Existing mathematical models give crude descriptions of the metabolic processes in action following a meal. Your initial work will concentrate on analysing how these processes vary with the proportion of fat and carbohydrate in the meal. As carbohydrate is the major factor determining the insulin response generated by the pancreas, and insulin regulates many metabolic processes in the liver, muscles and adipose tissue, a change to the composition of the meal has a widespread influence on the fluxes in many areas of the body.
Your initial study will consider the effect of the varying of meal compositions on the metabolic fluxes in the during and post-prandial phase (several hours following a meal).
The stages in the progression of insulin resistance from full health to type 2 diabetes is a matter of significant current interest from both a scientific perspective and in relation to public health policy.
The range of conditions from mild insulin resistance are commonly referred to under the umbrella term 'non-alcoholic fatty liver disease', or NAFLD. At the extreme end of this is the more serious condition of non-alcoholic steatohepatitis (NASH). We have data available on a range of individuals at various stages along the pathway to insulin resistance, detailing their responses to a standard meal following an overnight fast. Models of whole-body models of carbohydrate and fat metabolism are available at a range of scales and levels of detail. We aim to fit the mathematical model to the response of each individual in the study to the model, by determining the rate parameters of many processes for each individual. We aim to determine the correlation between the known classical measures of insulin resistance for each individual and the efficiency of processes in each tissue. We hope to uncover the order of progression of the disease, as insulin-resistance affects muscle, liver, adipose tissue and as the pancreas loses glucose-sensitivity. We then propose to extend the model, to make it applicable to more severe conditions such as NASH, and refine the model by including detailed mathematical modelling of other relevant metabolic pathways. A classic example of such a process is the manufacture of triacylglycerol in the liver through the diacylglycerol acyltransferase regulated processes. Recent experimental work has yielded data which will aid the construction of a detailed mathematical model useful for performing numerical simulations. Nationally, this is an area of active work. We have already established links with experimental groups in Reading, Leeds and Oxford, who have made data available to us.
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