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 have shown 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 occurred at sites occupied by the chromatin-modifying enzyme lysine-specific demethylase 1 (Lsd1) in islets. β Cell–specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient-response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.
Matthew Wortham, Fenfen Liu, Austin R. Harrington, Johanna Y. Fleischman, Martina Wallace, Francesca Mulas, Medhavi Mallick, Nicholas K. Vinckier, Benjamin R. Cross, Joshua Chiou, Nisha A. Patel, Yinghui Sui, Carolyn McGrail, Yesl Jun, Gaowei Wang, Ulupi S. Jhala, Roland Schüle, Orian S. Shirihai, Mark O. Huising, Kyle J. Gaulton, Christian M. Metallo, Maike Sander