Ricerc@Sapienza

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.