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A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells
The construction and characterization of a core kinetic model of the glucose-stimulated insulin secretion system (GSIS) in pancreatic β cells is described. The model consists of 44 enzymatic reactions, 59 metabolic state variables, and 272 parameters. It integrates five subsystems: glycolysis, the T...
Autores principales: | , , |
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Formato: | Texto |
Lenguaje: | English |
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Springer New York
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1998884/ https://www.ncbi.nlm.nih.gov/pubmed/17514510 http://dx.doi.org/10.1007/s00335-007-9011-y |
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author | Jiang, Nan Cox, Roger D. Hancock, John M. |
author_facet | Jiang, Nan Cox, Roger D. Hancock, John M. |
author_sort | Jiang, Nan |
collection | PubMed |
description | The construction and characterization of a core kinetic model of the glucose-stimulated insulin secretion system (GSIS) in pancreatic β cells is described. The model consists of 44 enzymatic reactions, 59 metabolic state variables, and 272 parameters. It integrates five subsystems: glycolysis, the TCA cycle, the respiratory chain, NADH shuttles, and the pyruvate cycle. It also takes into account compartmentalization of the reactions in the cytoplasm and mitochondrial matrix. The model shows expected behavior in its outputs, including the response of ATP production to starting glucose concentration and the induction of oscillations of metabolite concentrations in the glycolytic pathway and in ATP and ADP concentrations. Identification of choke points and parameter sensitivity analysis indicate that the glycolytic pathway, and to a lesser extent the TCA cycle, are critical to the proper behavior of the system, while parameters in other components such as the respiratory chain are less critical. Notably, however, sensitivity analysis identifies the first reactions of nonglycolytic pathways as being important for the behavior of the system. The model is robust to deletion of malic enzyme activity, which is absent in mouse pancreatic β cells. The model represents a step toward the construction of a model with species-specific parameters that can be used to understand mouse models of diabetes and the relationship of these mouse models to the human disease state. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00335-007-9011-y) contains supplementary material, which is available to authorized users. |
format | Text |
id | pubmed-1998884 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Springer New York |
record_format | MEDLINE/PubMed |
spelling | pubmed-19988842007-10-02 A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells Jiang, Nan Cox, Roger D. Hancock, John M. Mamm Genome Article The construction and characterization of a core kinetic model of the glucose-stimulated insulin secretion system (GSIS) in pancreatic β cells is described. The model consists of 44 enzymatic reactions, 59 metabolic state variables, and 272 parameters. It integrates five subsystems: glycolysis, the TCA cycle, the respiratory chain, NADH shuttles, and the pyruvate cycle. It also takes into account compartmentalization of the reactions in the cytoplasm and mitochondrial matrix. The model shows expected behavior in its outputs, including the response of ATP production to starting glucose concentration and the induction of oscillations of metabolite concentrations in the glycolytic pathway and in ATP and ADP concentrations. Identification of choke points and parameter sensitivity analysis indicate that the glycolytic pathway, and to a lesser extent the TCA cycle, are critical to the proper behavior of the system, while parameters in other components such as the respiratory chain are less critical. Notably, however, sensitivity analysis identifies the first reactions of nonglycolytic pathways as being important for the behavior of the system. The model is robust to deletion of malic enzyme activity, which is absent in mouse pancreatic β cells. The model represents a step toward the construction of a model with species-specific parameters that can be used to understand mouse models of diabetes and the relationship of these mouse models to the human disease state. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00335-007-9011-y) contains supplementary material, which is available to authorized users. Springer New York 2007-07-01 2007 /pmc/articles/PMC1998884/ /pubmed/17514510 http://dx.doi.org/10.1007/s00335-007-9011-y Text en © Springer Science+Business Media, LLC 2007 https://creativecommons.org/licenses/by-nc/2.0/ Open Access This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License ( https://creativecommons.org/licenses/by-nc/2.0 (https://creativecommons.org/licenses/by-nc/2.0/) ), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Article Jiang, Nan Cox, Roger D. Hancock, John M. A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells |
title | A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells |
title_full | A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells |
title_fullStr | A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells |
title_full_unstemmed | A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells |
title_short | A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells |
title_sort | kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1998884/ https://www.ncbi.nlm.nih.gov/pubmed/17514510 http://dx.doi.org/10.1007/s00335-007-9011-y |
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