A mathematical model of metabolic insulin signaling pathways

Abstract

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 postreceptor events including phosphorylation of insulin receptor substrate-1, activation of phosphatidylinositol 3-kinase, and subsequent activation of downstream kinases Akt and protein kinase C-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.

Integrative model of the response of yeast to osmotic shock

“…Previously, quantitative computational simulation proved to support understanding of regulatory systems [5][6][7][8][9][10] , characterizing threshold properties and bistability 11,12 , characteristic times 13,14 and feedback effects 12,[15][16][17][18][19] . The model presented here comprises receptor stimulation, the HOG signaling pathway, activation of gene expression, adaptation of cellular metabolism, glycerol accumulation and a thermodynamic description of the control of volume and osmotic pressure.…”

A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis

“…Binding of insulin leads to rapid autophosphorylation and endocytosis of the insulin-autophosphorylated insulin-IR complex and an increased receptor tyrosine protein kinase activity toward downstream signal mediators, such as the insulin receptor substrate-1 (IRS1). The dynamics of the IR-IRS1 interaction have also been modeled (6,7), and we recently completed a comprehensive and integrated experimental/modeling-based analysis of the early molecular events in IR signal transduction (8). Therein, we sorted out the importance of different possible feedback mechanisms during the first phase of the signaling and concluded that a negative feedback mechanism that requires endocytosis of IR is an essential part of the first 5 min of signaling.…”

“…More downstream events in insulin signaling have been less modeled, but one earlier model by Sedaghat et al (7) involves many of the most studied signaling intermediates. However, the model suffers from problems such as unrealistic parameters and concentrations.…”

A Mathematical Model of the Human Metabolic System and Metabolic Flexibility

“…Glucose-insulin metabolism has been extensively investigated with many models describing the effect of insulin supply on glucose metabolism [22][23][24][25] and conversely the effects of a controlled glucose supply on insulin dynamics [26]. More complex models have also been proposed [27][28][29]43] which although detailed are still limited to glucoseinsulin metabolism. There are also models focusing on the metabolism of a variety of lipoproteins in the body and the transport of and conversion between them [30].…”