The Antipsychotic Olanzapine Induces Apoptosis in Insulin-secreting Pancreatic β Cells by Blocking PERK-mediated Translational Attenuation
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- Ozasa Riwa
- Department of Biophysics, Graduate School of Science, Kyoto University
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- Okada Tetsuya
- Department of Biophysics, Graduate School of Science, Kyoto University
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- Nadanaka Satomi
- Department of Biophysics, Graduate School of Science, Kyoto University
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- Nagamine Takahiko
- Division of Psychiatric Internal Medicine, Ishii Memorial Hospital
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- Zyryanova Alisha
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre
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- Harding Heather
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre
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- Ron David
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre
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- Mori Kazutoshi
- Department of Biophysics, Graduate School of Science, Kyoto University
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Abstract
Patients with schizophrenia receive medication to alleviate various symptoms, but some efficacious second generation antipsychotics, particularly olanzapine, can cause obesity, dyslipidemia, and diabetes mellitus. It has been generally considered that olanzapine contributes to the development of diabetes by inducing obesity and subsequent insulin resistance. In this study, we examined the effect of olanzapine and risperidone, another second generation antipsychotic, on a hamster pancreatic β cell line, and found that both evoked mild endoplasmic reticulum (ER) stress, as evidenced by mild activation of the ER stress sensor molecule PERK. Surprisingly, only olanzapine induced marked apoptosis. Phosphorylation of the α subunit of eukaryotic initiation factor 2, an event immediately downstream of PERK activation, was not observed in cells treated with olanzapine, protein synthesis continued despite PERK activation, and ER stress was thereby sustained. Secretion of insulin was markedly inhibited, and both proinsulin and insulin accumulated inside olanzapine-treated cells. Inhibition of protein synthesis and knockdown of insulin mRNA, which result in less unfolded protein burden, both attenuated subsequent olanzapine-induced apoptosis. Given clinical observations that some patients taking olanzapine exhibit hyperlipidemia and hyperglycemia without gaining weight, our observations suggest that damage to pancreatic β cells may contribute to the undesirable metabolic consequences of olanzapine treatment in some cases.
Journal
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- Cell Structure and Function
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Cell Structure and Function 38 (2), 183-195, 2013
Japan Society for Cell Biology
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Details
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- CRID
- 1390282679671723264
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- NII Article ID
- 130004137596
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- NII Book ID
- AA0060007X
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- COI
- 1:STN:280:DC%2BC3sjmvVOntg%3D%3D
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- ISSN
- 13473700
- 03867196
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- NDL BIB ID
- 025316329
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- PubMed
- 23812432
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- Abstract License Flag
- Disallowed