Differential DNA Methylation and Expression of MicroRNAs in Adipose Tissue from Twin Pairs Discordant for Type 2 Diabetes

The prevalence of type 2 diabetes (T2D) is increasing worldwide but current treatments have limitations. MicroRNAs (miRNAs) may play a key role in the development of T2D and can be targets for novel therapies. Here, we examined whether T2D is associated with altered expression and DNA-methylation of miRNAs using adipose tissue from 14 monozygotic twin pairs discordant for T2D. Four members each of the miR-30 and let-7-families were downregulated in adipose tissue from subjects with T2D, which was confirmed in an independent case-control cohort. Further, DNA-methylation of five CpG sites annotated to gene promoters of differentially expressed miRNAs, including miR-30a and let-7a-3, was increased in T2D subjects. Luciferase experiments showed that increased DNA methylation of the miR-30a promoter reduced its transcription. Silencing of miR-30 in adipocytes resulted in reduced glucose uptake and TBC1D4 phosphorylation; downregulation of genes involved in demethylation and carbohydrate/lipid/amino acid metabolism; and upregulation of inflammatory genes. In conclusion, T2D is associated with differential DNA methylation and expression of miRNAs in adipose tissue. Downregulation of the miR-30 and let-7-families may lead to reduced glucose uptake and altered expression of key genes associated with T2D.