Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion.
Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene. In order to gain insight into the pathophysiology of this disease, we disrupted the wfs1 gene in mice. The mutant mice developed glucose intolerance or overt diabetes due to insufficient insulin secretion in vivo. Islets isolated from mutant mice exhibited a decrease in insulin secretion in response to glucose. The defective insulin secretion was accompanied by reduced cellular calcium responses to the secretagogue. Immunohistochemical analyses with morphometry and measurement of whole-pancreas insulin content demonstrated progressive beta-cell loss in mutant mice, while the alpha-cell, which barely expresses WFS1 protein, was preserved. Furthermore, isolated islets from mutant mice exhibited increased apoptosis, as assessed by DNA fragment formation, at high concentration of glucose or with exposure to endoplasmic reticulum-stress inducers. These results strongly suggest that WFS1 protein plays an important role in both stimulus-secretion coupling for insulin exocytosis and maintenance of beta-cell mass, deterioration of which leads to impaired glucose homeostasis. These WFS1 mutant mice provide a valuable tool for understanding better the pathophysiology of Wolfram syndrome as well as WFS1 function.
Ishihara
Hisamitsu
H
Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
Takeda
Satoshi
S
Tamura
Akira
A
Takahashi
Rui
R
Yamaguchi
Suguru
S
Takei
Daisuke
D
Yamada
Takahiro
T
Inoue
Hiroshi
H
Soga
Hiroyuki
H
Katagiri
Hideki
H
Tanizawa
Yukio
Y
Oka
Yoshitomo
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D005822:Genetic Vectors; D007120:Immunochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D016254:Mutagenesis, Insertional; D010179:Pancreas / Q000473:pathology; D014929:Wolfram Syndrome / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
D001786:Blood Glucose; D007328:Insulin; D008565:Membrane Proteins; C114987:wolframin protein