**12. Role of epigenetics in diabetes mellitus**

 Epigenetics addresses the relationship between genes, environmental exposure, and disease development. Additionally, epigenetics concerns heritable gene expression changes *without changes in the DNA sequence* itself, affecting how cells "read" genes. Many factors affect epigenetic modifications, such as age, lifestyle, family history, and disease status. Today, three major epigenetic systems are recognized: DNA methylation, histone modifications (the most well-characterized being acetylation), and non-coding RNA (ncRNA)-associated gene silencing ( **Figure 3** ).

 Epigenetic alterations such as DNA methylation and/or histone modifications alter the accessibility of genes to the transcriptional machinery by inducing either a relaxed/open or condensed/closed chromatin state. In general DNA methylation, principally of cytosines in gene promoters, condenses DNA and leads to gene silencing, whereas acetylation of histones opens up chromatin and is associated with

### **Figure 3.**

 *Epigenetic regulation of gene expression. Epigenetic alterations such as DNA methylation and/or histone modifications alter the accessibility of genes to the transcriptional machinery by inducing either a relaxed/open or condensed/closed chromatin state. Non-coding RNAs such as miRNAs also regulate the cell phenotype by repressing or enhancing the expression of gene transcripts. Conversely, these non-coding RNAs can themselves be epigenetically regulated.* 

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

gene activation ( **Figure 3** ). Non-coding RNAs such as miRNAs also regulate the cell phenotype by repressing or enhancing the expression of gene transcripts ( **Figure 3** ). Conversely, these non-coding RNAs can themselves be epigenetically regulated. Epigenetic changes often occur during an organism's lifetime and are sometimes transmitted to the next generation [ 38 ].

 Several studies suggest that epigenetics plays a vital role in the pathology of DM, especially T2D. Common T2D is likely to result from many genes interacting with different environmental factors ( **Figure 4** ) to produce a wide variation in the disease's clinical course [ 7 ], and as previously described for other multifactorial diseases such as hypertension [ 39 ]. In the model proposed by Arif et al. [ 39 ], epigenetic and genetic factors regulate phenotypes. Specifically, in addition to heritable Mendelian genetics, polygenic phenotypes, such as DM, are significantly affected by gene-environment interactions triggering epigenetic modifications ( **Figure 4** ). Indeed, previous studies have shown that epigenetic mechanisms can predispose individuals to the diabetic phenotype. Also, the altered homeostasis in T2D, such as prolonged hyperglycemia, dyslipidemia, and increased oxidative stress, could result from, and cause, epigenetic changes associated with the disease [ 40 ].

 As previously stated, the main insulin-producing cells in the pancreas are the β-cells, and epigenetic modifications play a critical role in establishing and maintaining their identity and function in physiological conditions [ 41 ]. Stable β-cell function is vital to the regulation of glucose levels in the bloodstream. In the case of diabetes, epigenetic dysregulation may result in the reduction of the expression of genes essential for β-cell function, the ectopic expression of genes that are not supposed to be expressed in β-cells, and loss of genetic imprinting, leading to loss of β-cell identity [ 40 ]. Consequently, this may lead to β-cell dysfunction and impaired insulin secretion, impairing the function of the pancreas, and in turn, causing widespread sequalae and finally disease in the whole organism, Thus, a causal chain is established whereby the environment causes disease in the following sequence: environment ⟶ chromatin ⟶ genes ⟶ cells ⟶ organs ⟶ organism [ 42 ]. The model proposed by Liu *et al* . goes a long way in establishing this causal chain ( **Figure 5** ) [ 42 ].

### **Figure 4.**

 *Influences on the expression of phenotypes. Development of polygenic conditions, such as diabetes, depend on complex and interacting genetic and environmental pathways.* 

### **Figure 5.**

 *A stratified view of gene-environment interactions during development and disease. Environmental effects are incorporated by epigenetic processes including chromatin remodeling to either inhibit or enhance gene expression. These effects are then manifested hierarchically in the sequence of cells to organs (i.e. pancreas) to organism. Disease etiology (for example diabetes) occurs in this hierarchical sequence.* 

 It's important to realize that many risk factors may lead to epigenetic dysregulation by causing this initial "disruption" to chromatin, such as hyperglycemia, physical inactivity, parental obesity, mitochondrial dysfunction, aging, and an abnormal intrauterine environment. Those factors can affect the epigenome at different time points throughout the lifetime of an individual. Moreover, the epigenome can change due to environmental factors, such as diet and exercise, because of the epigenome's plasticity. As a result, the epigenome is a good target for epigenetic drugs that may be used to induce insulin secretion and treat DM [ 40 ].

 Ultimately, epigenetics is vital to research DM and possible future treatments. It could be the solution to early detection and treatment, via timely detection and modification of relevant genes and reversal (normalization) of signaling pathways. But how do we identify these genes and pathways?
