Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

Akiyama, Mitoshi; Hatanaka, Masayuki; Ohta, Yoshihiro; Ueda, Kohei; Yanai, Akie; Uehara, Yusuke; Tanabe, Katsuya; Tsuru, Masatoshi; Miyazaki, Mutsuko; Saeki, Souichi; Saito, Takuya; Shinoda, Koh; Oka, Yoshitomo; Tanizawa, Yukio

doi:10.1007/s00125-009-1270-6

Cited by 69 publications

(52 citation statements)

References 51 publications

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“…It has been shown that WFS1-deficient pancreatic β cells have high baseline ER stress levels and impaired insulin synthesis and secretion. Thus, WFS1-deficient β cells are susceptible to ER stress mediated cell death (5,6,32,(40)(41)(42). The functions of WFS2 are still not clear.…”

Section: Discussionmentioning

confidence: 99%

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A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Kanekura

Hara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

133

160

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Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.Wolfram syndrome | endoplasmic reticulum | diabetes | neurodegeneration | treatment

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Section: Discussionmentioning

confidence: 99%

“…6A). GLP-1, pioglitazone, and rapamycin are FDA-approved drugs and have been shown to confer protection against ER stress-mediated cell death (27,(31)(32)(33). Dantrolene is another FDA-approved drug clinically used for muscle spasticity and malignant hyperthermia (34).…”

Section: Significancementioning

confidence: 99%

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Kanekura

Hara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

133

160

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“…Wolfram syndrome, caused by the WFS1 mutation and characterized by insulin-dependent diabetes mellitus and optic atrophy, is a prototypical human endoplasmic reticulum (ER) disease (Akiyama et al, 2009, Fonseca et al, 2005, Inoue et al, 1998, Ueda et al, 2005, Yamada et al, 2006). Genetic mutations in pro-insulin genes or Unfolded Protein Response (UPR) component genes also cause inherited diabetes accompanied by islet β-cell ER stress in both rodents and humans (Delépine et al, 2000, Harding et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function

et al. 2017

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In Wfs1−/−Ay/a islets, in association with endoplasmic reticulum (ER) stress, D-site-binding protein (Dbp) expression decreased and Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding protein 4 (E4bp4) expression increased, leading to reduced DBP transcriptional activity. Similar alterations were observed with chemically-induced ER stress. Transgenic mice expressing E4BP4 under the control of the mouse insulin I gene promoter (MIP), in which E4BP4 in β-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2 + response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Thus, molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in β-cell priming for insulin release by regulating β-cell metabolism and gene expressions. Because ER stress is also involved in the β-cell failure in more common Type-2 diabetes, understanding the currently identified ER stress-associated mechanisms warrants novel therapeutic and preventive strategies for both rare form and common diabetes.

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“…Wfs1 deficient mice have glucose intolerance associated with loss of pancreatic beta cells [7], [8], [9]. The gene product of WFS1 (WFS1) is an endoplasmic reticulum (ER) embedded protein, which has been implicated in various cellular functions such as insulin secretion [7], [10] and processing [10], cell cycle regulation [11], [12], the unfolded protein response [9], [13] and cAMP production [14]. On the other hand, WFS1 mutation was not identified in some patients, providing evidence of genetic heterogeneity for this disease.…”

Section: Introductionmentioning

confidence: 99%

Wolfram Syndrome in the Japanese Population; Molecular Analysis of WFS1 Gene and Characterization of Clinical Features

et al. 2014

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BackgroundWolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS.MethodologyThe minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing.Principal FindingsSixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations.Conclusion/SignificanceThis study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with WFS1 mutations, as demonstrated by the disease onset.

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Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

Cited by 69 publications

References 51 publications

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function

Wolfram Syndrome in the Japanese Population; Molecular Analysis of WFS1 Gene and Characterization of Clinical Features

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