Diabetes drug affects brain: Metformin “not just working in the liver or the gut, it's also acting in the brain”

People with type-2 diabetes will probably be familiar with the drug, Metformin, which has been prescribed to manage blood sugar for decades. However, scientists have never been completely sure exactly how the drug works - until now - and it could have far-reaching consequences in the treatment of the condition.

Research carried out at the Baylor College of Medicine in the United States indicated Metformin works directly through a brain pathway of patients. "It's been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver," said Makoto Fukuda, a pathophysiologist at Baylor.

"Other studies have found that it acts through the gut. We looked into the brain as it is widely recognized as a key regulator of whole-body glucose metabolism. We investigated whether and how the brain contributes to the anti-diabetic effects of metformin."

Baylor researchers previously identified a protein in the brain, called Rap1, as having an impact on glucose metabolism in a part of the brain called the ventromedial hypothalamus (VMH), with a 2025 study using mice showing metformin traveling to the VMH, where it helps tackle type 2 diabetes by essentially turning off Rap1. Mice without Rap1 saw no effects from Metformin, though other drugs did work, appearing to confirm the drug worked through the brain.

Meanwhile, the researchers also investigated which neurons metformin was affecting, which could have a far-reaching impact on future treatments.

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

And he said further research was needed among human subjects in order to improve treatment, targeting those specific cells. “These findings open the door to developing new diabetes treatments that directly target this pathway in the brain," the researcher added.

"In addition, metformin is known for other health benefits, such as slowing brain aging. We plan to investigate whether this same brain Rap1 signalling is responsible for other well-documented effects of the drug on the brain."

Fukuda added: "This discovery changes how we think about Metformin. It's not just working in the liver or the gut, it's also acting in the brain. We found that while the liver and intestines need high concentrations of the drug to respond, the brain reacts to much lower levels."

The Baylor research was published in Science Advances.