New Study Reveals Metformin's Hidden Effects on Brain Function and Health - Video

Metformin may lower blood sugar by acting on the brain, not just the liver

Metformin has been the most commonly used medicine for type 2 diabetes for over 60 years. Until now, scientists believed it mainly worked by reducing the amount of sugar released by the liver or by affecting the gut. However, a new study suggests that the brain also plays an important role in how metformin controls blood sugar.

Researchers from Baylor College of Medicine discovered that metformin works by blocking a protein called Rap1 in a part of the brain known as the ventromedial hypothalamus (VMH), which helps regulate blood sugar levels.

To test this, scientists used diabetic mice that did not have the Rap1 protein in this brain region. When these mice were given low doses of metformin, the medicine failed to lower their blood sugar. However, other diabetes treatments, such as insulin and GLP-1 medicines, still worked normally.

The team then injected extremely small amounts of metformin directly into the brains of diabetic mice. Even though the dose was thousands of times smaller than the amount taken by mouth, it still lowered blood sugar levels.

Researchers also found that metformin activates special brain cells called SF1 neurons, but only when Rap1 is present. Without Rap1, these neurons did not respond to the drug.

According to the researchers, this finding changes the understanding of how metformin works. They found that the brain responds to much lower amounts of the drug than the liver or intestines.

The discovery could help scientists develop new diabetes treatments that directly target this brain pathway. The researchers also plan to investigate whether the same brain mechanism may explain other reported benefits of metformin, such as its potential role in slowing brain aging.

REFERENCE: Hsiao-Yun Lin, Weisheng Lu, et al.; Low-dose metformin requires brain Rap1 for its antidiabetic action. Science Advances, 2025; 11 (31) DOI: 10.1126/sciadv.adu3700