Cargando…
Failure of the Adaptive Unfolded Protein Response in Islets of Obese Mice Is Linked With Abnormalities in β-Cell Gene Expression and Progression to Diabetes
The normal β-cell response to obesity-associated insulin resistance is hypersecretion of insulin. Type 2 diabetes develops in subjects with β-cells that are susceptible to failure. Here, we investigated the time-dependent gene expression changes in islets of diabetes-prone db/db and diabetes-resista...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636637/ https://www.ncbi.nlm.nih.gov/pubmed/23274897 http://dx.doi.org/10.2337/db12-0701 |
_version_ | 1782267358510841856 |
---|---|
author | Chan, Jeng Yie Luzuriaga, Jude Bensellam, Mohammed Biden, Trevor J. Laybutt, D. Ross |
author_facet | Chan, Jeng Yie Luzuriaga, Jude Bensellam, Mohammed Biden, Trevor J. Laybutt, D. Ross |
author_sort | Chan, Jeng Yie |
collection | PubMed |
description | The normal β-cell response to obesity-associated insulin resistance is hypersecretion of insulin. Type 2 diabetes develops in subjects with β-cells that are susceptible to failure. Here, we investigated the time-dependent gene expression changes in islets of diabetes-prone db/db and diabetes-resistant ob/ob mice. The expressions of adaptive unfolded protein response (UPR) genes were progressively induced in islets of ob/ob mice, whereas they declined in diabetic db/db mice. Genes important for β-cell function and maintenance of the islet phenotype were reduced with time in db/db mice, whereas they were preserved in ob/ob mice. Inflammation and antioxidant genes displayed time-dependent upregulation in db/db islets but were unchanged in ob/ob islets. Treatment of db/db mouse islets with the chemical chaperone 4-phenylbutyric acid partially restored the changes in several β-cell function genes and transcription factors but did not affect inflammation or antioxidant gene expression. These data suggest that the maintenance (or suppression) of the adaptive UPR is associated with β-cell compensation (or failure) in obese mice. Inflammation, oxidative stress, and a progressive loss of β-cell differentiation accompany diabetes progression. The ability to maintain the adaptive UPR in islets may protect against the gene expression changes that underlie diabetes development in obese mice. |
format | Online Article Text |
id | pubmed-3636637 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-36366372014-05-01 Failure of the Adaptive Unfolded Protein Response in Islets of Obese Mice Is Linked With Abnormalities in β-Cell Gene Expression and Progression to Diabetes Chan, Jeng Yie Luzuriaga, Jude Bensellam, Mohammed Biden, Trevor J. Laybutt, D. Ross Diabetes Original Research The normal β-cell response to obesity-associated insulin resistance is hypersecretion of insulin. Type 2 diabetes develops in subjects with β-cells that are susceptible to failure. Here, we investigated the time-dependent gene expression changes in islets of diabetes-prone db/db and diabetes-resistant ob/ob mice. The expressions of adaptive unfolded protein response (UPR) genes were progressively induced in islets of ob/ob mice, whereas they declined in diabetic db/db mice. Genes important for β-cell function and maintenance of the islet phenotype were reduced with time in db/db mice, whereas they were preserved in ob/ob mice. Inflammation and antioxidant genes displayed time-dependent upregulation in db/db islets but were unchanged in ob/ob islets. Treatment of db/db mouse islets with the chemical chaperone 4-phenylbutyric acid partially restored the changes in several β-cell function genes and transcription factors but did not affect inflammation or antioxidant gene expression. These data suggest that the maintenance (or suppression) of the adaptive UPR is associated with β-cell compensation (or failure) in obese mice. Inflammation, oxidative stress, and a progressive loss of β-cell differentiation accompany diabetes progression. The ability to maintain the adaptive UPR in islets may protect against the gene expression changes that underlie diabetes development in obese mice. American Diabetes Association 2013-05 2013-04-16 /pmc/articles/PMC3636637/ /pubmed/23274897 http://dx.doi.org/10.2337/db12-0701 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 Chan, Jeng Yie Luzuriaga, Jude Bensellam, Mohammed Biden, Trevor J. Laybutt, D. Ross Failure of the Adaptive Unfolded Protein Response in Islets of Obese Mice Is Linked With Abnormalities in β-Cell Gene Expression and Progression to Diabetes |
title | Failure of the Adaptive Unfolded Protein Response in Islets of Obese Mice Is Linked With Abnormalities in β-Cell Gene Expression and Progression to Diabetes |
title_full | Failure of the Adaptive Unfolded Protein Response in Islets of Obese Mice Is Linked With Abnormalities in β-Cell Gene Expression and Progression to Diabetes |
title_fullStr | Failure of the Adaptive Unfolded Protein Response in Islets of Obese Mice Is Linked With Abnormalities in β-Cell Gene Expression and Progression to Diabetes |
title_full_unstemmed | Failure of the Adaptive Unfolded Protein Response in Islets of Obese Mice Is Linked With Abnormalities in β-Cell Gene Expression and Progression to Diabetes |
title_short | Failure of the Adaptive Unfolded Protein Response in Islets of Obese Mice Is Linked With Abnormalities in β-Cell Gene Expression and Progression to Diabetes |
title_sort | failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in β-cell gene expression and progression to diabetes |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636637/ https://www.ncbi.nlm.nih.gov/pubmed/23274897 http://dx.doi.org/10.2337/db12-0701 |
work_keys_str_mv | AT chanjengyie failureoftheadaptiveunfoldedproteinresponseinisletsofobesemiceislinkedwithabnormalitiesinbcellgeneexpressionandprogressiontodiabetes AT luzuriagajude failureoftheadaptiveunfoldedproteinresponseinisletsofobesemiceislinkedwithabnormalitiesinbcellgeneexpressionandprogressiontodiabetes AT bensellammohammed failureoftheadaptiveunfoldedproteinresponseinisletsofobesemiceislinkedwithabnormalitiesinbcellgeneexpressionandprogressiontodiabetes AT bidentrevorj failureoftheadaptiveunfoldedproteinresponseinisletsofobesemiceislinkedwithabnormalitiesinbcellgeneexpressionandprogressiontodiabetes AT laybuttdross failureoftheadaptiveunfoldedproteinresponseinisletsofobesemiceislinkedwithabnormalitiesinbcellgeneexpressionandprogressiontodiabetes |