Genetics Impact Metformin Response to Diabetes

Research advances work towards targeted therapies for type 2 diabetes.

Genetic differences found among patients in a large international study for metformin may explain why some individuals respond significantly better to the drug.

Metformin is the most commonly used drug to treat type 2 diabetes, and more recently, has shown benefits against a wide variety of other diseases, which include Alzheimer’s disease, cancer, fatty liver disease, ovary syndrome, Parkinson’s disease, and even a potential anti-aging drug in clinical trials.

Although Metformin has been found to be beneficial for some individuals, it can be hit-or-miss in diabetic patients. According to the study, more than one-third of people with type 2 diabetes end up failing to respond to normal doses of the drug.

Why this happens is unknown, and it is still unclear how the drug actually works. Published in Nature Genetics, the new study is the first result reported from the Metformin Genetics Consortium.

“Right now we treat most people with type 2 diabetes the same, 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,” said lead researcher Kathy Giacomini, PhD.

During the 3-stage, genome-wide association study (GWAS), researchers enrolled 13,123 participants in order to identify genetic variants associated with differences in metformin response. The results of the study showed that a common variant of the gene SLC2A2 correlated with a strong response to metformin.

Giacomini said these findings are logical, because the gene encodes GLUT2, which is a glucose transporter protein responsible for regulating the movement of glucose between the liver, blood, and kidneys.

After examining gene expression data from 1226 human liver samples, researchers were able to confirm that individuals with this variant had less GLUT2 in the liver, and other metabolic tissues.

The reduction in GLUT2 resulted in the reduced ability to manage blood glucose; however, metformin appeared able to reverse this deficit, which could help explain its high efficacy in these types of patients.

“Metformin is an old drug that is widely used, yet we are still discovering more about how it works,” Giacomini said. “Although we’ve know 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.”

Also during the study, researchers were able to identify a compelling link between the new genetic variant and higher body weight, which is in-line with prior clinical observations that found metformin to be particularly effective in overweight patients.

“The normal dose of metformin used to treat patients with diabetes is between 500-mg and 2000-mg,” said co-lead study author Kaixin Zhou, PhD. “We have found that overweight people who carry 2 copies of the genetic variant respond much better to metformin, equivalent to receiving an extra 550-mg of the drug.”

Authors noted that the findings suggest that the biological causes of high blood sugar could vary in different people. They also highlighted the importance of a precision medicine approach for diabetes treatment.

“This is an exciting discovery that demonstrates how a patient’s genetics can determine how well, or poorly, a drug works,” said researcher Ewan Pearson, PhD. “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.”

In the inclusion of a large, ethnically diverse research cohort subset in the study, researchers found there was a much higher prevalence of the metformin-enhancing gene variant in African Americans than in other ethnic groups. In African Americans, nearly half carry 2 copies of the variant gene compared with approximately 10% of Caucasians.

The findings highlighted the importance of including diverse cohorts in precision medicine studies.

“We were able to analyze data from the largest published sample of African American patients on metformin thanks to the highly diverse participants from the Research Program on Genes, Environment, and Health, supported by Kaiser Permanente,” Giacomini said.

In future studies conducted by the Metformin Genetics Consortium, researchers plan to investigate more in-depth exactly how ethnicity effects metformin drug response. Furthermore, they will explore how genetics play into the side effects of the drug that makes it difficult for some patients to tolerate the effective doses.