Proposal to enhance linked research in human fat metabolism & pathophysiology between MRC HNR, MRC MDU and MRC EU

According to statistics reported by Diabetes UK in 2010, since 1996 the number of people diagnosed with diabetes has increased from 1.4 million to 2.6 million, and is set to rise to four million people by 2025. The majority of these cases are associated with type 2 diabetes (T2DM), with the increased prevalence arising from an increasingly aged population and the rise in overweight and obese people. However, there is increasing realisation that T2DM is not a homogenous disease and can arise from a number of different pathways related to diet, life style and genetic influences. Because of this there is increasing realisation that ‘one size’ does not fit all in terms of treatment. Indeed, certain individuals may particularly benefit from targeted diet and drug interventions as part of an approach referred to as ‘personalised medicine.’ This initiative sets out to understand the underlying pathways that influence why an individual might develop T2DM using analytical chemistry approaches to define patient groups according to their metabolism. We plan to use metabolic changes, termed biomarkers, to better identify patient groups who would benefit from particular treatments. This personalised medicine approach should improve health of individuals as well as providing a significant financial saving to the healthcare system.

With the increasing burden that type 2 diabetes (T2DM) and aspects of the metabolic syndrome place on the National Health Service and the wider economy there is a drive to stratify patients into treatment groups to maximise response to interventions to prevent insulin resistance (IR) be it through diet, physical activity or drug intervention. By its very definition the metabolic syndrome is a cluster of disorders. It is also now a widely held view that T2DM is a heterogeneous collection of pathological disorders all sharing the common outcome of hyperglycaemia. There is a growing realisation that effective treatments for complex disorders such as T2DM and dyslipidaemia will require “deep phenotyping” of the individuals to allow the implementation of personalised medicine and nutritional interventions.
This drive towards personalised medicine and nutrition has been impaired by the lack of personalised diagnosis. The limited development and validation of relatively few biomarkers hampers real stratification of individuals, and the majority of the current markers used for the diagnosis of the metabolic syndrome and T2DM are associated with the effects of the clinical endpoint or the clinical endpoint itself. One reason for this lack of translation is the difficulties of performing controlled intervention studies in humans to validate molecular mechanisms of a potential diagnostic biomarker alongside the biomarker discovery studies. As part of the MRC/Wellcome Trust funded Cambridge Initiative in Obesity and Metabolic Disease we are applying human intervention studies in order to better understand the mechanistic basis underpinning potential biomarkers developed within the groups led by Griffin and Bluck as well as collaborators at MRC Units and the University of Cambridge that make up the rest of the Initiative. To achieve this we are applying our world-class specialisms in high resolution mass spectrometry of lipids and stable isotope analysis for kinetic measurement of substrate flux to measure biomarkers and flux changes in well controlled human physiological interventions.
The current focus is in the understanding of the contribution of de novo lipogenesis (DNL) to fatty liver disease in those that are either considered healthy or have mild IR. From our previous work in lipodystrophic patients we know that triglycerides associated with DNL are increased in blood plasma and the activity of the pathway is raised as measured by stable isotope studies. We are currently conducting studies to directly measure DNL alongside blood plasma triglycerides using a combination of stable isotope techniques and high resolution mass spectrometry in different patient groups and at risk individuals.