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, Raghu Mirmira

Research output: Contribution to journalArticle

25 Citations (Scopus)

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

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Endoplasmic Reticulum Stress
Medical problems
Islets of Langerhans
Type 2 Diabetes Mellitus
Cell Survival
Cells
Insulin
CCAAT-Enhancer-Binding Proteins
Inflammation
Peptide Elongation Factors
Oxidative stress
Thapsigargin
Transcription
deoxyhypusine synthase
Ribosomes
Caspase 3
Transcriptional Activation
Lysine
Insulin Resistance
Elongation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Inhibition of deoxyhypusine synthase enhances islet β cell function and survival in the setting of endoplasmic reticulum stress and type 2 diabetes. / Robbins, Reiesha D.; Tersey, Sarah A.; Ogihara, Takeshi; Gupta, Dhananjay; Farb, Thomas B.; Ficorilli, James; Bokvist, Krister; Maier, Bernhard; Mirmira, Raghu.

In: Journal of Biological Chemistry, Vol. 285, No. 51, 17.12.2010, p. 39943-39952.

Research output: Contribution to journalArticle

Robbins, Reiesha D. ; Tersey, Sarah A. ; Ogihara, Takeshi ; Gupta, Dhananjay ; Farb, Thomas B. ; Ficorilli, James ; Bokvist, Krister ; Maier, Bernhard ; Mirmira, Raghu. / Inhibition of deoxyhypusine synthase enhances islet β cell function and survival in the setting of endoplasmic reticulum stress and type 2 diabetes. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 51. pp. 39943-39952.
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