Type 2 diabetes mellitus (T2DM) has developed into a major public health concern. Lifestyle and behavioural factors play an important role in determining T2DM risk. While the majority of studies in the field have characterised diabetes aetiology on the basis of genetics, new findings suggest the potential involvement of epigenetic mechanisms in T2DM as a crucial interface between the effects of genetic predisposition and environmental infuences. Epigenetics refers to changes in gene function that cannot be explained by changes in DNA sequence, with DNA methylation patterns/histone modifications that can confer important contributions to epigenetic memory.
Current literature clearly shows that variations in "normal" DNA methylation pattern are correlated with many aspects of diabetes, including susceptibility, insulin resistance, and diabetes complications development.
Since previous data have evidenced that the poly ADP-ribosylation (PARylation) process may control DNA methylation pattern, the goal of the present project is to clarify the possible connection between PARylation and changes of DNA methylation pattern in T2D pathogenesis. Hyperglycemia (HG), through the oxidative stress, may be responsible for PARP enzymes activation, which could change DNA methylation profiles in T2DM. Attention will be focused on impairment of active DNA demethylation process because the contribution of this pathway in diabetes pathology is less characterized. To this end, we plan to investigate in peripheral blood cells from a cohort of T2DM patients: 1) how the presence of oxidation products of the demethylation pathway (5hmC, 5fC) is associated to different levels of HbA1c (ndex of average glucose over the preceding weeks-to-months) 2) whether defective DNA demethylation pathways which translate into dysfunctional effects that impinge on glucose metabolism are controlled by the PARylation process.
Highlights
Relevance: the project points out the molecular links between HG and epimutations underlying aetiology, progression and development of complications in T2DM.
Innovativeness: PARylation may be considered a key process able to transduce the HG insults into variations of the epigenetic code, paving the way to the exploitation of PARP inhibitors in diabetes management.
Originality: PARylation could constitute a link between oxidative stress, typical of HG condition, and epigenetic deregulation.
Feasibility: The project will unite expertise in PARylation and DNA methylation with expertise in clinical medicine of diabetes. The applicants to the project and their collaborators have the right background and possess the basic equipment to address the experimental aims of the project. The recruitment of patients involved in the study has been already accomplished and this may allow shorter times to complete the project.
The hyperglycaemia-driven overproduction of reactive oxygen species and oxidative stress are the major biochemical abnormalities underlying diabetes pathogenesis and complications and have been proposed as the primary mediators of glucotoxicity. In this process, the ROS-mediated activation of PARP1 has been proposed to trigger cell death and impairment of glucose disposal. More recently, it was found that glucotoxicity generates permanent changes of the expression of genes associated with the control of glucose homeostasis through epigenetic regulatory mechanisms. This finding offers an elegant explanation of the phenomenon of "metabolic memory", which accounts for the correlation between transient/chronic poor glycaemic control and the irreversible progression of diabetes complications. In this context, by investigating the link between PARP activation and HG-induced DNA methylation defects, this project aims to collect initial evidence that may form an understanding for the mechanistic basis of the emerging connection between defective glucose metabolism and epigenetic modifications of chromatin in diabetes.
Further, far-reaching relevant implications of this research include the use of PARP inhibitors as new therapeutic drugs in the management of diabetes by delaying some complications thus improving the patient outcome. In addition, PARs could be exploited as indicators of peripheral DNA damage and cellular stress and they would represent new biomarkers for the follow-up monitoring of patients with diabetes.