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

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posted on 27.07.2021, 17:50 by Emma Nilsson, Magdalena Vavakova, Alexander Perfilyev, Johanna Säll, Per-Anders Jansson, Pernille Poulsen, Jonathan Lou S. Esguera, Lena Eliasson, Allan Vaag, Olga Göransson, Charlotte Ling
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.

Funding

This work was supported by the Swedish Research Council (Grants Dnr 2016-02486, 2018- 02567 and 2019-01406, Strategic Research Area Exodiab Dnr 2009-1039); Region Skåne and ALF; the Novo Nordisk foundation; the Swedish Foundation for Strategic Research Dnr IRC15- 0067; the Syskonen Svensson Foundation; the Diabetes Foundation; Kungliga Fysiografiska Sällskapet i Lund; Magnus Bergvall Foundation; Åke Wiberg Foundation; the European Foundation for the Study of Diabetes/Lilly Foundation; the Söderberg Foundation; and the Påhlsson Foundation. The Swedish twins was recruited from the Swedish Twin Registry, which is supported by grants from the Swedish Department of Higher Education and the Swedish Research Council.

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