Metformin Works Better for Some Diabetics Because of Gene Variant, Study Finds

Investigators in an international research effort have found genetic evidence as to why the world’s most common treatment for type 2 diabetes, metformin, benefits some people more than others.

Metformin has long been known to act differently on each patient, but the reasons for this largely confounded scientists. Researchers from the Metformin Genetics Consortium — which includes Oxford University — investigated how metformin worked in 13,123 people of different ethnicities, and identified a change in the DNA code for a particular gene (a genetic variant) that influences the drug’s effectiveness.

The study, “Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin,” found that overweight people carrying two copies of a specific variant in the SLC2A2 gene responded markedly better to metformin. The study was published in the journal Nature Genetics.

Researchers believe their findings represent an important step toward personalized medicine in the treatment of type 2 diabetes.

“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, the Robert Turner professor of diabetic medicine at Oxford, said in a press release.

Scientists know that the protein GLUT2 plays an important role in transporting glucose inside the body, but hadn’t previously considered the possibility that variation in the gene encoding this transporter (SLC2A2 gene, also called GLUT2 gene) would alter how metformin works.

Consortium researchers identified a genetic variant in the gene encoding GLUT2, and showed that people carrying this variant had lower levels of GLUT2 in the liver and other tissues, resulting in a defect in how the body handles glucose. Metformin acts to specifically reverse this deficiency, resulting in a better drug response in people carrying this gene variant.

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

Researchers say further work is necessary to understand how GLUT2 influences the way metformin works inside the body. Metformin, a 50-year-old drug used by millions worldwide, has been demonstrated to protect against heart disease, and eye and kidney disease in type 2 diabetes patients, and may be beneficial against cancer. Metformin is currently in clinical testing to assess whether it can promote a healthier aging process.

“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 personalized therapy for Type 2 diabetes, moving away from a ‘one size fits all’ approach to ensure people receive the best treatment possible,” said Dr. Elizabeth Robertson, director of research at Diabetes UK.

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