Type 2 diabetes mellitus (T2DM) is a polygenic metabolic disease identified by elevated blood glucose levels due to pancreatic beta-cell practical impairment and insulin resistance in tissues such as skeletal muscle, fat and the liver. Countless people around the globe are detected with diabetes, and its occurrence is approximated to double by 2030. It has become one of the most tough public health concerns of 21st century and the fifth leading cause of death worldwide. The American Diabetes Association (ADA) approximates that 1.7 million Americans are diagnosed with diabetes every year, which indicates about 4,660 brand-new diagnoses of diabetes daily. Of the 30 million individuals who currently have diabetes in the United States, about 90% have T2DM.
Type 2 Diabetes Mellitus and Epigenetics
This chronic disease process is accompanied by complications in various important organs and can be related to a greater risk for cardiovascular events, neurological changes, kidney disability, osteoporosis, cognitive problems (CI) and dementia. Though diabetes has a strong hereditary component, as it tends to run in households, environment also has a considerable function in activating this condition. The notable risk factors for establishing diabetes are obesity, advance in age, and sedentary lifestyle with absence of physical activity. However, many people with these risk factors do not develop diabetes and research studies indicate that intricate interaction in between genes and environment through epigenetic adjustments makes a person prone to establish diabetes. Epigenetic mechanisms and their function in the advancement of diabetes and the significance of the environment in forming the epigenome of an individual exists in this post.
Epigenetics is the study of heritable modifications in gene function with no change in the nucleotide sequence. The human body’s growth, development and metabolism are carefully crafted by the epigenetic systems, which influence chromatin structure and DNA accessibility, causing changing ‘on’ or ‘off’ our genes at strategic times and areas. This type of guideline of gene expression by the epigenetic systems discusses how cells with the exact same DNA can distinguish into different cell types with different phenotypes. A person’s phenotype is thus determined not only by genome but also by his/her epigenome.
The significant epigenetic mechanisms that can alter gene expression are DNA methylation, histone adjustment, and non-coding RNA-mediated paths. Briefly, in DNA methylation, a methyl group is added at the 5-carbon of the cytosine to form 5-methylcytosine. DNA methylation normally leads to gene silencing or reduced gene expression. Another epigenetic mechanism which plays an important role in gene switching ‘on’ and ‘off’ is histone adjustment. Histones are globular proteins around which DNA coils to form nucleosomes. Histone modifications occur by enzyme catalyzed reactions such as lysine acetylation, lysine/arginine methylation, serine/threonine phosphorylation, and lysine ubiquitination/SUMOylation. These adjustments in histones bring substantial changes in their functions leading to promotion or repression of gene transcription. The 3rd epigenetic system in controling gene expression is micro RNAs. MicroRNAs (miRNA) are a class of non-coding single stranded RNAs of 19-25 nucleotides in length, which are reported to have a key function in the policy of gene expression.
Genes, Environment and Epigenetics
Though numerous hereditary variations are revealed to contribute to the development of T2DM, to date just PPARG, KCNJ11 and TCF7L2 are recognized genes related to common kinds of T2DM. Genome-wide association studies (GWAS) of recent times are helping in discovering and identifying more genes responsible for T2DM and might offer a complete list of hereditary variants related to this disease in the future. Diabetes is multifactorial disease indicating its emergence in people with hereditary predisposition that depends on other factors.
Environment is reported to play a significant function in causing diabetes. Lots of environmental factors are known to cause changes in gene expression through epigenetic adjustments, such as transformed DNA methylation or histone modifications. It is proposed that the ecological aspects activate an intracellular signal, which, in turn marks the exact chromatin site for epigenetic adjustments leading to modified gene expression.
Some of the ecological factors taking place during embryogenesis (such as maternal diet and intrauterine nutrition) and early development could affect health and disease states even in adulthood. In addition to these, exposure to heavy metals, pesticides, cigarette smoking, as well as deficiencies of some nutrients (folate and methionine) can promote alteration in epigenetic pathways. Furthermore, weight problems and age are also revealed to alter these epigenetic systems and might lead to T2DM.
Also read: Is Type 2 Diabetes Genetic?
Epigenetics of Diabetes
In recent years many reports highly point to the crucial function of epigenetic modifications in the development and pathogenesis of cancer, asthma, arthritis, hypertension, and so on. Recently epigenetic modifications are likewise implicated in the development of T2DM. Genes involved in the production and release of insulin are reported to be changed in diabetic islets compared with non-diabetic ones.
Analysis of pancreatic beta cells from diabetic and healthy individuals revealed epigenetic changes in approximately 850 genes with a fold modification between 5-59%. Over 100 of the genes likewise had modified expression and a lot of these might add to minimized insulin production. About 17 prospect genes for type 2 diabetes consisting of TCF7L2, THADA, KCNQ1, FTO, and IRSI were reported to be differentially methylated in pancreatic islets of type 2 diabetic population. Increased expression and reduced methylation of CDKN1A and PDE7B gene in type 2 diabetes was reported to result in impaired glucose-stimulated insulin release. This observation provides an evidence of diabetes associated epigenetic adjustments and associated impaired insulin release.
A gene EXOC3L2, a member of exocyst complex, plays a role in exocytosis of insulin from the beta cells. This gene was found to be under-expressed and hypermethylated in type 2 diabetes pancreatic islets. Just recently it is pointed out that small changes in gene expression may have a noticable impact on diabetes over extended periods of time. In numerous tissues PPARGC1A gene encodes a transcriptional coactivator which manages mitochondrial oxidative metabolism. Expression of this gene was favorably associated to glucose-stimulated insulin release from human islet cells. In type 2 diabetic pancreatic islets the DNA methylation of PPARGC1A promoter was reported to be doubled and the expression of PPARGC1A gene was considerably reduced in contrast to non-diabetic islet cells. This gene was also down-regulated in individuals who were physically non-active, a lifestyle which is developed to be one of the risk factors for diabetes.
Another gene UNC13B located on chromosome -9, is found to be hyper-methylated in diabetic patients and hyperglycemia upregulates its expression and is implicated in diabetic nephropathy.
MicroRNAs (miRNA) are also shown to be associated with glucose homeostasis and diabetes. One of the miRNAs particular to pancreatic islets is miR-375. Over-expression of this miRNA is discovered to lower glucose-stimulated insulin release while its inhibition led to increase in insulin secretion. An inverse correlation between miRNA-192, miRNA-9 and insulin secretion was likewise reported, indicating that miRNAs might contribute in diabetes.
Histone modifications are likewise reported in diabetic patients. An in vitro study revealed increased histone acetylation which in turn promoted inflammatory gene expression. Last but not least, hyperglycemia caused histone adjustments and DNA methylation of pro-inflammatory genes activating the vascular swelling are likewise reported. Therefore emergence of diabetes in a person is rather complicated and results from the complex interaction between genes and environment. Numerous studies point to epigenetic adjustments in moderating this interaction.
Diabetes is a complicated metabolic condition defined by hyperglycemia, insufficient insulin secretion and insulin resistance. Incidence of diabetes is growing at a worrying rate at about 4660 new cases daily in the United States. This disease runs in households, indicating that it has a genetic origin and genome broad association studies suggest about 100 gene variations associated with this disease. Though genes incline a person to develop this disease, environment likewise contributes to its frequency. The risk factors for diabetes consist of sedentary lifestyle, obesity and aging. Therefore development of diabetes in an individual is quite complicated and results from the intricate interaction in between genes and environment. Lots of studies point to epigenetic modifications (DNA methylation and histone modifications) in moderating this interaction.