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Stimulation of Autophagy Improves Endoplasmic Reticulum Stress–Induced Diabetes
Accumulation of misfolded proinsulin in the β-cell leads to dysfunction induced by endoplasmic reticulum (ER) stress, with diabetes as a consequence. Autophagy helps cellular adaptation to stress via clearance of misfolded proteins and damaged organelles. We studied the effects of proinsulin misfold...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609555/ https://www.ncbi.nlm.nih.gov/pubmed/23274896 http://dx.doi.org/10.2337/db12-1474 |
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author | Bachar-Wikstrom, Etty Wikstrom, Jakob D. Ariav, Yafa Tirosh, Boaz Kaiser, Nurit Cerasi, Erol Leibowitz, Gil |
author_facet | Bachar-Wikstrom, Etty Wikstrom, Jakob D. Ariav, Yafa Tirosh, Boaz Kaiser, Nurit Cerasi, Erol Leibowitz, Gil |
author_sort | Bachar-Wikstrom, Etty |
collection | PubMed |
description | Accumulation of misfolded proinsulin in the β-cell leads to dysfunction induced by endoplasmic reticulum (ER) stress, with diabetes as a consequence. Autophagy helps cellular adaptation to stress via clearance of misfolded proteins and damaged organelles. We studied the effects of proinsulin misfolding on autophagy and the impact of stimulating autophagy on diabetes progression in Akita mice, which carry a mutation in proinsulin, leading to its severe misfolding. Treatment of female diabetic Akita mice with rapamycin improved diabetes, increased pancreatic insulin content, and prevented β-cell apoptosis. In vitro, autophagic flux was increased in Akita β-cells. Treatment with rapamycin further stimulated autophagy, evidenced by increased autophagosome formation and enhancement of autophagosome–lysosome fusion. This was associated with attenuation of cellular stress and apoptosis. The mammalian target of rapamycin (mTOR) kinase inhibitor Torin1 mimicked the rapamycin effects on autophagy and stress, indicating that the beneficial effects of rapamycin are indeed mediated via inhibition of mTOR. Finally, inhibition of autophagy exacerbated stress and abolished the anti-ER stress effects of rapamycin. In conclusion, rapamycin reduces ER stress induced by accumulation of misfolded proinsulin, thereby improving diabetes and preventing β-cell apoptosis. The beneficial effects of rapamycin in this context strictly depend on autophagy; therefore, stimulating autophagy may become a therapeutic approach for diabetes. |
format | Online Article Text |
id | pubmed-3609555 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-36095552014-04-01 Stimulation of Autophagy Improves Endoplasmic Reticulum Stress–Induced Diabetes Bachar-Wikstrom, Etty Wikstrom, Jakob D. Ariav, Yafa Tirosh, Boaz Kaiser, Nurit Cerasi, Erol Leibowitz, Gil Diabetes Original Research Accumulation of misfolded proinsulin in the β-cell leads to dysfunction induced by endoplasmic reticulum (ER) stress, with diabetes as a consequence. Autophagy helps cellular adaptation to stress via clearance of misfolded proteins and damaged organelles. We studied the effects of proinsulin misfolding on autophagy and the impact of stimulating autophagy on diabetes progression in Akita mice, which carry a mutation in proinsulin, leading to its severe misfolding. Treatment of female diabetic Akita mice with rapamycin improved diabetes, increased pancreatic insulin content, and prevented β-cell apoptosis. In vitro, autophagic flux was increased in Akita β-cells. Treatment with rapamycin further stimulated autophagy, evidenced by increased autophagosome formation and enhancement of autophagosome–lysosome fusion. This was associated with attenuation of cellular stress and apoptosis. The mammalian target of rapamycin (mTOR) kinase inhibitor Torin1 mimicked the rapamycin effects on autophagy and stress, indicating that the beneficial effects of rapamycin are indeed mediated via inhibition of mTOR. Finally, inhibition of autophagy exacerbated stress and abolished the anti-ER stress effects of rapamycin. In conclusion, rapamycin reduces ER stress induced by accumulation of misfolded proinsulin, thereby improving diabetes and preventing β-cell apoptosis. The beneficial effects of rapamycin in this context strictly depend on autophagy; therefore, stimulating autophagy may become a therapeutic approach for diabetes. American Diabetes Association 2013-04 2013-03-14 /pmc/articles/PMC3609555/ /pubmed/23274896 http://dx.doi.org/10.2337/db12-1474 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Original Research Bachar-Wikstrom, Etty Wikstrom, Jakob D. Ariav, Yafa Tirosh, Boaz Kaiser, Nurit Cerasi, Erol Leibowitz, Gil Stimulation of Autophagy Improves Endoplasmic Reticulum Stress–Induced Diabetes |
title | Stimulation of Autophagy Improves Endoplasmic Reticulum Stress–Induced Diabetes |
title_full | Stimulation of Autophagy Improves Endoplasmic Reticulum Stress–Induced Diabetes |
title_fullStr | Stimulation of Autophagy Improves Endoplasmic Reticulum Stress–Induced Diabetes |
title_full_unstemmed | Stimulation of Autophagy Improves Endoplasmic Reticulum Stress–Induced Diabetes |
title_short | Stimulation of Autophagy Improves Endoplasmic Reticulum Stress–Induced Diabetes |
title_sort | stimulation of autophagy improves endoplasmic reticulum stress–induced diabetes |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609555/ https://www.ncbi.nlm.nih.gov/pubmed/23274896 http://dx.doi.org/10.2337/db12-1474 |
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