Computational Modelling of Glucose Uptake Mechanism in the Small Intestine

Abstract

Glucose is the main source of energy in the body and small intestine is where the most of the absorption and digestion of food nutrient take place. Transport of nutrients and specially glucose via the small intestine cell can activate the signaling pathways and feedback mechanisms that regulate effects over a range of time and length scales (e.g. expression of glucose transporter proteins, insulin secretion, appetite regulation, and growth). The main aim of this thesis is to build a computational model of glucose uptake through the small intestine cell in order to improve our understanding of the complex mechanism. The integrated model is implemented in OpenCOR which is an open source modeling environment by using CellML language which is for representing the biological and mathematical model. We used some of the existing models in the physiome model repository in order to build and expand our composite model. Our model consist all the transporters involved in glucose and electrolyte transports. We first developed a model of glucose uptake under iso-osmotic condition which was validated with some experimental results. It has been always a controversy around the existence of glucose transporter (GLUT2) in the apical membrane of the intestinal cell. The model showed the existence of apical GLUT2 in the cell membrane and necessity of having that in glucose uptake through the small intestine cell in order to explain the experimental data. The model was then expanded by adding water transporters to the model in order to make a model more realistic and also study of the effect of apical GLUT2 in cell volume regulation. The model was validated against some intestinal loop data and it revealed that having apical GLUT2 can decrease the cell volume changes in face of high glucose in the intestinal lumen. All of the transporters has an individual mechanistic model which can be used separately in another model. Finally we developed the model of apical GLUT2 translocation and how this process is controlled. This model helps us to understand the complex mechanism of GLUT2 translocation in the apical membrane and how it affects the glucose absorption. The model is implemented under modular approach in open access environment, which makes it easier to expand, reuse and modify in the future. The model provides more insight to glucose uptake process by small intestine and gives scientists the ability to predict some of the parameters that are difficult to measure experimentally and also to study the role of each transporters in controlling of some diseases.