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Epigenetic changes, in particular DNA methylation processes, play a role in the pathogenesis and progression of type 2 diabetes mellitus (T2DM) linking genetic and environmental factors. To clarify this role, we have analyzed in patients with different duration of T2DM: (i) expression levels of methyl-CpG-binding domain protein 2 (MBD2) as marker of DNA methylation, and ii) methylation changes in 22 genes connected to cellular stress and toxicity. We have analyzed MBD2mRNA expression levels in16 patients and 12 controls and the methylation status of stress and toxicity genes in four DNA pools: (i) controls; (ii) newly-diagnosed T2DM patients; (iii) patients with T2DM duration of <5 years and (iv) of >5 years. The MBD2expression levels were 10.4-times increased on average in T2DM patients compared to controls. Consistent increase in DNA methylation fraction with the increase in T2DM duration was observed in Prdx2and SCARA3genes, connected to oxidative stress protection and in BRCA1and Tp53tumor-suppressor genes. In conclusion, increased MBD2expression in patients indicated general dysregulation of DNA methylation in T2DM. The elevated methylation of Prdx2and SCARA3genes suggests disturbance in oxidative stress protection in T2DM. The increased methylation of BRCA1and Tp53genes unraveled an epigenetic cause for T2DM related increase in cancer risk.