Study reveals how our genes can alter action of the most commonly used Type 2 diabetes drug

Researchers in an international study have uncovered new genetic evidence of how the benefits of the world's most commonly used Type 2 diabetes drug may vary between individuals.

Metformin, a drug used by hundreds of millions of people with Type 2 diabetes worldwide, 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. Metformin is also undergoing new clinical trials to determine if it can promote healthy aging.

Genetic studies such as these can provide important clues to underlying mechanisms, and may go some way to explaining why different treatments work particularly well - or poorly - in a given individual. This study is also testament to the value of international, collaborative research.
Mark McCarthy, Robert Turner Professor of Diabetic Medicine

It has been known for some time that metformin works better in some people than others but the reasons for this have not been understood. Now research carried out by the large international Metformin Genetics Consortium, including Oxford University researchers, has identified a genetic variant (a change in the DNA code for a particular gene) that alters how well metformin works.

Researchers found that overweight people carrying two copies of a genetic variant responded so much better to metformin that it was equivalent to receiving an extra 550mg of the drug.

They say their findings represent a significant step towards personalised, targeted therapy in the treatment of Type 2 diabetes.

The research has been funded by Wellcome, Diabetes UK and the National Institutes of Health in the US and is published in the journal Nature Genetics, investigated how well metformin worked in 13,123 participants of different ethnicity.

The Metformin Genetics Consortium identified a genetic variant in the gene encoding the glucose transporter GLUT2, a protein that plays an important role in transporting glucose inside the body. They showed that those people who carried this variant had reduced levels of GLUT2 in the liver and other tissues resulting in a defect in how the body handles glucose. Metformin acted to specifically reverse this deficiency resulting in a better response to metformin in people carrying this gene variant.

Metformin is a widely used drug but researchers are still discovering more about how it works. Scientists have known that GLUT2 is important for glucose transport for many years, but had not previously thought that variation in the gene encoding this transporter would alter how metformin works.

Mark McCarthy, Robert Turner Professor of Diabetic Medicine at Oxford, said: 'It may be surprising that we still understand so little about the ways in which metformin, the most widely-used treatment for type 2 diabetes, works. Genetic studies such as these can provide important clues to underlying mechanisms, and may go some way to explaining why different treatments work particularly well - or poorly - in a given individual. This study is also testament to the value of international, collaborative research.'

This finding helps move forward the major efforts being made to personalise therapies for individuals with type 2 diabetes and to make more effective use of the drugs that are already available.
Professor Rury Holman, Diabetes Trials Unit Director

Dr Kaixin Zhou, a lead researcher at the University of Dundee explained: 'The genetic effect was greatest in more overweight people. The normal dose of metformin used to treat patients with diabetes is between 500mg and 2000mg. We have found that overweight people who carry two copies of the genetic variant respond much better to metformin, equivalent to receiving an extra 550mg of the drug.'

Dr Elizabeth Robertson, Director of Research at Diabetes UK, said, 'This study sheds important light on why people with Type 2 diabetes respond differently to metformin, and could be used to identify distinct groups of patients or develop new therapies in the future. Altogether, this research represents an exciting step towards personalised therapy for Type 2 diabetes, moving away from a 'one size fits all' approach to ensure people receive the best treatment possible.

'Further work is now needed to understand how GLUT2 influences the way that metformin works inside the body, and we're very pleased to see research funded by Diabetes UK moving the field of Type 2 diabetes treatment forwards.'

The paper, Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin, is published in Nature Genetics (doi:10.1038/ng.3632).