Hyperglycemia Regulated Circulating MicroRNAs and Their Effects on Renal Function Decline in Type 2 Diabetes

Background: It has been reported that microRNAs (miRNAs) play an important role in the pathogenesis of diabetic complications. We aimed to search for circulating miRNA that were associated with hyperglycemia in type 2 diabetes and examine their effects on renal function decline. Methods: Using the next-generation sequencing-based HTG EdgeSeq miRNA platform, a total of 2,083 miRNAswere measured in baseline plasma specimens obtained from73 subjects with type 2 diabetes (T2D) and normal renal function (discovery panel) and 136 subjects with T2D and impaired renal function (replication panel). Subjects in both panels were followed for 6–12 years to determine eGFR decline. Results: We identified 11 candidate miRNAsthat were strongly associated with elevated levels of glycated hemoglobin (HbA1c) in both screening and replication panels. Using bioinformatics analyses, we found that the candidate miRNAs targeted proteins of 6 pathways (the Ras signaling pathway, Signaling pathways regulating pluripotency of stem cells, the MAPK pathway, Glutamatergic synapse, the Rap 1 signaling pathway, and the AMPK signaling pathway). Importantly, 4 of these 11 miRNAs were significantly associated with risk of renal function decline. Conclusion: There were few previous reports about the association between circulating miRNAs, hyperglycemia, and diabetic kidney disease in T2D. The present study comprehensively examined and identified hyperglycemia-regulated miRNAs in human samples. Our finding are novel in that circulatingmiRNAsregulated by hyperglycemia are associated with risk of eGFR decline in T2D.