Metabolism as a central regulator of -cell chromatin state

Pancreatic beta-cells are critical mediators of glucose homeostasis in the body, and proper cellular nutrient metabolism is critical to beta-cell function. Several interacting signaling networks that uniquely control beta-cell metabolism produce essential substrates and co-factors for catalytic reactions, including reactions that modify chromatin. Chromatin modifications, in turn, regulate gene expression. The reactions that modify chromatin are therefore well-positioned to adjust gene expression programs according to nutrient availability. It follows that dysregulation of nutrient metabolism in beta-cells may impact chromatin state and gene expression through altering the availability of these substrates and co-factors. Metabolic disorders such as type 2 diabetes (T2D) can significantly alter metabolite levels in cells. This suggests that a driver of beta-cell dysfunction during T2D may be the altered availability of substrates or co-factors necessary to maintain beta-cell chromatin state. Induced changes in the beta-cell chromatin modifications may then lead to dysregulation of gene expression, in turn contributing to the downward cascade of events that leads to the loss of functional beta-cell mass, and loss of glucose homeostasis, that occurs in T2D.