Metabolism as a central regulator of β‐cell chromatin state

Pancreatic β‐cells are critical mediators of glucose homeostasis. Metabolites that are controlled by mitochondria are essential co‐factors in DNA and histone modification reactions. These modifications have impacts on gene expression. Thus, via these metabolites, changes in mitochondrial activity can alter gene expression. Metabolic disorders that alter levels of these metabolites thereby can affect β‐cell chromatin state, gene expression, and function. Pancreatic β‐cells are critical mediators of glucose homeostasis in the body, and proper cellular nutrient metabolism is critical to β‐cell function. Several interacting signaling networks that uniquely control β‐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 β‐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 β‐cell dysfunction during T2D may be the altered availability of substrates or co‐factors necessary to maintain β‐cell chromatin state. Induced changes in the β‐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 β‐cell mass, and loss of glucose homeostasis, that occurs in T2D.