Inhibition of deoxyhypusine synthase enhances islet β cell function and survival in the setting of endoplasmic reticulum stress and type 2 diabetes

Reiesha D. Robbins, Sarah A. Tersey, Takeshi Ogihara, Dhananjay Gupta, Thomas B. Farb, James Ficorilli, Krister Bokvist, Bernhard Maier, Raghavendra G. Mirmira

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Islet βcell dysfunction resulting from inflammation, ER stress, and oxidative stress is a key determinant in the progression from insulin resistance to type 2 diabetes mellitus. It was recently shown that the enzyme deoxyhypusine synthase (DHS) promotes early cytokine-induced inflammation in the β cell. DHS catalyzes the conversion of lysine to hypusine, an amino acid that is unique to the translational elongation factor eIF5A. Here, we sought to determine whether DHS activity contributes to β cell dysfunction in models of type 2 diabetes in mice and β cell lines. A 2-week treatment of obese diabetic C57BLKS/J-db/db mice with the DHS inhibitor GC7 resulted in improved glucose tolerance, increased insulin release, and enhanced β cell mass. Thapsigargin treatment of β cells in vitro induces a picture of ER stress and apoptosis similar to that seen in db/db mice; in this setting, DHS inhibition led to a block in CHOP (CAAT/enhancer binding protein homologous protein) production despite >30-fold activation of Chop gene transcription. Blockage of CHOP translation resulted in reduction of downstream caspase-3 cleavage and near-complete protection of cells from apoptotic death. DHS inhibition appeared to prevent the cytoplasmic co-localization of eIF5A with the ER, possibly precluding the participation of eIF5A in translational elongation at ER-based ribosomes. We conclude that hypusination by DHS is required for the ongoing production of proteins, particularly CHOP, in response to ER stress in the β cell.

Original languageEnglish (US)
Pages (from-to)39943-39952
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number51
DOIs
StatePublished - Dec 17 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Inhibition of deoxyhypusine synthase enhances islet β cell function and survival in the setting of endoplasmic reticulum stress and type 2 diabetes'. Together they form a unique fingerprint.

  • Cite this