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Sugars are abundant components of diet and are essential for supplying our metabolic needs. Sucrose from our food is broken down in the intestine to produce both glucose and fructose. These sugars are absorbed into the blood stream and act as a supply of nutrient for tissue metabolism. Sugar disposal occurs via uptake into selective tissues that utilise specialised membrane tranporters or GLUTs. Recent genome analysis has indicated that the GLUT family of proteins includes some new un-characterised isoforms. There are now known to be 13 mammalian GLUTs which have a range of substrate preference and tissue distributions. Some of the GLUT proteins transport glucose in preference to fructose while others preferentially transport fructose and some rarer sugars. Our research interests include an investigation of the substrate preferences of the transporter proteins. This involves utilisation of chemical biology approaches for the design and chemical synthesis of sugar analogues and inhibitors of the GLUT proteins. Anormal disposal and utilisation of sugars gives rise to diseases that include obesity and type 2 diabetes.
In type 2 diabetes, insulin fails to adequately stimulate glucose transfer to tissues. The incidences of both obesity and type 2 diabetes have been steadily increasing in both the US and now the UK over recent years. It is now estimated that 19.8% of the US population are obese and 7.3% have type 2 diabetes. The UK has an estimated 3% of the population (1.4 million) with type 2 diabetes. The extremely high levels constitute an epidemic which has important implications in terms of management of these diseases by individuals and by the Health Care services. The scale of the epidemic worldwide is predicted to expand with 150 million suffers now, 220 million by 2010 and 300 million by 2025. Although once considered a maturity onset disease (prevalent in the over 40s) there is very recent evidence for type 2 diabetes in teenagers. Lack of exercise is thought to contribute to the prevalence of type 2 diabetes but the incidence of this disease is most strongly correlated with diet. Dietary factors that may contribute to the increases in obesity and type 2 diabetes include high fat and high sucrose. Understanding the basis for disposal of excess amounts of fats, glucose and fructose is vital to the success of any long term battle against these diseases.
In insulin responsive tissues such as fat, heart and skeletal muscle, the distribution of the glucose transporter called GLUT4 is particularly important for glucose disposal. In type 2 diabetes, there is impaired insulin-stimulated GLUT4 recruitment from its intracellular storage compartment to the cell surface. Our research on GLUT4 involves investigation of the mechanisms by which this protein is moved around cells and accumulates in a reservoir compartment in the absence of any stimulus. Formation of this reservoir compartment is vital to insulin action as once this compartment is formed, insulin stimulation of the cells leads to release of the protein to the cell surface where it catalyses increased uptake of glucose into the cells. Exercise of muscle produces a stimulus that can also lead to release GLUT4 to the cell surface. The mechanism is different to that used when cells respond to insulin but the end result is the same, more GLUT4 appears at the surface when there is more demand for glucose metabolism in the cells. Because the mechanism for exercise- induced stimulation is different, for suffers from type 2 diabetes there is potential therapeutic benefit to be gained by exercise or from pharmaceuticals that stimulate the exercise pathway that leads to enhanced GLUT4 levels at the cell surface. Diabetes is one of the major contributors to death from coronary heart disease. The uptake of sugars in heart is insulin stimulated but this process can be inhibited if the interior of the heart cells becomes too acidic. Part of our research programme aims to determine the mechanism of heart cell pH maintenance and investigates the means by which this is linked to impaired glucose uptake and utilisation. Improved understanding will aid in the development of heart disease therapies.
Ten most cited publications