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

doi:10.1074/jbc.m110.170142

Abstract

Islet β cell 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.

Highlights

Obesity and diabetes is complex, but it is apparent that a direct correlation exists between increasing visceral fat and insulin resistance [1,2,3]
It is clear that defects in insulin secretion at the level of the islet ␤ cell are paramount in the transition from a normoglycemic, insulin-resistant state to frank diabetes [5], and it is postulated that underlying genetic defects at the level of the ␤ cell differentiates those who develop diabetes from those who do not [6]
To determine whether the rate of hypusination correlates with islet dysfunction in the setting of type 2 diabetes, we studied two obese stains of mice (C57BL6/J-db/db and C57BLKS/J-db/db) that harbor homozygous truncations in the leptin receptor but exhibit differing degrees of metabolic control and islet function

Summary

Introduction

Obesity and diabetes is complex, but it is apparent that a direct correlation exists between increasing visceral fat and insulin resistance [1,2,3]. Role of Deoxyhypusine Synthase in ␤ cell ER Stress siRNA-mediated depletion of eIF5A1 protected pancreatic islets from cytokine-induced inflammation in vitro and preserved glycemic control in the streptozotocin inflammatory model of diabetes in mice in vivo, in both cases by blocking the apparent translation of the Nos gene encoding inducible nitric oxide synthase. These effects were phenocopied when islets or whole animals were treated with N1-guanyl-1,7-diaminoheptane (GC7), a drug that inhibits DHS [13]. Our findings reveal a heretofore unappreciated role for DHS and hypusinated eIF5A in the islet ER stress response and point to DHS as a potential therapeutic target in type 2 diabetes

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Results

Conclusion