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Model-Based Hypothesis Testing of Key Mechanisms in Initial Phase of Insulin Signaling
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
Linköping University, Department of Electrical Engineering, Automatic Control. Linköping University, The Institute of Technology.
Linköping University, Department of Electrical Engineering. Linköping University, The Institute of Technology.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
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2008 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 4, no 6Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Public Library of Science , 2008. Vol. 4, no 6
Keyword [en]
Type 2 diabetes, Insulin receptor
National Category
Medical and Health Sciences Control Engineering
Identifiers
URN: urn:nbn:se:liu:diva-46066DOI: 10.1371/journal.pcbi.1000096OAI: oai:DiVA.org:liu-46066DiVA: diva2:266962
Note

© 2008 Cedersund et al.

Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2013-07-22

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Cedersund, GunnarRoll, JacobDanielsson, AnnaTidefelt, HenrikStrålfors, Peter

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Cedersund, GunnarRoll, JacobDanielsson, AnnaTidefelt, HenrikStrålfors, Peter
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