Nutrient regulation of the islet epigenome controls adaptive insulin secretion.
J Clin Invest
; 133(8)2023 04 17.
Article
em En
| MEDLINE
| ID: mdl-36821378
ABSTRACT
Adaptation of the islet ß 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 ß 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. ß 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.
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Base de dados:
MEDLINE
Assunto principal:
Ilhotas Pancreáticas
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Diabetes Mellitus Tipo 2
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Células Secretoras de Insulina
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article