Insulin Signaling Pathway Model in Adipocyte Cells

Abstract

Background: Worldwide, type 2 diabetes mellitus (T2DM) is one of the most pervasive and fastgrowing disorders, bringing long-term adverse effects. T2DM arises from pancreatic β-cells deficiency to produce enough insulin or when the body cannot effectively use the insulin produced by such cells. Accordingly, early diagnosis will decrease the long-term effects and high-healthcare costs of diabetes. Objective: The objective is developing an integrated mathematical model of the insulin signaling network based on Brännmark's model, which can simulate the signaling events more comprehensively with the added key components. Methods: In this study, a thorough mathematical model of the insulin signaling network was developed by expanding the previously validated model and incorporating the glycogen synthesis module. Parameters (69 parameters) of the integrated model were evaluated by a genetic algorithm by fitting the model predictions to eighty percent of experimental data from the literature. Twenty percent of the experimental data were used to evaluate the final optimized model. Results: The time-response curves indicate that the GS phosphorylation reaches its maximum in response to 10-7 M insulin after 4 min, while the maximum phosphorylated GSK3 is attained within ~50 min. The doseresponse curves for the GSP and GSK3 of the insulin signaling intermediaries in response to the increased concentration of insulin, after 10 min, in the input from 0-100 nM exhibits a decreasing trend, whereas an increasing trend was observed for the GS and GSK3P. The GSK and GS phosphorylation sensitivity was enhanced by increasing the initial insulin concentration level from 0.001 to 100 nM. However, the sensitivity of GSK3 to insulin concentration changes (from 0.001 to 100 nM) was 3-fold higher than GS sensitivity. Conclusion: Considerably, the trends of all signaling components simulated by the expanded model shows high compatibility with experimental data (R2 ≥ 0.9), which approves the accuracy of the proposed model. The proposed mathematical model can be used in many biological systems and combined with the whole-body model of the blood glucose regulation system for a better understanding of the causes and potential treatment of type 2 diabetes. Although, this model is not a complete description of insulin signaling, yet it can make profound contributions to improvements regarding other important components and signaling branches such as epidermal growth factor (EGF) signaling, as well as signaling in other cell types in the model structure of future works.