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Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach
BACKGROUND: Sodium tungstate is known to be an effective anti-diabetic agent, able to increase beta cell mass in animal models of diabetes, although the molecular mechanisms of this treatment and the genes that control pancreas plasticity are yet to be identified. Using a transcriptomics approach, t...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2741493/ https://www.ncbi.nlm.nih.gov/pubmed/19715561 http://dx.doi.org/10.1186/1471-2164-10-406 |
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author | Altirriba, Jordi Barbera, Albert Del Zotto, Héctor Nadal, Belen Piquer, Sandra Sánchez-Pla, Alex Gagliardino, Juan J Gomis, Ramon |
author_facet | Altirriba, Jordi Barbera, Albert Del Zotto, Héctor Nadal, Belen Piquer, Sandra Sánchez-Pla, Alex Gagliardino, Juan J Gomis, Ramon |
author_sort | Altirriba, Jordi |
collection | PubMed |
description | BACKGROUND: Sodium tungstate is known to be an effective anti-diabetic agent, able to increase beta cell mass in animal models of diabetes, although the molecular mechanisms of this treatment and the genes that control pancreas plasticity are yet to be identified. Using a transcriptomics approach, the aim of the study is to unravel the molecular mechanisms which participate in the recovery of exocrine and endocrine function of streptozotocin (STZ) diabetic rats treated with tungstate, determining the hyperglycemia contribution and the direct effect of tungstate. RESULTS: Streptozotocin (STZ)-diabetic rats were treated orally with tungstate for five weeks. Treated (STZ)-diabetic rats showed a partial recovery of exocrine and endocrine function, with lower glycemia, increased insulinemia and amylasemia, and increased beta cell mass achieved by reducing beta cell apoptosis and raising beta cell proliferation. The microarray analysis of the pancreases led to the identification of three groups of differentially expressed genes: genes altered due to diabetes, genes restored by the treatment, and genes specifically induced by tungstate in the diabetic animals. The results were corroborated by quantitative PCR. A detailed description of the pathways involved in the pancreatic effects of tungstate is provided in this paper. Hyperglycemia contribution was studied in STZ-diabetic rats treated with phloridzin, and the direct effect of tungstate was determined in INS-1E cells treated with tungstate or serum from untreated or treated STZ-rats, observing that tungstate action in the pancreas takes places via hyperglycemia-independent pathways and via a combination of tungstate direct and indirect (through the serum profile modification) effects. Finally, the MAPK pathway was evaluated, observing that it has a key role in the tungstate-induced increase of beta cell proliferation as tungstate activates the mitogen-activated protein kinase (MAPK) pathway directly by increasing p42/p44 phosphorylation and indirectly by decreasing the expression of raf kinase inhibitor protein (Rkip), a negative modulator of the pathway. CONCLUSION: In conclusion, tungstate improves pancreatic function through a combination of hyperglycemia-independent pathways and through its own direct and indirect effects, whereas the MAPK pathway has a key role in the tungstate-induced increase of beta cell proliferation. |
format | Text |
id | pubmed-2741493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-27414932009-09-11 Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach Altirriba, Jordi Barbera, Albert Del Zotto, Héctor Nadal, Belen Piquer, Sandra Sánchez-Pla, Alex Gagliardino, Juan J Gomis, Ramon BMC Genomics Research Article BACKGROUND: Sodium tungstate is known to be an effective anti-diabetic agent, able to increase beta cell mass in animal models of diabetes, although the molecular mechanisms of this treatment and the genes that control pancreas plasticity are yet to be identified. Using a transcriptomics approach, the aim of the study is to unravel the molecular mechanisms which participate in the recovery of exocrine and endocrine function of streptozotocin (STZ) diabetic rats treated with tungstate, determining the hyperglycemia contribution and the direct effect of tungstate. RESULTS: Streptozotocin (STZ)-diabetic rats were treated orally with tungstate for five weeks. Treated (STZ)-diabetic rats showed a partial recovery of exocrine and endocrine function, with lower glycemia, increased insulinemia and amylasemia, and increased beta cell mass achieved by reducing beta cell apoptosis and raising beta cell proliferation. The microarray analysis of the pancreases led to the identification of three groups of differentially expressed genes: genes altered due to diabetes, genes restored by the treatment, and genes specifically induced by tungstate in the diabetic animals. The results were corroborated by quantitative PCR. A detailed description of the pathways involved in the pancreatic effects of tungstate is provided in this paper. Hyperglycemia contribution was studied in STZ-diabetic rats treated with phloridzin, and the direct effect of tungstate was determined in INS-1E cells treated with tungstate or serum from untreated or treated STZ-rats, observing that tungstate action in the pancreas takes places via hyperglycemia-independent pathways and via a combination of tungstate direct and indirect (through the serum profile modification) effects. Finally, the MAPK pathway was evaluated, observing that it has a key role in the tungstate-induced increase of beta cell proliferation as tungstate activates the mitogen-activated protein kinase (MAPK) pathway directly by increasing p42/p44 phosphorylation and indirectly by decreasing the expression of raf kinase inhibitor protein (Rkip), a negative modulator of the pathway. CONCLUSION: In conclusion, tungstate improves pancreatic function through a combination of hyperglycemia-independent pathways and through its own direct and indirect effects, whereas the MAPK pathway has a key role in the tungstate-induced increase of beta cell proliferation. BioMed Central 2009-08-28 /pmc/articles/PMC2741493/ /pubmed/19715561 http://dx.doi.org/10.1186/1471-2164-10-406 Text en Copyright © 2009 Altirriba et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Altirriba, Jordi Barbera, Albert Del Zotto, Héctor Nadal, Belen Piquer, Sandra Sánchez-Pla, Alex Gagliardino, Juan J Gomis, Ramon Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach |
title | Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach |
title_full | Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach |
title_fullStr | Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach |
title_full_unstemmed | Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach |
title_short | Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach |
title_sort | molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2741493/ https://www.ncbi.nlm.nih.gov/pubmed/19715561 http://dx.doi.org/10.1186/1471-2164-10-406 |
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