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Essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status
Energy sensing is indispensable to balance anabolic and catabolic processes for the maintenance of cell viability. Pancreatic β cells are especially relevant because of their involvement in the coordination of insulin secretion when glucose concentration arises in the local milieu. In this work, we...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769003/ https://www.ncbi.nlm.nih.gov/pubmed/31583121 http://dx.doi.org/10.1038/s41420-019-0219-x |
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author | Marqués, Patricia Kamitz, Anne Bartolomé, Alberto Burillo, Jesús Martínez, Helena Jiménez, Beatriz Fernández-Rhodes, María Guillén, Carlos Benito, Manuel |
author_facet | Marqués, Patricia Kamitz, Anne Bartolomé, Alberto Burillo, Jesús Martínez, Helena Jiménez, Beatriz Fernández-Rhodes, María Guillén, Carlos Benito, Manuel |
author_sort | Marqués, Patricia |
collection | PubMed |
description | Energy sensing is indispensable to balance anabolic and catabolic processes for the maintenance of cell viability. Pancreatic β cells are especially relevant because of their involvement in the coordination of insulin secretion when glucose concentration arises in the local milieu. In this work, we uncover the increased susceptibility of pancreatic β cells to cell death in response to different energy stressors. Upon glucose decline, from 25 to 5 mM, caused by stimulation with either 2-deoxyglucose or metformin, only pancreatic β cells showed an increase in cell death. Very interestingly, when we transfected either mouse insulinoma cell or human embryo kidney cells with a phospho-mutant form of B cell lymphoma 2 associated agonist of cell death at serine 155 (BAD S155D), an increase in the pro-survival factor B cell lymphoma 2 was detected in pancreatic β cells and not in human embryonic kidney cells in the presence of the energetic stressors. This data suggests that the protective capacity of this mutant form is only present in cells that present glucokinase. In contrast, upon hyperactivation of mechanistic target of rapamycin complex 1 signaling by knocking-down tuberous sclerosis complex protein, we observed increased susceptibility to cell death in response to energy stress in both pancreatic and non-pancreatic β cells. Therefore, mechanistic target of rapamycin complex 1 signaling presents a dual effect on cell viability. On the one hand, a chronic inhibition of mechanistic target of rapamycin complex 1 activity in response to the energy status is deleterious for pancreatic β cells, being attenuated by the overexpression of B cell lymphoma 2 associated agonist of cell death S155D. On the other hand, mechanistic target of rapamycin complex 1 hyperactivity provokes a susceptibility to energetic stress-induced cell death. Taken together, these results may open potential implications for the use of glucokinase activators or mechanistic target of rapamycin complex 1 modulators for the maintenance of pancreatic β cells for longer periods of time avoiding its loss in different pathologies such as type 2 diabetes mellitus. |
format | Online Article Text |
id | pubmed-6769003 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-67690032019-10-03 Essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status Marqués, Patricia Kamitz, Anne Bartolomé, Alberto Burillo, Jesús Martínez, Helena Jiménez, Beatriz Fernández-Rhodes, María Guillén, Carlos Benito, Manuel Cell Death Discov Article Energy sensing is indispensable to balance anabolic and catabolic processes for the maintenance of cell viability. Pancreatic β cells are especially relevant because of their involvement in the coordination of insulin secretion when glucose concentration arises in the local milieu. In this work, we uncover the increased susceptibility of pancreatic β cells to cell death in response to different energy stressors. Upon glucose decline, from 25 to 5 mM, caused by stimulation with either 2-deoxyglucose or metformin, only pancreatic β cells showed an increase in cell death. Very interestingly, when we transfected either mouse insulinoma cell or human embryo kidney cells with a phospho-mutant form of B cell lymphoma 2 associated agonist of cell death at serine 155 (BAD S155D), an increase in the pro-survival factor B cell lymphoma 2 was detected in pancreatic β cells and not in human embryonic kidney cells in the presence of the energetic stressors. This data suggests that the protective capacity of this mutant form is only present in cells that present glucokinase. In contrast, upon hyperactivation of mechanistic target of rapamycin complex 1 signaling by knocking-down tuberous sclerosis complex protein, we observed increased susceptibility to cell death in response to energy stress in both pancreatic and non-pancreatic β cells. Therefore, mechanistic target of rapamycin complex 1 signaling presents a dual effect on cell viability. On the one hand, a chronic inhibition of mechanistic target of rapamycin complex 1 activity in response to the energy status is deleterious for pancreatic β cells, being attenuated by the overexpression of B cell lymphoma 2 associated agonist of cell death S155D. On the other hand, mechanistic target of rapamycin complex 1 hyperactivity provokes a susceptibility to energetic stress-induced cell death. Taken together, these results may open potential implications for the use of glucokinase activators or mechanistic target of rapamycin complex 1 modulators for the maintenance of pancreatic β cells for longer periods of time avoiding its loss in different pathologies such as type 2 diabetes mellitus. Nature Publishing Group UK 2019-09-30 /pmc/articles/PMC6769003/ /pubmed/31583121 http://dx.doi.org/10.1038/s41420-019-0219-x Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Marqués, Patricia Kamitz, Anne Bartolomé, Alberto Burillo, Jesús Martínez, Helena Jiménez, Beatriz Fernández-Rhodes, María Guillén, Carlos Benito, Manuel Essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status |
title | Essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status |
title_full | Essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status |
title_fullStr | Essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status |
title_full_unstemmed | Essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status |
title_short | Essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status |
title_sort | essential role of glucokinase in the protection of pancreatic β cells to the glucose energetic status |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769003/ https://www.ncbi.nlm.nih.gov/pubmed/31583121 http://dx.doi.org/10.1038/s41420-019-0219-x |
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