Metformin has been used for years to help people with type 2 diabetes control their blood sugar.
Now, scientists have discovered that the drug also has a significant impact on the brain.
“It’s been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver,” says study corresponding author and Baylor College of Medicine associate professor of paediatrics and nutrition Dr Makoto Fukuda.
“We looked into the brain as it is widely recognised as a key regulator of whole-body glucose metabolism.”
In 2025, the researchers in the United States found that metformin affects a specific pathway in the brain, in addition to how it works in the rest of the body.
The study focused on a protein called Rap1, which is found in a part of the brain called the ventromedial hypothalamus (VMH).
The scientists discovered that metformin lowers blood sugar by reducing the activity of Rap1 in this brain region.
To test this, the researchers used specially modified mice that did not have Rap1 in the VMH.
These mice were fed a high-fat diet to mimic diabetes.
When given low doses of metformin, their blood sugar levels did not improve.
However, other diabetes treatments like insulin and GLP-1 (glucagon-like peptide-1) drugs still worked, showing that this effect is specific to how metformin works in the brain.
In another experiment, very small amounts of metformin were injected directly into the brains of diabetic mice.
Even at extremely low doses, the drug significantly reduced blood sugar levels.
The researchers then studied which brain cells were involved.
They found that certain neurons, called SF1 neurons in the VMH, became active when metformin was present, but only if Rap1 was also present.
In mice that lacked Rap1 in these neurons, metformin did not affect brain activity or blood sugar.
This confirmed that Rap1 is essential for the drug’s action in the brain.
“These findings open the door to developing new diabetes treatments that directly target this pathway in the brain,” Assoc Prof Fukuda says.
“In addition, metformin is known for other health benefits, such as slowing brain ageing.
“We plan to investigate whether this same brain Rap1 signaling is responsible for other well-documented effects of the drug on the brain.” – dpa-AFX
