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Mathematical models for a mechanistic understanding of type 2 diabetes development Faulkner, Katharine R.

Abstract

Type 2 diabetes is a chronic disease that affects about 6.28% of people worldwide and there are very few known cases of reversal of the disease. As an individual becomes diabetic, there are many physiological changes that occur, but it is unclear which of these changes are the main drivers of the progression to the disease. Through mathematical modelling, we provide insight into which factors may be key to type 2 diabetes development and make predictions about how to delay, avoid or reverse onset. In particular, we focus on changes to pancreas functioning and lipid handling throughout the body. This dissertation begins with analysis of mouse data from Skovso et al. (2021) and an adaptation to the model by Topp et al. (2000) to include insulin negative feedback at the beta cells, the pancreatic cells that produce insulin. We find that female mice are generally more insulin sensitive than male mice at all ages. The model predicts that beta cell insulin resistance allows for stability of blood glucose when peripheral insulin sensitivity is lost. Next, we adapt and extend the Topp model to explore the effect of lipid toxicity (lipotoxicity) at the beta cells on type 2 diabetes progression and compare this Lipotoxicity Model to data from Hansen and Bodkin (1990). The model has qualitative changes to the system that allow for movement between healthy and diseased states that match the sudden changes in state seen in the data. The bifurcation structure of the system predicts the difficulty we see in reversing diabetes, with reversal requiring dramatic changes to lipid regulation, glucose input or total functional beta cell mass. Finally, we expand the Lipotoxicity Model into a more detailed description of whole body lipid metabolism and storage. The Adipose Filling Model includes the effects of fat storage overflow in order to explore lipid dysregulation in pre-diabetic individuals. We find that low fat storage capacity increases risk of type 2 diabetes and can speed up onset.

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Attribution-NonCommercial-NoDerivatives 4.0 International