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

• Published in: Diabetes (New York, N.Y.) Vol. 70; no. 10; pp. 2402 - 2418
• Main Authors: Nilsson, Emma, Vavakova, Magdalena, Perfilyev, Alexander, Säll, Johanna, Jansson, Per-Anders, Poulsen, Pernille, Esguerra, Jonathan Lou S., Eliasson, Lena, Vaag, Allan, Göransson, Olga, Ling, Charlotte
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.10.2021
• Subjects: 3T3-L1 Cells; Adipocytes; Adipose tissue; Adipose Tissue - metabolism; Adipose Tissue - pathology; Aged; Amino acids; Animals; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - pathology; Body fat; Carbohydrate metabolism; Case-Control Studies; Cells, Cultured; Clinical Medicine; Cohort Studies; CpG islands; Demethylation; Denmark; Deoxyribonucleic acid; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diseases in Twins - genetics; DNA; DNA Methylation; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Gene Expression; Gene silencing; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - pathology; Gigantism - genetics; Gigantism - pathology; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Humans; Immune system; Intellectual Disability - genetics; Intellectual Disability - pathology; Klinisk medicin; Lipid metabolism; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Phosphorylation; Sweden; Twins, Monozygotic - genetics; Denmark; Sweden
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db20-0324

The prevalence of type 2 diabetes (T2D) is increasing worldwide, but current treatments have limitations. 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 of subjects with T2D versus control subjects, which was confirmed in an independent T2D 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 versus control subjects. Luciferase experiments showed that increased DNA methylation of the miR-30a promoter reduced its transcription in vitro. 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 immune system genes. In conclusion, T2D is associated with differential DNA methylation and expression of miRNAs in adipose tissue. Downregulation of the miR-30 family may lead to reduced glucose uptake and altered expression of key genes associated with T2D.