Quick Facts

• Metformin works by turning off a protein called Rap1 in the brain’s ventromedial hypothalamus
• The brain responds to much lower doses than the liver and intestines require
• This discovery could lead to new diabetes treatments targeting the brain directly

Scientists have discovered that metformin, America’s second-most prescribed medication with over 85 million annual prescriptions, works through the brain in addition to the liver and gut.

Researchers at Baylor College of Medicine found that metformin lowers blood sugar by turning off a protein called Rap1 in the brain’s ventromedial hypothalamus. The findings were published in Science Advances.

“It’s been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver,” said Dr. Makoto Fukuda, the study’s lead author and associate professor of pediatrics-nutrition at Baylor. “This discovery changes how we think about metformin.”

The research team tested their theory by injecting tiny amounts of metformin directly into diabetic mice brains. Blood sugar dropped significantly with doses thousands of times smaller than typical oral doses.

“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.

Brain Pathway Discovery

The study identified specific neurons called SF1 neurons that activate when metformin enters the brain. These neurons are located in the ventromedial hypothalamus, a brain region that controls metabolism.

When metformin blocks the Rap1 protein in this area, it triggers a cascade that ultimately lowers blood glucose levels throughout the body.

“We also investigated which cells in the VMH were involved in mediating metformin’s effects,” Fukuda said. “We found that SF1 neurons are activated when metformin is introduced into the brain, suggesting they’re directly involved in the drug’s action.”

Treatment Implications

The discovery opens new possibilities for diabetes treatment. Instead of targeting the liver or gut, future medications could work directly on the brain pathway.

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

Metformin has been used for over 60 years to treat type 2 diabetes, affecting approximately 8.9% of the U.S. population. Between 30% and 40% of diabetic Americans take metformin as first-line treatment.

The research may also explain metformin’s other documented benefits, including slowing brain aging. A 2024 study found metformin slowed biological aging clocks in male primates by several years, with a 6.1-year regression in brain aging markers.

The ongoing TAME trial is investigating metformin’s anti-aging properties in humans. Researchers plan to study whether the newly identified brain pathway explains these broader health effects.

Read more: Scientists Discover A New Brain Benefit Of A Widely Used Diabetes Medication