Giacomini co-led study finds gene variant affecting response to leading diabetes drug

Metformin is the most widely used initial medication for controlling blood sugar (glucose) in type 2 diabetes, a disease affecting 350 million people worldwide. The drug helps reduce their risk of complications leading to heart, eye, and kidney disease.

But there are major differences in metformin response and more than a third of patients fail to achieve acceptable blood glucose control from the drug.

Now, the Metformin Genetics Consortium, an international collaboration of several dozen researchers co-led by UCSF School of Pharmacy faculty member Kathy Giacomini, PhD, has analyzed the genes of more than 13,000 patients, looking for variations associated with differences in their drug response (pharmacogenomics). Such findings should enable precision medicine—tailoring more effective drug dosing or selection based on an individual’s genetics.

The first result of this largest precision medicine study of a diabetes drug to date, published in Nature Genetics on August 8, 2016, is the discovery of a specific genetic variation that is correlated with a much stronger response to metformin. Indeed, the same genetic variant was also associated with higher body weight, which fits with previous clinical observations that metformin is particularly effective in overweight patients.

“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 milligrams of the drug,” said Kaixin Zhou, PhD, of the University of Dundee in Scotland. (A normal dose for diabetes ranges from 500 mg to 2000 mg.) Zhou co-lead-authored the new paper with Sook Wah Yee, PhD, of the Giacomini Lab.

Metformin is an old drug that is widely used, yet we are still discovering more about how it works.

—Sook Wah Yee, PhD

The study included genomic analysis of more than 2,500 patients of non-European ancestry. It found a much higher prevalence of the metformin-enhancing gene variant in African Americans than in other ethnic groups—highlighting the value of having diverse study subjects in precision medicine studies.

“Right now we treat most people with type 2 diabetes the same,” said Giacomini, “but we wanted to discover whether there might be a specific genetic marker that could let us take a precision medicine approach to prescribing and dosing this common diabetes medication.”

The study also examined how the variation in the gene, SLC2A2, yielded the difference in drug response: It reduces levels of a transporter protein, GLUT2, which regulates the movement of glucose across cell membranes, including between the liver and the blood. Metformin slows the liver’s production of glucose, and the genetic variant in SLC2A2 results in enhanced effects of metformin on blood glucose levels.

“Metformin is an old drug that is widely used, yet we are still discovering more about how it works,” said Yee. “Although we’ve known that GLUT2 is important for glucose transport for many years, we had not previously thought that the variation in the gene encoding this transporter would alter how metformin works.”

The Giacomini Lab is based in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.



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