Epigenetics of diabetes Type 2

In recent years it has become apparent that the environment and underlying mechanisms affect gene expression and the genome outside of the central dogma of biology. It has been found that many epigenetic mechanisms are involved in the regulation and expression of genes such as DNA methylation and chromatin remodeling. These epigenetic mechanisms are believed to be a contributing factor to pathological diseases such as type 2 diabetes. An understanding of the epigenome of Diabetes patients may help to elucidate otherwise hidden causes of this disease. In recent years it has become apparent that the environment and underlying mechanisms affect gene expression and the genome outside of the central dogma of biology. It has been found that many epigenetic mechanisms are involved in the regulation and expression of genes such as DNA methylation and chromatin remodeling. These epigenetic mechanisms are believed to be a contributing factor to pathological diseases such as type 2 diabetes. An understanding of the epigenome of Diabetes patients may help to elucidate otherwise hidden causes of this disease. The PPARGC1A gene regulates genes involved in energy metabolism. Since Type 2 diabetes is characterized by chronic hyperglycaemia as a result of impaired pancreatic beta cell function and insulin resistance in peripheral tissues, it was thought that the gene might be downregulated in type 2 diabetes patients through DNA methylation. The defects in pancreatic beta cell function and insulin resistance in peripheral tissues were thought to be the result of impaired ATP production from reduced oxidative phosphorylation. It was found that the mRNA expression of PPARGC1A was markedly reduced in pancreatic islets from type 2 diabetic donors compared with that of non-diabetic donors. Using bisulfite testing, it was also found that there was an approximately twofold increase in DNA methylation of the PPARGC1A promoter of human islet cells from diabetics as compared to non-diabetic human islet cells. This means that expression from the PPARGC1A genes were turned down in the diabetic patients. Further testing revealed that the more PPARGC1A was expressed, the more insulin was released from the islets, and as expected, in diabetic patients there was less PPARGC1A expressed and also less insulin secreted. This data supports the idea that PPARGC1A expression is reduced in animal models of diabetes and human diabetes and is associated with impaired insulin secretion. PGC-1α can modulate glucose-mediated insulin secretion in human islets, most likely through an effect on ATP production. In human type 2 diabetic islets, reduced PPARGC1A mRNA levels were associated with impaired glucose-mediated insulin secretion. It was suggested that DNA methylation was the mechanism through which the PPARGC1A gene was turned down. In a different study where transcriptional changes due to a risk factors for diabetes, were examined, changes in the methylation patterns of the PPARGC1A gene were also found. In the study done on physical inactivity, where subjects were required to have a sustained bed-rest of 10 days and were then examined, it was also found that there was significant downregulation of the PPARGC1A gene. In addition, it was shown that after the bed rest, there was a marked increase in DNA methylation of the PPARGC1A gene along with a decrease in mRNA expression. Another risk factor is low birth weight (LBW), and in a study done on that, it was found that there was increased DNA methylation in the LBW patients' muscle cells. Micro RNAs (miRNA) are single-stranded transcribed RNAs of 19–25 nucleotides in length that are generated from endogenous hairpin structured transcripts throughout the genome. Recent studies have shown that miRNAs have pivotal roles in many different gene regulatory pathways. A subset of miRNAs has been shown to be involved in metabolic regulation of glucose homeostasis and in epigenetics of diabetes type 2. Pancreatic islet-specific miR-375 inhibits insulin secretion in mouse pancreatic β-cells by inhibiting the expression of the protein myotrophin. An overexpression of miR-375 can completely suppress glucose-induced insulin secretion, while inhibition of native miR-375 will increase insulin secretion. In another study, increasing the level of miR-9, a different miRNA, resulted in a severe defect in glucose-stimulated insulin release. This happens because miR-9 down-regulated the transcription factor Onecut2 (OC2) that controls the expression of Rab27a effector granuphilin, a key factor in controlling insulin release. Also miR-192 levels have been shown to be increased in glomeruli isolated from diabetic mice when compared to non-diabetic mice, suggesting that it is involved as well. Since miR-192 was shown to regulate extracellular matrix proteins collagen 1-α 1 and 2 (Col1α1 and 2) that accumulate during diabetic nephropathy, miR-192 may play a role in kidney diseases as well. A correlation between elevated Notch signaling pathway gene expression, which is important for cell to cell communication, and diabetic nephropathy has also been shown. MiR-143 has also been experimentally shown to regulate genes that are crucial for adipocyte differentiation, (including GLUT4, Hormone-sensitive lipase, the fatty acid-binding protein, aP2 and PPAR-γ2), demonstrating that miRNAs are also involved in fat metabolism and endocrine function in humans. Epigenetics may play a role in a wide array of vascular complications and in diabetes. The epigenetic variations involved with diabetes can change chromatin structure as well as gene expression. Regardless of whether glycemic control has been achieved through treatment these epigenetic mechanisms are lasting and do not change with the alteration of diet. The most common vascular complication in patients with Type 2 Diabetes is retinopathy which causes many patients to go blind. Studies showed that retinal damage persisted even after the reversal of hyperglycemia in dogs. Studies with streptozotocin injected Type 1 diabetes rats showed that the re-institution of glycemic control after a short period of hyperglycemia had protective effects in the eyes, including reduction in parameters of oxidant stress and inflammation. However, specimens with prolonged diabetes failed to show similar protection. It was then seen with endothelial cells (which line blood vessels) cultured in high glucose that there was a sustained increase in the expression of key extracellular and pro-fibrotic genes and persistently increased oxidant stress, after subsequent glucose normalization. These studies show that the deleterious effects of prior hyperglycemic exposure have long-lasting effects on target organs even after subsequent glycaemic control underscoring the beneficial effects of intensive glycemic control in diabetes. The persistence of these symptoms points to epigenesis as an underlying cause. Studies have shown that the islet dysfunction and development of diabetes in rats is associated with epigenetic silencing via DNA methylation of the gene Pdx1 promoter, which produces a key transcription factor that regulates beta-cell differentiation and insulin gene expression. Silencing at this promoter decreases the amount of beta-cells produced which leads to insulin resistance and the inability of the beta-cells to produce an important peptide that prevents vascular deterioration and neuropathy caused from vascular inflammatory responses.