Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Abstract: 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

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: The journal of clinical investigation. - 133, 8 (2023) , e165208, ISSN: 1558-8238

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2023
• Creator: Wortham, Matthew ; Liu, Fenfen ; Harrington, Austin R. ; Fleischman, Johanna Y. ; Wallace, Martina ; Mulas, Francesca ; Mallick, Medhavi ; Vinckier, Nicholas K. ; Cross, Benjamin R. ; Chiou, Joshua ; Patel, Nisha A. ; Sui, Yinghui ; McGrail, Carolyn ; Jun, Yesl ; Wang, Gaowei ; Jhala, Ulupi S. ; Schüle, Roland ; Shirihai, Orian S. ; Huising, Mark O. ; Gaulton, Kyle J. ; Metallo, Christian M. ; Sander, Maike

Further information

• DOI: 10.1172/jci165208
• URN: urn:nbn:de:bsz:25-freidok-2362016
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:50 PM CET