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Diabetes Drug Used For More Than 60 Years Found to Unexpectedly Affect The Brain
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Metformin, a primary treatment for type 2 diabetes for over six decades, has been found to unexpectedly affect the brain, according to a 2025 study published in Science Advances. The drug, first synthesized in 1922, was the second most commonly prescribed medication in the US in 2023. Researchers at Baylor College of Medicine discovered that metformin's glucose-lowering action involves the brain, not just the liver and gut as previously thought.
For years, scientists believed metformin worked by activating an enzyme called AMPK in the liver to reduce glucose output. However, recent evidence has pointed to multiple modes of action. The research team, led by neurobiologist Makoto Fukuda, investigated whether the brain contributes to metformin's anti-diabetic effects. They focused on the ventromedial nucleus of the hypothalamus (VMH), a region known to regulate blood glucose and energy balance.
The study used genetically modified mice lacking the protein Rap1 in the VMH. When fed a high-fat diet to mimic type 2 diabetes, these mice did not experience metformin's glucose-lowering effect. Meanwhile, they responded normally to insulin and GLP-1 agonists, confirming that metformin specifically relies on the VMH Rap1 pathway.
In a separate experiment with obese mice, injecting just 1 microgram of metformin directly into the brain significantly reduced blood glucose levels. This dose was several thousand times lower than oral or peripheral doses used in rodent studies, suggesting the brain is highly sensitive to metformin. The drug works by activating SF1 neurons, which help regulate metabolism, appetite, and energy balance.
"This discovery changes how we think about metformin," said Fukuda. "It's not just working in the liver or the gut; it's also acting in the brain." The researchers noted that decades of research have revealed a much more complex picture of metformin's action across multiple organs.
These findings matter because metformin is taken by millions of patients worldwide. Understanding its brain pathway could lead to new treatments for diabetes and potentially other conditions. Prior research has also suggested that metformin may slow brain aging.
The discovery opens avenues for developing targeted therapies that activate the VMH pathway without requiring high systemic doses. Future research will explore how this brain mechanism can be harnessed clinically, potentially improving diabetes management and neurological health.
