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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...

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Autores principales: Chan, Jeng Yie, Luzuriaga, Jude, Bensellam, Mohammed, Biden, Trevor J., Laybutt, D. Ross
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
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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.
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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
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