title: Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice.
abstract: OBJECTIVE
  The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death.
  
  
  METHODS
  We studied the effect of breeding Wfs1 ( -/- ) mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A ( y ) /a). We also treated the mice with pioglitazone.
  
  
  RESULTS
  Wfs1 ( -/- ) mice bred on a C57BL/6J background rarely develop overt diabetes by 24 weeks of age, showing only mild beta cell loss. However, Wfs1 ( -/- ) A ( y ) /a mice developed selective beta cell loss and severe insulin-deficient diabetes as early as 8 weeks. This beta cell loss was due to apoptosis. In Wfs1 ( +/+ ) A ( y ) /a islets, levels of ER chaperone immunoglobulin-binding protein (BiP)/78 kDa glucose-regulated protein (GRP78) and phosphorylation of eukaryotic translation initiation factor 2, subunit alpha (eIF2alpha) apparently increased. Levels of both were further increased in Wfs1 ( -/- ) A ( y ) /a murine islets. Electron micrography revealed markedly dilated ERs in Wfs1 (-/-) A ( y ) /a murine beta cells. Interestingly, pioglitazone treatment protected beta cells from apoptosis and almost completely prevented diabetes development.
  
  
  CONCLUSIONS
  Wfs1-deficient beta cells are susceptible to ER stress. Increased insulin demand prompts apoptosis in such cells in vivo. Pioglitazone, remarkably, suppresses this process and prevents diabetes. As common WFS1 gene variants have recently been shown to confer a risk of type 2 diabetes, our findings may be relevant to the gradual but progressive loss of beta cells in type 2 diabetes.
authors.affiliation: Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Akiyama
authors.forename: M
authors.initials: M
authors.lastname: Hatanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Ohta
authors.forename: K
authors.initials: K
authors.lastname: Ueda
authors.forename: A
authors.initials: A
authors.lastname: Yanai
authors.forename: Y
authors.initials: Y
authors.lastname: Uehara
authors.forename: K
authors.initials: K
authors.lastname: Tanabe
authors.forename: M
authors.initials: M
authors.lastname: Tsuru
authors.forename: M
authors.initials: M
authors.lastname: Miyazaki
authors.forename: S
authors.initials: S
authors.lastname: Saeki
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Shinoda
authors.forename: Y
authors.initials: Y
authors.lastname: Oka
authors.forename: Y
authors.initials: Y
authors.lastname: Tanizawa
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000172:deficiency* / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D007328:Insulin; D008565:Membrane Proteins; D045162:Thiazolidinediones; C114987:wolframin protein; D000077205:Pioglitazone