Department of Biology & Biochemistry
University of Bath
Bath, BA2 7AY, United Kingdom
Fax: +44 1225 386779
Email: G.D.Holman@bath.ac.uk
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.