Identification of circulating hsa_circ_0063425 and hsa_circ_0056891 as novel biomarkers for detection of type 2 diabetes.

PURPOSE Circular RNAs (circRNAs) are involved in the development of diseases by regulating gene expression and 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). METHODS circRNA expression profiles were screened by microarray between five new T2D cases and five healthy controls. The expression of candidate circRNAs that may be involved in the insulin 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 composed of 313 subjects. The miRNA targets of circRNAs were verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. RESULTS Low expressed circ_0063425 and hsa_circ_0056891 were independent predictors of T2D, IFG and insulin resistance. The two-circRNA panel had a high diagnostic accuracy for discriminating T2D and IFG from healthy controls, especially when body mass index (BMI) was integrated. miR-19a-3p and miR-1-3p were identified as the miRNA targets of hsa_circ_0063425 and hsa_circ_0056891, respectively. Significantly 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. CONCLUSION 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.