Adaptation of the islet β-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we show that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in β-cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurs at sites occupied by the chromatin-modifying enzyme Lsd1 in islets. We demonstrate that β-cell-specific deletion of Lsd1 leads to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited similar epigenetic and transcriptional changes. Moreover, genetic variants associated with fasting glucose and type 2 diabetes are enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined. Our findings reveal that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome. MainThe ability to regulate nutrient metabolism in response to feeding and fasting is necessary for metabolic homeostasis. Nutrient utilization is acutely regulated by hormones and metabolites that change in response to feeding state 1 . If an energy state persists, adaptive control mechanisms increasingly influence nutrient metabolism. This is exemplified by adaptation of liver metabolism to fasting, wherein a network of nutrient-and hormoneresponsive transcriptional complexes act in tandem with epigenetic changes to drive metabolic rewiring coupled to changes in fuel availability 2-6 . Understanding how feeding
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