Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function

Research output: Contribution to journalArticle

Abstract

Transcriptional changes control β-cell survival in response to inflammatory stress. Posttranslational modifications of histone and non-histone transcriptional regulators activate or repress gene transcription, but the link to cell-fate signaling is unclear. Inhibition of lysine deacetylases (KDACs) protects β cells from cytokine-induced apoptosis and reduces type 1 diabetes incidence in animals. We hypothesized that also lysine demethylases (KDMs) regulate β-cell fate in response to inflammatory stress.Expression of the demethylase Kdm6B was upregulated by proinflammatory cytokines suggesting a possible role in inflammation-induced β-cell destruction. Inhibition of KDM6 demethylases using the selective inhibitor GSK-J4 protected insulin-producing cells and human and mouse islets from cytokine-induced apoptosis by blunting nuclear factor (NF)-κB signaling and endoplasmic reticulum (ER) stress response gene expression. GSK-J4 furthermore increased expression of insulin gene and glucose-stimulated insulin secretion. Expression of genes regulating purinergic and cytokine ligand-receptor interactions was downregulated following GSK-J4 exposure, while expression of genes involved in cell maintenance and survival was upregulated. These data suggest that KDMs are important regulators of inflammation-induced β-cell dysfunction and death.

Details

Authors
  • Marie Balslev Backe
  • Jan Legaard Andersson
  • Karl Bacos
  • Dan Ploug Christensen
  • Jakob Bondo Hansen
  • Jerzy Jòzef Dorosz
  • Michael Gajhede
  • Tina Dahlby
  • Madhusudhan Bysani
  • Line Hyltoft Kristensen
  • Charlotte Ling
  • Lars Olsen
  • Thomas Mandrup-Poulsen
Organisations
External organisations
  • University of Copenhagen
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
  • Cell and Molecular Biology

Keywords

  • Apoptosis, Diabetes, Gene expression, Inflammation, Lysine demethylases, β cells
Original languageEnglish
Pages (from-to)47-56
JournalMolecular and Cellular Endocrinology
Volume460
Publication statusPublished - 2018
Publication categoryResearch
Peer-reviewedYes