26 December 2010

Genetics reveals new clue into how the most commonly used diabetes drug works

Researchers in the UK have uncovered new genetic evidence of how the world's most commonly used diabetes drugs might save lives.

Metformin, a drug used by hundreds of millions of people with diabetes world wide, has been in use for over 50 years. It has been shown to protect against heart disease, and eye and kidney disease in people with Type 2 diabetes, and has also been shown to have benefits against cancer.

In spite of its huge success, scientists have not known exactly how metformin works. Now research carried out at the University of Dundee, the University of Oxford, and the Wellcome Trust Sanger Institute as part of the Wellcome Trust Case Control Consortium, has revealed new mechanisms for this old drug.

The research has been funded by The Wellcome Trust and Diabetes UK and is published in the journal Nature Genetics.

Dr Ewan Pearson, Professor Colin Palmer and colleagues, based in the Biomedical Research Institute at the University of Dundee, used anonymous data from a clinical information system of patients with diabetes, linked to donated blood samples from 20,000 people in Tayside.

They were able to determine how well metformin worked in 2800 people, and identified an area of chromosome 11, which includes a gene called ATM, that altered how well people respond to metformin.

This finding was replicated by researchers in Oxford using a large prospective clinical trial, the UK Prospective Diabetes Study, in over 1100 people taking metformin for the treatment of diabetes. Additional studies have since confirmed that ATM is important in regulating how metformin works.

The ATM gene, short for Ataxia Telangiectasia Mutated, is a gene that is known to be involved in the DNA damage response system of cells, a mechanism that if faulty can lead to the development of cancer, said Dr Pearson.

'In one of the largest studies of its kind, we have used the genetics of drug response, otherwise known as pharmacogenetics, to investigate how metformin works,' said Dr Pearson. 'We were expecting to find genes involved in blood sugar regulation so the finding that ATM is involved in metformin response was totally unexpected. Although ATM has been widely studied by cancer scientists, no one previously thought it had a role in how this commonly used diabetes drug worked. Our finding therefore draws together mechanisms that protect against cancer and lower blood sugar, suggesting a new area for diabetes drug development.'

Professor Colin Palmer said, 'This is an important development in defining how individuals may respond differently to diabetes drugs, but further work is required before we have enough information to be able to reliably use genetic testing in the clinic to guide treatment of common forms of type 2 diabetes.'

Professor Peter Donnelly, who leads the Wellcome Trust Case Control Consortium at the University of Oxford and was a lead investigator in this study, said, 'We have shown how useful genetics can be in shedding new light on how drugs work. In addition, this study is the first to robustly identify a gene to be involved in how metformin works, and is therefore an important first step towards understanding how an individual’s genes can affect the way they respond to treatment.'

Diabetes UK has now awarded Dr Pearson further funding to continue his research using new genetic techniques on a population of 8,000 people with Type 2 diabetes .

Dr Iain Frame, Director of Research at leading health charity Diabetes UK, said 'This study is a great example of how research can produce unexpectedly exciting results. The benefits for people with Type 2 diabetes may not be immediate but any research that increases our knowledge of how effectively drugs work in different individuals is hugely important.

'This is why Diabetes UK is funding Dr Pearson to continue this important line of research and this is likely to have significant impact in the future for people with Type 2 diabetes and the costs involved to the NHS in treating Type 2 diabetes.'

NOTES TO EDITORS

The Wellcome Trust is a global charity dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk.

Diabetes UK is the leading charity for the 3.5 million people in the UK with diabetes, funding research, campaigning and helping people living with the condition. For more information visit www.diabetes.org.uk.

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