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Computational modelling of the regulation of Insulin signalling by oxidative stress

Lookup NU author(s): Dr Graham Smith, Dr Daryl Shanley

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Abstract

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.


Publication metadata

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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