clinem/dgab101.
Circular RNAs (circRNAs), which are involved in the development of diseases by regulating gene expression, have become promising novel biomarkers for diseases.
The aim of the present study was to identify the circulating circRNA biomarkers for early detection of type 2 diabetes (T2D).
The circRNA expression profiles were screened by microarray and compared between 5 new T2D cases and 5 healthy controls. The expression of candidate circRNAs that may be involved in the insulin phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway were validated by RT-qPCR in a second sample with 30 T2D cases and 30 controls. The association between circRNAs and T2D and their clinical significances were further assessed by logistic regression model, correlation analysis, and ROC curve in a large cohort comprising 313 subjects. The microRNA (miRNA) targets of circRNAs were verified by dual-luciferase reporter assay and RNA immunoprecipitation assay.
Low expressed circ_0063425 and hsa_circ_0056891 were independent predictors of T2D, impaired fasting glucose (IFG), and insulin resistance. The 2-circRNA panel had a high diagnostic accuracy for discriminating T2D and IFG from healthy controls, especially when body mass index was integrated. miR-19a-3p and miR-1-3p were identified as the miRNA targets of hsa_circ_0063425 and hsa_circ_0056891, respectively. Significant positive correlations were found between the expression levels of AKT and hsa_circ_0063425, PI3K and hsa_circ_0056891, in the total sample and subgroups stratified by glucose levels.
Downregulated hsa_circ_0063425 and hsa_circ_0056891 might contribute to the pathogenesis of T2D. They are valuable circulating biomarkers for early detection of T2D, which may be involved in regulation of PI3K/AKT signaling.
环状RNA（circRNA）通过调控基因表达参与疾病发展，已成为很有前景的新型疾病生物标志物。
本研究旨在鉴定用于2型糖尿病（T2D）早期检测的循环circRNA生物标志物。
通过微阵列筛选circRNA表达谱，并在5例新发T2D患者和5例健康对照之间进行比较。在另一个包含30例T2D患者和30例对照的样本中，通过RT-qPCR验证可能参与胰岛素磷脂酰肌醇3激酶/蛋白激酶B（PI3K/Akt）信号通路的候选circRNA的表达。在一个包含313名受试者的大型队列中，通过逻辑回归模型、相关性分析和ROC曲线进一步评估circRNA与T2D之间的关联及其临床意义。通过双荧光素酶报告基因检测和RNA免疫沉淀检测验证circRNA的微小RNA（miRNA）靶点。
低表达的circ_0063425和hsa_circ_0056891是T2D、空腹血糖受损（IFG）和胰岛素抵抗的独立预测因子。该双circRNA组合对区分T2D和IFG与健康对照具有较高的诊断准确性，尤其是在纳入体重指数时。miR-19a-3p和miR-1-3p分别被鉴定为hsa_circ_0063425和hsa_circ_0056891的miRNA靶点。在总样本以及按血糖水平分层的亚组中，发现AKT与hsa_circ_0063425、PI3K与hsa_circ_0056891的表达水平之间存在显著正相关。
hsa_circ_0063425和hsa_circ_0056891的下调可能促成T2D的发病机制。它们是用于T2D早期检测的有价值的循环生物标志物，可能参与PI3K/AKT信号的调控。
