**13. DNA methylation, and the pathogenesis and potential treatment of type 2 diabetes mellitus**

 As mentioned, DNA methylation and histone modifications (typically acetylation but there are others such as phosphorylation, ribosylation, ubiquitylation, sumoylation, and citrullination [ 43 ]), are the main mechanisms in which epigenetics affects cell phenotype and biological processes ( **Figure 3** ).

 Of the two, DNA methylation has been the most well-studied by microarray. During methylation of DNA, 5-methylcytosine is created by DNA methyltransferases modifying cytosines. Most of this occurs in CpG islands in the promoter regions in multiple protein-coding genes. Methylation of cytosines at the promoter regions is associated with the repression of transcription. Repressors that bind to methylated CpG islands then initiate a cascade that results in the second primary mechanism of

### *Diabetes and Epigenetics DOI: http://dx.doi.org/10.5772/intechopen.104653*

epigenetic regulation: namely histone modifications and the recruitment of histone deacetylases (or transferases) [27]. Repression of multiple genes could then lead to the DM phenotype. But we need to identify what these genes are.

Bansal and Pinney [44] reviewed studies where both DNA methylation and gene expression changes were reported. DNA methylation status had a strong inverse correlation with gene expression, suggesting that this may be a potential future therapeutic target. They highlighted the emerging use of genome-wide DNA methylation profiles as biomarkers to predict patients at risk of developing diabetes or specific complications of diabetes.

Indeed, developing predictive models that incorporate both genetic information *and* DNA methylation changes may be effective diagnostic approaches for *all* types of diabetes and could lead to additional innovative therapies.

For example, one study used the genome-wide Infinium 450K array and identified 1,649 CpG sites, and 853 genes that include TCF7L2, FTO, KCNQ1, IRS1, CDKN1A, and PDE7B. Significant changes in DNA methylation were found in donors that have T2D compared to controls. Also, increased DNA methylation at the promoter of CDKN1A and PDE7B was associated with decreased transcriptional activity in clonal *in vitro*, as well as impaired glucose-stimulated insulin secretion [45].

Another genome-wide study of DNA methylation using the Infinium27K array found 276 differentially-methylated CpG sites, of which 96% were hypomethylated in islets of diabetic compared to non-diabetic donors [46]. Changes in differential DNA methylation were correlated with expression changes of 34 genes assessed by microarray [46].

We are also conducting our own genome-wide methylation studies using a human *in vitro* model of diabetes based on induced pluripotent stem cell-derived β-cells.

Interestingly, bariatric surgery appears to be capable of partially *reversing* the obesity-related and diabetic epigenome [47]. The identification of potential epigenetic biomarkers predictive of the success of bariatric surgery may open new doors to personalized therapy for severe obesity and diabetes, which is cause for great optimism [47].
