60-Year-Old Diabetes Drug Metformin Now Shown to Work Directly on 1 Brain Area

A common and long-used diabetes drug, metformin, has been found to have an unexpected and direct effect on the brain, according to new research. Scientists at the Baylor College of Medicine in the United States have discovered a specific pathway in the brain where the drug operates to combat Type 2 diabetes.

This landmark finding, published in Science Advances and reported on 23 November 2025, suggests that metformin works not just by reducing glucose production in the liver or acting through the intestine, as previously assumed, but also by directly influencing the brain. This discovery could pave the way for new, more targeted treatments for diabetes.

The Brain Mechanism Uncovered

Metformin has been prescribed for over 60 years to regulate blood sugar in people with Type 2 diabetes, yet its precise mechanism of action was not fully understood.

• Researchers focused on the brain, recognised as a central regulator of glucose metabolism. Pathophysiologist Makoto Fukuda of Baylor noted, “We wanted to understand if, and how, it contributed to the antidiabetic effects of metformin.”
• Tests on mice showed that metformin reaches a brain area called the ventromedial hypothalamus (VMH).
• In the VMH, the drug helps fight Type 2 diabetes by “deactivating” a brain protein known as Rap1.
• In genetically modified mice lacking Rap1, metformin had no effect on a diabetes-like state, a strong indication that the drug acts specifically through this brain mechanism.
• The study also pinpointed the specific neurons affected: SF1 neurons were found to activate when metformin was introduced into the brain, suggesting a direct role in the drug’s action.

Dr. Fukuda stated, “This discovery changes our perception of metformin. It acts not only on the liver or the intestine, but also on the brain… The brain reacts to much lower doses than those necessary for other organs.”

Broader Implications and Future Research

This new understanding of metformin’s action mechanism has significant implications beyond diabetes:

• Targeted Treatments: The findings could lead to the creation of much more targeted treatments for diabetes that directly target this newly identified brain pathway. Dr. Fukuda affirmed, “These discoveries open the way for new treatments against diabetes that would directly target this brain pathway.”
• Anti-Ageing Effects: Metformin is also known as a gerotherapeutic—a drug capable of slowing certain ageing processes by, for example, limiting DNA damage or stimulating longevity genes.
• Reduced Mortality Risk: Previous studies, including a 2025 study of over 400 menopausal women, found that those taking metformin had a 30% reduced risk of dying before age 90 compared to those on another antidiabetic drug (sulphonylureas).
• Other Benefits: The drug has also been shown to slow brain ageing, increase life expectancy, reduce brain damage, and may even decrease the risk of developing long COVID. The researchers plan to investigate if the same Rap1 mechanism explains these additional effects.

Drug Profile and Safety

Metformin is an enduring, low-cost medication that works by reducing the liver’s glucose production and improving insulin efficacy.

It is generally safe, though common gastrointestinal side effects (including nausea, diarrhea, and abdominal pain) affect up to 75% of users. Complications can also arise in patients with kidney failure.

The next step for researchers is to confirm these results in humans. If verified, the effects of metformin could be reinforced or optimised, potentially widening its usage beyond diabetes.

Source: Defi Media