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Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice
Insulin-producing β cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, initiates progression from β-cell dysfunction to β-cell dedifferentiation. The identification of pathways involved in ded...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013715/ https://www.ncbi.nlm.nih.gov/pubmed/27572106 http://dx.doi.org/10.1038/ncomms12631 |
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author | Kim-Muller, Ja Young Fan, Jason Kim, Young Jung R. Lee, Seung-Ah Ishida, Emi Blaner, William S. Accili, Domenico |
author_facet | Kim-Muller, Ja Young Fan, Jason Kim, Young Jung R. Lee, Seung-Ah Ishida, Emi Blaner, William S. Accili, Domenico |
author_sort | Kim-Muller, Ja Young |
collection | PubMed |
description | Insulin-producing β cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, initiates progression from β-cell dysfunction to β-cell dedifferentiation. The identification of pathways involved in dedifferentiation may provide clues to its reversal. Here we isolate and functionally characterize failing β cells from various experimental models of diabetes and report a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (ALDH(+)) as β cells become dedifferentiated. Flow-sorted ALDH(+) islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA, and include a Neurogenin3-positive subset. RNA sequencing analysis demonstrates that ALDH(+) cells are characterized by: (i) impaired oxidative phosphorylation and mitochondrial complex I, IV and V; (ii) activated RICTOR; and (iii) progenitor cell markers. We propose that impaired mitochondrial function marks the progression from metabolic inflexibility to dedifferentiation in the natural history of β-cell failure. |
format | Online Article Text |
id | pubmed-5013715 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50137152016-09-20 Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice Kim-Muller, Ja Young Fan, Jason Kim, Young Jung R. Lee, Seung-Ah Ishida, Emi Blaner, William S. Accili, Domenico Nat Commun Article Insulin-producing β cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, initiates progression from β-cell dysfunction to β-cell dedifferentiation. The identification of pathways involved in dedifferentiation may provide clues to its reversal. Here we isolate and functionally characterize failing β cells from various experimental models of diabetes and report a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (ALDH(+)) as β cells become dedifferentiated. Flow-sorted ALDH(+) islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA, and include a Neurogenin3-positive subset. RNA sequencing analysis demonstrates that ALDH(+) cells are characterized by: (i) impaired oxidative phosphorylation and mitochondrial complex I, IV and V; (ii) activated RICTOR; and (iii) progenitor cell markers. We propose that impaired mitochondrial function marks the progression from metabolic inflexibility to dedifferentiation in the natural history of β-cell failure. Nature Publishing Group 2016-08-30 /pmc/articles/PMC5013715/ /pubmed/27572106 http://dx.doi.org/10.1038/ncomms12631 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Kim-Muller, Ja Young Fan, Jason Kim, Young Jung R. Lee, Seung-Ah Ishida, Emi Blaner, William S. Accili, Domenico Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice |
title | Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice |
title_full | Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice |
title_fullStr | Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice |
title_full_unstemmed | Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice |
title_short | Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice |
title_sort | aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013715/ https://www.ncbi.nlm.nih.gov/pubmed/27572106 http://dx.doi.org/10.1038/ncomms12631 |
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