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Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes
Second-generation antipsychotics are widely used to medicate patients with schizophrenia, but may cause metabolic side effects such as diabetes, which has been considered to result from obesity-associated insulin resistance. Olanzapine is particularly well known for this effect. However, clinical st...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671685/ https://www.ncbi.nlm.nih.gov/pubmed/33198886 http://dx.doi.org/10.7554/eLife.60970 |
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author | Ninagawa, Satoshi Tada, Seiichiro Okumura, Masaki Inoguchi, Kenta Kinoshita, Misaki Kanemura, Shingo Imami, Koshi Umezawa, Hajime Ishikawa, Tokiro Mackin, Robert B Torii, Seiji Ishihama, Yasushi Inaba, Kenji Anazawa, Takayuki Nagamine, Takahiko Mori, Kazutoshi |
author_facet | Ninagawa, Satoshi Tada, Seiichiro Okumura, Masaki Inoguchi, Kenta Kinoshita, Misaki Kanemura, Shingo Imami, Koshi Umezawa, Hajime Ishikawa, Tokiro Mackin, Robert B Torii, Seiji Ishihama, Yasushi Inaba, Kenji Anazawa, Takayuki Nagamine, Takahiko Mori, Kazutoshi |
author_sort | Ninagawa, Satoshi |
collection | PubMed |
description | Second-generation antipsychotics are widely used to medicate patients with schizophrenia, but may cause metabolic side effects such as diabetes, which has been considered to result from obesity-associated insulin resistance. Olanzapine is particularly well known for this effect. However, clinical studies have suggested that olanzapine-induced hyperglycemia in certain patients cannot be explained by such a generalized mechanism. Here, we focused on the effects of olanzapine on insulin biosynthesis and secretion by mouse insulinoma MIN6 cells. Olanzapine reduced maturation of proinsulin, and thereby inhibited secretion of insulin; and specifically shifted the primary localization of proinsulin from insulin granules to the endoplasmic reticulum. This was due to olanzapine’s impairment of proper disulfide bond formation in proinsulin, although direct targets of olanzapine remain undetermined. Olanzapine-induced proinsulin misfolding and subsequent decrease also occurred at the mouse level. This mechanism of olanzapine-induced β-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine. |
format | Online Article Text |
id | pubmed-7671685 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-76716852020-11-18 Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes Ninagawa, Satoshi Tada, Seiichiro Okumura, Masaki Inoguchi, Kenta Kinoshita, Misaki Kanemura, Shingo Imami, Koshi Umezawa, Hajime Ishikawa, Tokiro Mackin, Robert B Torii, Seiji Ishihama, Yasushi Inaba, Kenji Anazawa, Takayuki Nagamine, Takahiko Mori, Kazutoshi eLife Cell Biology Second-generation antipsychotics are widely used to medicate patients with schizophrenia, but may cause metabolic side effects such as diabetes, which has been considered to result from obesity-associated insulin resistance. Olanzapine is particularly well known for this effect. However, clinical studies have suggested that olanzapine-induced hyperglycemia in certain patients cannot be explained by such a generalized mechanism. Here, we focused on the effects of olanzapine on insulin biosynthesis and secretion by mouse insulinoma MIN6 cells. Olanzapine reduced maturation of proinsulin, and thereby inhibited secretion of insulin; and specifically shifted the primary localization of proinsulin from insulin granules to the endoplasmic reticulum. This was due to olanzapine’s impairment of proper disulfide bond formation in proinsulin, although direct targets of olanzapine remain undetermined. Olanzapine-induced proinsulin misfolding and subsequent decrease also occurred at the mouse level. This mechanism of olanzapine-induced β-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine. eLife Sciences Publications, Ltd 2020-11-17 /pmc/articles/PMC7671685/ /pubmed/33198886 http://dx.doi.org/10.7554/eLife.60970 Text en © 2020, Ninagawa et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Ninagawa, Satoshi Tada, Seiichiro Okumura, Masaki Inoguchi, Kenta Kinoshita, Misaki Kanemura, Shingo Imami, Koshi Umezawa, Hajime Ishikawa, Tokiro Mackin, Robert B Torii, Seiji Ishihama, Yasushi Inaba, Kenji Anazawa, Takayuki Nagamine, Takahiko Mori, Kazutoshi Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes |
title | Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes |
title_full | Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes |
title_fullStr | Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes |
title_full_unstemmed | Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes |
title_short | Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes |
title_sort | antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671685/ https://www.ncbi.nlm.nih.gov/pubmed/33198886 http://dx.doi.org/10.7554/eLife.60970 |
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