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.

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Regards,
Morgan E,
Editorial Manager,
Journal of Clinical Diabetes.

E-mail: clindiabetes@eclinicalsci.com