title: Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis.
abstract: OBJECTIVE
  Wolfram syndrome is an autosomal recessive disorder characterised by childhood diabetes mellitus, optic atrophy and severe neurodegeneration, resulting in premature death. The aim of this study was to investigate the mechanisms responsible for the phenotype of carbohydrate intolerance and loss of pancreatic beta cells in this disorder.
  
  
  METHODS
  To study the role of the Wolfram gene (Wfs1) in beta cells, we developed a mouse model with conditional deletion of Wfs1 in beta cells by crossing floxed Wfs1 exon 8 animals with mice expressing Cre recombinase under the control of a rat insulin promoter (RIP2-Cre). Complementary experiments using RNA interference of Wfs1 expression were performed in mouse insulinoma (MIN6) cell lines (WfsKD).
  
  
  RESULTS
  Male knockout mice (betaWfs(-/-)) began developing variable and progressive glucose intolerance and concomitant insulin deficiency, compared with littermate controls, by 12 weeks of age. Analysis of islets from betaWfs(-/-) mice revealed a reduction in beta cell mass, enhanced apoptosis, elevation of a marker of endoplasmic reticulum stress (immunoglobulin heavy chain-binding protein [BiP]), and dilated endoplasmic reticulum with decreased secretory granules by electron microscopy. WfsKD cell lines had significantly increased apoptosis and elevated expression of the genes encoding BiP and C/EBP-homologous protein (CHOP), two markers of endoplasmic reticulum stress.
  
  
  CONCLUSIONS
  These results indicate that (1) lack of expression of Wfs1 in beta cells was sufficient to result in the diabetes mellitus phenotype; (2) beta cell death occurred by an accelerated process of apoptosis; and (3) lack of Wfs1 was associated with dilated endoplasmic reticulum and increased markers of endoplasmic reticulum stress, which appears to be a significant contributor to the reduction in beta cell survival.
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St Louis, MO 63110-1010, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Riggs
authors.forename: E
authors.initials: E
authors.lastname: Bernal-Mizrachi
authors.forename: M
authors.initials: M
authors.lastname: Ohsugi
authors.forename: J
authors.initials: J
authors.lastname: Wasson
authors.forename: S
authors.initials: S
authors.lastname: Fatrai
authors.forename: C
authors.initials: C
authors.lastname: Welling
authors.forename: J
authors.initials: J
authors.lastname: Murray
authors.forename: R E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: P L
authors.initials: PL
authors.lastname: Herrera
authors.forename: M A
authors.initials: MA
authors.lastname: Permutt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001786:Blood Glucose / Q000032:analysis; D049109:Cell Proliferation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000473:pathology* / Q000502:physiology; D007340:Insulinoma / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000473:pathology; D010641:Phenotype
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008565:Membrane Proteins; C114987:wolframin protein