Metformin, a diabetes drug used for over 60 years, has been found to work directly in the brain, according to a new study published in Science Advances. Researchers at Baylor College of Medicine in the US identified a brain pathway through which the drug lowers blood glucose, challenging the long-held belief that it primarily acts on the liver.
The study, led by pathophysiologist Makoto Fukuda, focused on the ventromedial hypothalamus (VMH), a brain region known to regulate glucose metabolism. Experiments on mice showed that metformin travels to the VMH and deactivates a protein called Rap1, which is involved in glucose regulation. When mice were bred without Rap1, metformin had no effect on diabetes-like conditions, suggesting this brain mechanism is crucial for the drug's action.
Further analysis revealed that metformin activates SF1 neurons in the VMH, indicating these cells are directly involved in the drug's effects. Fukuda noted that these findings could lead to new diabetes treatments targeting this specific brain pathway. He added that the team plans to investigate whether the same Rap1 signalling is responsible for metformin's other benefits, such as slowing brain aging.
Metformin is also known as a gerotherapeutic, capable of slowing aging processes. A 2025 study of over 400 postmenopausal women found that those taking metformin had a 30% lower risk of dying before age 90 compared to those on another diabetes drug, sulfonylurea. However, side effects such as nausea, diarrhoea, and stomach discomfort affect up to 75% of patients, and risks increase for those with kidney impairment.
The researchers emphasised that human studies are needed to confirm these findings. If validated, the discovery could enhance metformin's potency and expand its use for conditions beyond diabetes, including brain aging and long COVID.
