Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells
Second-generation antipsychotics (SGAs), in particular, olanzapine and clozapine, have been associated with the development of type 2 diabetes mellitus (T2D) and metabolic syndrome in individuals with schizophrenia. In this context, beta cell dysfunction is a plausible mechanism by which SGAs cause...
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MDPI AG
2022-05-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/12/5/443 |
| _version_ | 1797497948834103296 |
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| author | Diana Grajales Patricia Vázquez Rosa Alén Ana B. Hitos Ángela M. Valverde |
| author_facet | Diana Grajales Patricia Vázquez Rosa Alén Ana B. Hitos Ángela M. Valverde |
| author_sort | Diana Grajales |
| collection | DOAJ |
| description | Second-generation antipsychotics (SGAs), in particular, olanzapine and clozapine, have been associated with the development of type 2 diabetes mellitus (T2D) and metabolic syndrome in individuals with schizophrenia. In this context, beta cell dysfunction is a plausible mechanism by which SGAs cause T2D. Herein, we analyzed the direct effects of olanzapine, a commonly prescribed SGA with diabetogenic properties, on the INS-1 (821/13) beta cell line and isolated pancreatic islets. Treatment of INS-1 beta cells with non-toxic concentrations of olanzapine (3–6 μM) during 4 h activated endoplasmic reticulum (ER) stress-mediated signaling by increasing PERK/eIF2α phosphorylation, IRE-1 phosphorylation and XBP-1 splicing. Moreover, glucose-stimulated insulin secretion (GSIS) was inhibited when olanzapine was present for 16 h. The insulin secretory function of INS-1 cells was restored by inhibiting olanzapine-induced ER stress with tauroursodeoxycholic acid (TUDCA). Similar effects of olanzapine with or without TUDCA on ER-stress-mediated signaling and GSIS were found in pancreatic islets from female mice. Our results indicate that early activation of ER stress in pancreatic beta cells is a potential mechanism behind the alterations in glucose homeostasis induced by olanzapine. |
| first_indexed | 2024-03-10T03:26:26Z |
| format | Article |
| id | doaj.art-d12cd7fb0c09439ead49148c368f90f6 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T03:26:26Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-d12cd7fb0c09439ead49148c368f90f62023-11-23T12:07:33ZengMDPI AGMetabolites2218-19892022-05-0112544310.3390/metabo12050443Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta CellsDiana Grajales0Patricia Vázquez1Rosa Alén2Ana B. Hitos3Ángela M. Valverde4Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), 28029 Madrid, SpainSecond-generation antipsychotics (SGAs), in particular, olanzapine and clozapine, have been associated with the development of type 2 diabetes mellitus (T2D) and metabolic syndrome in individuals with schizophrenia. In this context, beta cell dysfunction is a plausible mechanism by which SGAs cause T2D. Herein, we analyzed the direct effects of olanzapine, a commonly prescribed SGA with diabetogenic properties, on the INS-1 (821/13) beta cell line and isolated pancreatic islets. Treatment of INS-1 beta cells with non-toxic concentrations of olanzapine (3–6 μM) during 4 h activated endoplasmic reticulum (ER) stress-mediated signaling by increasing PERK/eIF2α phosphorylation, IRE-1 phosphorylation and XBP-1 splicing. Moreover, glucose-stimulated insulin secretion (GSIS) was inhibited when olanzapine was present for 16 h. The insulin secretory function of INS-1 cells was restored by inhibiting olanzapine-induced ER stress with tauroursodeoxycholic acid (TUDCA). Similar effects of olanzapine with or without TUDCA on ER-stress-mediated signaling and GSIS were found in pancreatic islets from female mice. Our results indicate that early activation of ER stress in pancreatic beta cells is a potential mechanism behind the alterations in glucose homeostasis induced by olanzapine.https://www.mdpi.com/2218-1989/12/5/443olanzapineER stressbeta cellsecond-generation antipsychoticsschizophreniatype 2 diabetes |
| spellingShingle | Diana Grajales Patricia Vázquez Rosa Alén Ana B. Hitos Ángela M. Valverde Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells Metabolites olanzapine ER stress beta cell second-generation antipsychotics schizophrenia type 2 diabetes |
| title | Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells |
| title_full | Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells |
| title_fullStr | Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells |
| title_full_unstemmed | Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells |
| title_short | Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells |
| title_sort | attenuation of olanzapine induced endoplasmic reticulum stress improves insulin secretion in pancreatic beta cells |
| topic | olanzapine ER stress beta cell second-generation antipsychotics schizophrenia type 2 diabetes |
| url | https://www.mdpi.com/2218-1989/12/5/443 |
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