Diabetes drug metformin affects the brain, study finds: Here’s how

(NewsNation) — For more than 60 years, doctors have prescribed metformin as a frontline treatment for Type 2 diabetes.

Now, researchers say they’ve uncovered something that was hiding in plain sight: Part of the drug’s power over blood sugar comes from the brain.

A team at Baylor College of Medicine has identified a brain-based pathway that plays a significant role in how metformin controls blood glucose.

The findings, published in the journal Science Advances, could reshape how scientists develop future diabetes therapies.

“It’s been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver,” said Dr. Makoto Fukuda, associate professor of pediatrics and nutrition at Baylor and the study’s corresponding author. “We looked into the brain as it is widely recognized as a key regulator of whole-body glucose metabolism.”

Scientists identified Rap1 protein as key to drug’s brain effects

The research centered on a protein called Rap1, found in a region of the brain known as the ventromedial hypothalamus, or VMH.

Researchers found that metformin’s ability to lower blood sugar at clinically relevant doses depends on its suppression of Rap1 activity in that specific brain area.

To test the connection, the Fukuda lab used genetically engineered mice that lacked Rap1 in the VMH. The animals were placed on a high-fat diet to simulate Type 2 diabetes.

When given low doses of metformin, their blood sugar did not improve.

Other diabetes treatments, including insulin and GLP-1 agonists, continued to work normally, suggesting the problem was specific to metformin’s brain pathway.

Brain tissue responds to far lower drug doses than the liver or gut

Researchers also delivered tiny amounts of metformin directly into the brains of diabetic mice. Even at doses thousands of times lower than a standard oral dose, blood sugar levels dropped significantly.

“We found that while the liver and intestines need high concentrations of the drug to respond, the brain reacts to much lower levels,” Fukuda said.

The team then looked at which brain cells were responsible. 

They found that neurons known as SF1 neurons, located in the VMH, became electrically active when metformin was introduced to the brain. That activity, however, only occurred when Rap1 was present.

In mice engineered to lack Rap1 in those neurons, metformin did not affect electrical activity or blood sugar — confirming that Rap1 is required for the drug to engage that brain circuit.

Findings may lead to new, more targeted diabetes treatments

The discovery carries implications beyond explaining how an old drug works. 

Most diabetes medications do not target the brain at all, yet metformin appears to have been doing so unnoticed for decades.

The drug has also been studied for potential benefits beyond blood sugar control, including possible effects on brain aging.

Fukuda said the team plans to investigate whether the same Rap1 signaling pathway is behind those effects as well.

“These findings open the door to developing new diabetes treatments that directly target this pathway in the brain,” he said.

The research was conducted in collaboration with scientists from Louisiana State University, Nagoya University in Japan and Meiji University in Japan. Funding came from the National Institutes of Health, the American Heart Association, the American Diabetes Association and several other foundations.

Copyright 2026 Nexstar Media Inc. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

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