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Am J Physiol Endocrinol Metab (July 2, 2002). doi:10.1152/ajpendo.00571.2001
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Articles in PresS, published online ahead of print July 2, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00571.2001
Submitted on January 7, 2002
Accepted on June 25, 2002

A Mathematical Model of Metabolic Insulin Signaling Pathways

Ahmad R. Sedaghat1, Arthur Sherman2, and Michael J. Quon1*

1 Cardiology Branch, NIH, NHLBI, Bethesda, MD, USA
2 Mathematical Biology Branch, NIH, NIDDK, Bethesda, MD, USA

* To whom correspondence should be addressed. E-mail: quonm{at}nih.gov.

We develop a mathematical model that explicitly represents many of the known signaling components mediating translocation of the insulin responsive glucose transporter GLUT4 to gain insight into the complexities of metabolic insulin signaling pathways. A novel mechanistic model of post-receptor events including phosphorylation of IRS-1, activation of PI 3-kinase, and subsequent activation of downstream kinases Akt and PKC-{zeta} is coupled with previously validated subsystem models of insulin receptor binding, receptor recycling, and GLUT4 translocation. A system of differential equations is defined by the structure of the model. Rate constants and model parameters are constrained by published experimental data. Model simulations of insulin dose-response experiments agree with published experimental data and also generate expected qualitative behaviors such as sequential signal amplification and increased sensitivity of downstream components. We examined the consequences of incorporating feedback pathways as well as representing pathological conditions such as increased levels of protein tyrosine phosphatases to illustrate the utility of our model for exploring molecular mechanisms. We conclude that mathematical modeling of signal transduction pathways is a useful approach for gaining insight into the complexities of metabolic insulin signaling.




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