Inclusion of a glycogen regulation mathematical model into a contextual metabolic framework Public Deposited

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  • March 21, 2019
  • Todd, Abby Jo
    • Affiliation: College of Arts and Sciences, Department of Mathematics
  • While we generally eat infrequently, metabolic processes within our body tightly regulate blood glucose levels. The metabolic system is comprised of various tissues, each of which contains specific regulatory pathways that determine the function of the tissue within the system. These tissues and their localized metabolic functions, complement one another through inter-tissue metabolic highways to form the entire metabolic system. The liver is a key control center of metabolism and thus, the mathematical model described in this thesis is heavily liver-centric. Though all hepatocytes, or liver cells, are capable of similar metabolic functions, the rate at which these functions are carried out depends on the location of the hepatocytes within the liver. At the intracellular level, the various metabolic pathways contain many intersections. Though the intracellular components of the metabolic system are spatially localized, I assume a well-mixed cell and ignore spatial heterogeneity While physiological layering is important to accurately model metabolism, the layering of regulation within the system is also of interest for our model. The biochemical processes that make up metabolic pathways are regulated on many levels, such as by metabolites, hormones and enzymes, and also at a pre-protein level through transcription. While the model developed here does not include all levels of metabolic control it does address the need for understanding of metabolism from a multi-level perspective. The main conclusions from this study are that while fats are utilized to help produce glucose during periods of low blood glucose levels, resulting ketone bodies are kept at a minimal level and that heatmaps are an effective visual tool in evaluating model simulations. The enzyme circuit of the glycogen regulatory system allows for efficient modification of activity of enzymes to quickly increase the rate at which excess glucose is stored as glycogen. Also, as blood glucose levels drop, this enzyme circuitry is modified so that glycogen, amino acids and fats are broken down to produce glucose so that blood glucose levels are stabilized. The proposed model suggests that while fats are utilized in this process, ketone bodies resulting from lipolysis are kept at low levels, which is essential to protect the system from ketoacidosis. A mathematical model of a reduced glycogen regulatory circuit was developed and compared to a model of the full glycogen regulatory circuit. Though simulations of these models were similar in isolation, they produced different results when immersed in a contextual model which captured the multiple tissue environment of the metabolic system. This method allowed investigation into the effects of the enzyme cascade in the glycogen regulatory system. Heatmaps enabled quick assessment of model simulations and were vital for obtaining an overall fluxomic picture of the state of the system.
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  • Elston, Timothy
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  • University of North Carolina at Chapel Hill
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