Circulating miRNA Profiles Associated With Hyperglycemia in Patients With Type 1 Diabetes Mellitus.

We investigated plasma microRNA (miRNA) profiles associated with variation of hyperglycemia, measured as hemoglobin A(1c) (HbA(1c)), in two panels of patients with type 1 diabetes (T1D). Using the HTG Molecular Diagnostics EdgeSeq platform, 2,083 miRNAs were measured in plasma from 71 patients included in a screening panel. Quantitative real-time PCR was used to measure the candidate miRNAs in plasma from 95 patients included in an independent replication panel. We found 10 miRNAs replicated in both panels and 4 with high statistical significance. The strongest positive correlations with HbA(1c) were found with miR-125b-5p (r(s) = 0.40, P = 6.0 x 10(-5)) and miR-365a-3p (r(s) = 0.35, P = 5.9 x 10(-4)). The strongest negative correlations were found with miR-5190 (r(s) = -0.30, P = 0.003) and miR-770-5p (r(s) = -0.27, P = 0.008). Pathway analysis revealed that 50 Kyoto Encyclopedia of Genes and Genomes pathways were significantly enriched by genes targeted by these four miRNAs. The axon guidance signaling pathway was enriched (P < 1 x 10(-7)) by genes targeted by all four miRNAs. In addition, three other pathways (Rap1 signaling, focal adhesion, and neurotrophin signaling) were also significantly enriched but with genes targeted by only by three of the identified miRNAs. In conclusion, our study identified four circulating miRNAs that were influenced by variation in hyperglycemia. Dysregulation of these miRNAs, which are associatedwith hyperglycemia in patients with T1D, may contribute to the development of diabetes complications. However, there are multitudes of possible mechanisms/pathways through which dysregulation of these miRNAs may impact risk of diabetes complications.