Study deepens understanding of how Metformin works

EU-funded scientists say they have genetic proof of how a commonly used diabetes drug works for patient treatment. On a global scale, the drug metformin has been treating people with type 2 diabetes for many years. Not only does it lower the risk of heart, eye and kidney disease in diabetics, but it has shown it can fight cancer as well. his latest research provides major insight into how this drug works. Scientists from the University of Dundee in the UK used anonymous data from a clinical information system of people with diabetes, linked to donated blood samples from 20,000 people in the Scottish region of Tayside.

They found that metformin worked well in 2,800 patients, and discovered an area of chromosome 11, which includes a gene called ATM (ataxia telangiectasia mutated), that altered how well people respond to metformin. Dundee’s Dr Ewan Pearson pointed out how ATM is involved in the DNA (deoxyribonucleic acid) damage response system of cells; a defective mechanism can trigger cancer.

Their colleagues from the University of Oxford replicated the Dundee finding in more than 1,100 people using metformin for their treatment. They used the prospective clinical trial, the UK Prospective Diabetes Study, for their investigation. Further studies have also confirmed how crucial a role ATM plays in regulating the mechanisms of metformin.

‘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,’ explains Dr Pearson, a member of Dundee’s Biomedical Research Institute and one of the authors of the study. ‘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.’

Co-author Professor Colin Palmer, also from the Biomedical Research Institute, noted that while this is a groundbreaking development, more work is needed to ensure that genetic testing can be used reliably in the clinic ‘to guide treatment of common forms of type 2 diabetes.’

Professor Peter Donnelly, head of Oxford’s Wellcome Trust Case Control Consortium and a lead investigator in the study, says: ‘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.’

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