MicroRNA Biomarkers Target Genes and Pathways Associated with Type 2 Diabetes.

AIMS: /Hypothesis: Our prior analysis of the Diabetes Prevention Program study identified a subset of five miRNAs that predict incident type 2 diabetes. The purpose of this study was to identify mRNAs and biological pathways targeted by these five miRNAs to elucidate potential mechanisms of risk and responses to the tested interventions.

METHODS: Using experimentally validated data from miRTarBase version 8.0 and R (2021), we identified mRNAs with strong evidence to be regulated by individual or combinations of the five predictor miRNAs. Overrepresentation of the mRNA targets was assessed in pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation database.

RESULTS: The five miRNAs targeted 167 pathways and 122 mRNAs. Nine of the pathways have known associations with type 2 diabetes: Insulin signaling, Insulin resistance, Diabetic cardiomyopathy, Type 2 diabetes, AGE-RAGE signaling in diabetic complications, HIF-1 signaling, TGF-beta signaling, PI3K/Akt signaling, and Adipocytokine signaling pathways. Vascular endothelial growth factor A (VEGFA) has prior genetic associations with risk for type 2 diabetes and was the most commonly targeted mRNA for this set of miRNAs.

CONCLUSIONS/INTERPRETATION: These findings show that miRNA predictors of incident type 2 diabetes target mRNAs and pathways known to underlie risk for type 2 diabetes. Future studies should evaluate miRNAs as potential therapeutic targets for preventing and treating type 2 diabetes.