Epigenetic harbingers of vascular endothelial dysfunction in type 2 diabetes
Inflammation from immune system cells underlies many type 2 diabetes (T2D) complications, including the endothelial cell dysfunction that precedes T2D-associated vasculopathies. Although the precise role of pro-inflammatory immune cells in T2D-associated endothelial dysfunction is unknown, we and others have demonstrated epigenetic (non-DNA encoded) mechanisms undoubtedly regulate T2D-associated immune cell cytokines. Our published work identified epigenetic changes in blood T cells that associate with increased pro-inflammatory T cell function in human T2D. These data raise the possibility that a more comprehensive analysis of epigenetic changes in circulating T cells will provide a practical yet accurate indicator of both inflammation and inflammation-associated complications in T2D. We will test the hypothesis that epigenetic mechanisms reflect cytokine-mediated inflammation and inflammation-associated endothelial cell dysfunction in T2D through two Aims: 1. We will identify epigenetic DNA marks that associate with vascular endothelium dysfunction by identifying methylated and de-methylated DNA domains in blood T cells from subjects that have been characterized for endothelial function and metabolic health; and 2. We will determine the relationship between T cell DNA methylation patterns and systemic physiological parameters of obese/T2D subjects. We anticipate that demethylation of T cell cytokine genes and additional (less obvious) regions of T cell DNA will positively correlate with endothelial cell dysfunction, T cell inflammation and systemic inflammation/metabolic status. Importantly, our proof-of-principle approach directly addresses a stated goal of the DCC: the identification of epigenetic changes in circulating cells that reflect two T2D complications, endothelial dysfunction and inflammation. Future work will expand this analysis to epigenetic changes that can be targeted by currently available drugs that regulate epigenetic processes, with the long-term goal of using such drugs to alleviate T2D-associated complications.

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