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Lookup NU author(s): Dr Graham Smith, Dr Daryl Shanley
Background: Existing models of insulin signalling focus on short term dynamics, rather than the longer term dynamics necessary to understand many physiologically relevant behaviours. We have developed a model of insulin signalling in rodent adipocytes that includes both transcriptional feedback through the Forkhead box type O (FOXO) transcription factor, and interaction with oxidative stress, in addition to the core pathway. In the model Reactive Oxygen Species are both generated endogenously and can be applied externally. They regulate signalling though inhibition of phosphatases and induction of the activity of Stress Activated Protein Kinases, which themselves modulate feedbacks to insulin signalling and FOXO.Results: Insulin and oxidative stress combined produce a lower degree of activation of insulin signalling than insulin alone. Fasting (nutrient withdrawal) and weak oxidative stress upregulate antioxidant defences while stronger oxidative stress leads to a short term activation of insulin signalling but if prolonged can have other effects including degradation of the insulin receptor substrate (IRS1) and FOXO. At high insulin the protective effect of moderate oxidative stress may disappear.Conclusion: Our model is consistent with a wide range of experimental data, some of which is difficult to explain. Oxidative stress can have effects that are both up-and down-regulatory on insulin signalling. Our model therefore shows the complexity of the interaction between the two pathways and highlights the need for such integrated computational models to give insight into the dysregulation of insulin signalling along with more data at the individual level.
Author(s): Smith GR, Shanley DP
Publication type: Article
Publication status: Published
Journal: BMC Systems Biology
Year: 2013
Volume: 7
Online publication date: 24/05/2013
Acceptance date: 19/04/2013
Date deposited: 23/10/2014
ISSN (electronic): 1752-0509
Publisher: BioMed Central Ltd
URL: http://dx.doi.org/10.1186/1752-0509-7-41
DOI: 10.1186/1752-0509-7-41
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