The Clore Laboratory for Diabetes and Obesity Research

The Clore Laboratory was founded in 1986 as a result of capital funding from the Clore Foundation, to Professor Anne Beloff-Chain. Professor Chain, the wife of Nobel Laureate Sir Ernst Chain, was a prominent scientist in her own right with strong interests in obesity and diabetes. Her research was concerned with the possible role of a hormone released by the pituitary gland at the base of the brain and involved in the regulation of food intake and energy metabolism.

Since 1994 the Clore Laboratory has focused on diabetes and obesity research and established an international reputation. Today it houses 15 research scientists working on the identification of new targets for pharmaceutical intervention and evaluating potential pioneering therapies.

The Clore Laboratory is today led by Professors Mike Cawthorne and Jon Arch. Both have published extensively and have international reputations. Mike Cawthorne was awarded the Society of Medicines Research award in 2001 for drug discovery for the identification of insulin resistance as a causative factor in type 2 diabetes and the discovery of the insulin sensitiser drug Avandia, now marketed by GlaxoSmithKline. Jon Arch is an expert on obesity, particularly drugs acting to stimulate energy metabolism as a means of achieving weight loss.

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Obesity and Type 2 Diabetes

The world is currently facing an obesity and diabetes epidemic. Indeed in many countries diabetes leading to cardiovascular disease has replaced infectious disease as the major cause of death. Obesity is known to be a major risk factor for type 2 diabetes (formerly called adult onset diabetes), as well as a number of other diseases including cardiovascular disease, osteoarthritis and some cancers. Approximately 1 billion people are obese with some 300 million being classed as clinically obese. Currently there are around 190 million diabetes sufferers in the world with at least 90% of these having the type 2 form. This number is projected to increase to between 300 and 350 million by 2025 with much of this increase occurring in countries undergoing rapid industrial development such as India, China and South America. This increase is fuelled by lifestyle and dietary changes and its origins are already evident with the increase in childhood obesity.

Diabetes not only increases mortality, it also affects quality of life through blindness, impotence (50% of male diabetics are impotent as a result of vascular damage), limb amputations, kidney failure. The healthcare costs of diabetics are typically twice those of non-diabetics and the economic cost of diabetes in the US is estimated at around $100 billion per annum with 50% of these costs being direct healthcare costs.

There are currently only two drugs marketed for obesity and these have limited efficacy. A third drug acting at the cannabinoid receptor is likely to be available in the next year or so. For diabetes, current treatments including the recently launched insulin sensitisers such as rosiglitazone, at best slow the progression of the disease so that diabetic complications and progression towards a requirement for insulin therapy is delayed but not stopped. There is currently no cure for diabetes.

Both obesity and type 2 diabetes represent areas of huge unmet clinical need and there is a requirement for better therapeutic agents. There is also a need to understand why some patients progress more rapidly to secondary complications, whereas others with similarly poor glycaemic control do not develop complications such as blindness, kidney disease and macrovascular and microvascular disease.

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Major recent achievements of the Clore Laboratory

Following the discovery of leptin in 1994 as a putative signalling hormone produced by fat tissue and acting on the brain to regulate energy metabolism in order to maintain a constant body mass index, work at the Clore Laboratory provided the first demonstration of multiple effects in other tissues such as pancreatic islets, intestine and skeletal muscle. In pancreatic islets, leptin was shown to inhibit insulin secretion and insulin mRNA but increase proliferation of pancreatic b-cells.
As a result of discoveries concerning leptin and islet cell proliferation, it was hypothesised by us that a relative lack of leptin reaching the foetus might occur in small for gestational age offspring, who are prone to developing central obesity and type 2 diabetes in adult life, when faced with a Western type diet. Small for gestational age babies commonly occur in malnourished and still growing teenage mothers and in those who smoke. Using rodent models, we have shown that leptin given to pregnant dams during the third trimester and lactation provides life-long prevention of obesity and diabetes in the offspring. As a result of this work Dr Claire Stocker was awarded the New Investigator prize by the International Association for the Study of Obesity in 2002.
In vivo studies have demonstrated the potential of the Phytopharm extract P57 as a potential obesity and diabetes therapeutic. This extract is derived from the cactus Hoodia, traditionally used by Kalahari bushmen to ward off hunger.
Collaborative studies with companies in the US, UK and Germany have contributed to the identification of 4 new potential therapeutics that are now being taken forward into clinical studies.
Students training in the Clore Laboratory are awarded MPhil / DPhil degrees by the University. These students come from Europe, Asia, Africa and the Far East as well as the UK. In 2002 one of the Clore research students was given the 'Best Student Award' in the UK by the Association for the Study of Obesity.
Over the last ten years, Clore Laboratory scientists have published numerous scientific papers and have been invited to give lectures to a large number of international audiences.

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Current research objectives

In addition to the training of new researchers in the field of diabetes and obesity, and to the ultimate goal of identifying improved methods of treatment, the research group has a number of specific objectives as follows:

To define the mechanism of the life-long preventative effect of maternally administered leptin on the development of type 2 diabetes and obesity in the offspring.
To identify the genomic transcriptional changes associated with life-long protection from type 2 diabetes and obesity in order to define new molecular targets for therapy. Such targets will be developed with a commercial partner.
To employ novel mechanisms to identify molecular changes associated with failure of the pancreatic b-cell and to identify factors that promote islet cell generation and thereby preserving the insulin secretion. Identification of such factors could result in new therapies.
To identify plant-based therapeutics that could provide a local source of anti-diabetic therapy for countries that cannot afford classical pharmaceuticals. The laboratory has a range of contacts worldwide to provide samples as well as a commercial partner.
To work with biotech and pharma companies to identify and validate new molecular targets and evaluate the therapeutic potential of pioneering therapeutics in pre-clinical studies.

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Funding needs

The Clore Laboratory receives no infrastructure grant from the Government unlike the Higher Education establishments in the State sector. The Clore Laboratory obtains all of its funding by donation, through competitive grant applications or through industrial collaboration. Each year a sum of around £750K is needed for the following.

Named Chair for Professor Cawthorne to include secretarial support and research funding support (£250K over 3 years).
Named Chair for Professor Jon Arch to include laboratory manager and research funding support (£300K over 3 years).
Named post-doctoral research fellowships for researchers (£120-£200K over 3 years).
Named DPhil studentships to provide scholarship for student plus laboratory expenses (£75K over 3 years).
Equipment to update laboratory and to develop new skills including equipment for immunohistochemistry, molecular biology, storage of important medical samples, analysis equipment. The cost of individual items range from £3K to £250K with many items in the £7K to £20K range.

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