Physiological Modelling of Metabolic Risk (PMMR)

The incidence of metabolic diseases such as diabetes and high blood pressure is increasing world-wide. There is considerable evidence that this is due to change in dietary habits which, in the long-term, cause severe impairments of the metabolism of macronutrients (carbohydrate, fat and protein) in the diet. This research programme uses specialized techniques to compare the fate of these macronutrients in health and well-characterized diseases such as diabetes and cardiovascular disease, and to use this information to investigate what factors cause disease to develop. This may lead to strategies which can be adopted by the general population to arrest or even reverse the progression of these diseases.
One particular area of research is to understand how much of each component of a meal is used to supply energy immediately, how much is stored, and whether the store the nutrients enter is temporary or long-term. It is known that this partitioning is different to normal in some severe metabolic diseases, and this programme sets out to assess when the onset of this change occurs, and whether it can be prevented by adopting a different lifestyle.
In order to conduct this research we need to use innovative methodologies so that we can investigate particular metabolic processes in isolation, usually by using harmless stable isotope probes. Generally the extent to which these processes occur can be quantified only in the context of the mathematical models we are developing.

The principal aim of the programme is to investigate how the fate of dietary macronutrients in the post-absorptive state is altered in the progression to metabolic disease. This is achieved by the use and development of novel stable isotope methodologies to provide data which allows the modelling and subsequent quantification of post-prandial irregularities underlying diabetes and cardiovascular disease, and to use these technologies to study dietary changes to prevent, slow or reverse the progression of these diseases.
Specific Objectives:-
(1) Determination of the extent to which various metabolic processes are altered in chronic disease states, such as diabetes mellitus, severe insulin resistance, and hypertension. Principally this focuses on energy expenditure and macronutrient oxidation, with particular attention to substrate partitioning and buffering in the post-prandial state.
(2) To interpolate these findings in order to inform investigations in the nominally healthy population to understand the aetiology of these diseases, and the possibility of arresting or reversing progression by nutritional (or other) means within the context of a normal lifestyle. Typically this requires measuring changes in metabolism due to a dietary intervention.
(3) Development of new, minimally invasive, tests based on stable isotope methods to complement the existing tools for metabolic studies, principally in the area of lipogenesis, whole-body lipolysis, lipid trafficking, and hepatic function.
(4) Exploitation of innovations in instrumentation and data handling to enhance the performance of established techniques. This includes the application of novel statistical methods and mathematical analysis to interpretation of the experimental data.
(5) To further establish methodologies in clinical research which are still considered to be under development so that they become considered routine (for example gastric emptying, nitric oxide production, insulin secretion, physiologically relevant tests of hepatic and peripheral insulin sensitivity).
Although firmly embedded at MRC-HNR, within this programme there are extensive collaborations with other workers in Cambridge, the rest of the UK, and overseas. The programme leader is also jointly responsible (with Dr Jules Griffin) for HNR’s part of the Wellcome Trust/MRC Cambridge initiative for Obesity and metabolic Diseases announced in May 2013, which provides interaction and collaboration with MRC metabolic diseases Unit and other researchers at Addenbrooke’s Hospital and various departments in the University. These links are reinforced by the programme leader also acting as a clinical scientist at the Wellcome Trust CRF at Addenbrooke’s where additional facilities for the programme (whole-body calorimeters and the use of magnetic resonance spectroscopy) are available, and further scientific collaborations are maintained.