Researchers look at the role genes play in the effectiveness metformin

New personalised treatment for people with type 2 diabetes could soon be possible after researchers found a link between genes and the effect of taking metformin for the condition.

Previous research had shown that metformin can have more effective results in some people than others, but the reasons for this had not been understood. A new study carried out by the international Metformin Genetics Consortium and led by the University of Dundee and University of California, San Francisco has identified a genetic variant (a change in the DNA code for a particular gene) that alters how well metformin works.

The international study looked at how well metformin worked in 13,123 people of different backgrounds and the results were recently published in the journal Nature Genetics.

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

Metformin is one of the most widely taken treatments for type 2 diabetes around the world

Metformin is used by hundreds of millions of people with type 2 diabetes worldwide and has been available for more than 50 years. The drug is proven 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. There are currently trials being held to confirm if metformin could also have benefits in healthy aging. 

The Metformin Genetics Consortium identified a genetic variant in the gene encoding a protein that plays an important role in transporting glucose inside the body (the glucose transporter GLUT2). They showed that people who carried this gene variant had reduced levels of the GLUT2 protein in the liver and other tissues resulting in a weakness in how the body could handle glucose. Metformin was found to act to specifically reverse this deficiency resulting in a better response to metformin in people carrying this gene variant.

Dr Sook Wah Yee, based in the Department of Bioengineering and Therapeutic Sciences at the University of California, said: “Metformin is an old drug that is widely used, yet we are still discovering more about how it works. Although we’ve known that GLUT2 is important for glucose transport for many years, we had not previously thought that variation in the gene encoding this transporter would alter how metformin works.”

Dr Kaixin Zhou, of the School of Medicine at the University of Dundee, said: “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.”

Professor Ewan Pearson, of the School of Medicine at the University of Dundee, added: “This is an exciting discovery that demonstrates how a patient’s genetics can determine how well, or poorly, a drug works. We need to undertake further clinical studies before we can change the way we use metformin, but this finding suggests that some patients should be treated with higher doses than others to achieve the same effect. This really does move us a step closer to truly targeted therapy in the treatment of diabetes.”

Professor Kathleen Giacomini, of the Department of Bioengineering and Therapeutic Sciences at the University of California, San Francisco highlighted that the study was the largest precision medicine study on an anti-diabetic drug performed to date and made possible by the international collaboration of the Metformin Genetics Consortium. She added: “We are excited that the study included individuals from multiple ethnic groups who are participants in the Research Program on Genes, Environment, and Health, supported by Kaiser Permanente.”

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