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Model-Based Hypothesis Testing of Key Mechanisms in Initial Phase of Insulin Signaling
Type 2 diabetes is characterized by insulin resistance of target organs, which is due to impaired insulin signal transduction. The skeleton of signaling mediators that provide for normal insulin action has been established. However, the detailed kinetics, and their mechanistic generation, remain inc...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2424138/ https://www.ncbi.nlm.nih.gov/pubmed/18551197 http://dx.doi.org/10.1371/journal.pcbi.1000096 |
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author | Cedersund, Gunnar Roll, Jacob Ulfhielm, Erik Danielsson, Anna Tidefelt, Henrik Strålfors, Peter |
author_facet | Cedersund, Gunnar Roll, Jacob Ulfhielm, Erik Danielsson, Anna Tidefelt, Henrik Strålfors, Peter |
author_sort | Cedersund, Gunnar |
collection | PubMed |
description | Type 2 diabetes is characterized by insulin resistance of target organs, which is due to impaired insulin signal transduction. The skeleton of signaling mediators that provide for normal insulin action has been established. However, the detailed kinetics, and their mechanistic generation, remain incompletely understood. We measured time-courses in primary human adipocytes for the short-term phosphorylation dynamics of the insulin receptor (IR) and the IR substrate-1 in response to a step increase in insulin concentration. Both proteins exhibited a rapid transient overshoot in tyrosine phosphorylation, reaching maximum within 1 min, followed by an intermediate steady-state level after approximately 10 min. We used model-based hypothesis testing to evaluate three mechanistic explanations for this behavior: (A) phosphorylation and dephosphorylation of IR at the plasma membrane only; (B) the additional possibility for IR endocytosis; (C) the alternative additional possibility of feedback signals to IR from downstream intermediates. We concluded that (A) is not a satisfactory explanation; that (B) may serve as an explanation only if both internalization, dephosphorylation, and subsequent recycling are permitted; and that (C) is acceptable. These mechanistic insights cannot be obtained by mere inspection of the datasets, and they are rejections and thus stronger and more final conclusions than ordinary model predictions. |
format | Text |
id | pubmed-2424138 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-24241382008-06-20 Model-Based Hypothesis Testing of Key Mechanisms in Initial Phase of Insulin Signaling Cedersund, Gunnar Roll, Jacob Ulfhielm, Erik Danielsson, Anna Tidefelt, Henrik Strålfors, Peter PLoS Comput Biol Research Article Type 2 diabetes is characterized by insulin resistance of target organs, which is due to impaired insulin signal transduction. The skeleton of signaling mediators that provide for normal insulin action has been established. However, the detailed kinetics, and their mechanistic generation, remain incompletely understood. We measured time-courses in primary human adipocytes for the short-term phosphorylation dynamics of the insulin receptor (IR) and the IR substrate-1 in response to a step increase in insulin concentration. Both proteins exhibited a rapid transient overshoot in tyrosine phosphorylation, reaching maximum within 1 min, followed by an intermediate steady-state level after approximately 10 min. We used model-based hypothesis testing to evaluate three mechanistic explanations for this behavior: (A) phosphorylation and dephosphorylation of IR at the plasma membrane only; (B) the additional possibility for IR endocytosis; (C) the alternative additional possibility of feedback signals to IR from downstream intermediates. We concluded that (A) is not a satisfactory explanation; that (B) may serve as an explanation only if both internalization, dephosphorylation, and subsequent recycling are permitted; and that (C) is acceptable. These mechanistic insights cannot be obtained by mere inspection of the datasets, and they are rejections and thus stronger and more final conclusions than ordinary model predictions. Public Library of Science 2008-06-20 /pmc/articles/PMC2424138/ /pubmed/18551197 http://dx.doi.org/10.1371/journal.pcbi.1000096 Text en Cedersund et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Cedersund, Gunnar Roll, Jacob Ulfhielm, Erik Danielsson, Anna Tidefelt, Henrik Strålfors, Peter Model-Based Hypothesis Testing of Key Mechanisms in Initial Phase of Insulin Signaling |
title | Model-Based Hypothesis Testing of Key Mechanisms in Initial Phase of Insulin Signaling |
title_full | Model-Based Hypothesis Testing of Key Mechanisms in Initial Phase of Insulin Signaling |
title_fullStr | Model-Based Hypothesis Testing of Key Mechanisms in Initial Phase of Insulin Signaling |
title_full_unstemmed | Model-Based Hypothesis Testing of Key Mechanisms in Initial Phase of Insulin Signaling |
title_short | Model-Based Hypothesis Testing of Key Mechanisms in Initial Phase of Insulin Signaling |
title_sort | model-based hypothesis testing of key mechanisms in initial phase of insulin signaling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2424138/ https://www.ncbi.nlm.nih.gov/pubmed/18551197 http://dx.doi.org/10.1371/journal.pcbi.1000096 |
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