At a Glance
- Scientists discovered that the common diabetes drug metformin exerts its anti-diabetic effects through a previously unknown pathway involving the brain’s ventromedial hypothalamic nucleus.
- The drug’s ability to lower blood sugar depends on its inhibition of a small protein called Rap1 located within this specific brain region, acting as a crucial molecular switch.
- Genetically modified mice lacking Rap1 in their forebrain were resistant to metformin’s glucose-lowering effects, confirming the protein’s indispensable role in the drug’s primary mechanism of action.
- Injecting minuscule doses of metformin directly into the brain significantly reduced high blood sugar, demonstrating the brain’s high sensitivity to the drug compared to other peripheral organs.
- This research redefines our understanding of metformin and opens up the possibility of developing new diabetes therapies that can more precisely target the newly identified neural signaling pathway.
For more than 60 years, metformin has been the frontline medication for managing type 2 diabetes, yet the complete picture of how it controls blood sugar has remained a puzzle. Researchers at the Baylor College of Medicine and their international collaborators have now identified a surprising new player in the drug’s effectiveness: the brain. In a study published in Science Advances, researchers reveal a previously unknown neural pathway that metformin activates, a discovery that could revolutionize the treatment of diabetes.
It has long been thought that metformin works primarily on peripheral organs, such as reducing the liver’s glucose production or acting through the gut. The new research, however, shifts the focus to the central nervous system. Scientists investigated the brain’s role as a key regulator of the body’s metabolism and zeroed in on the ventromedial hypothalamus, or VMH, a region crucial for controlling energy balance. They found that metformin’s ability to lower blood sugar depends on its power to inhibit a small protein within the VMH called Rap1, which acts like a molecular switch.
To prove this brain-centric mechanism, the team conducted a series of experiments in mice. In mice genetically engineered to lack the Rap1 protein in their forebrain, low-dose metformin failed to lower their blood sugar, though other diabetes drugs still worked. In a striking demonstration, researchers administered a dose of metformin directly into the brains of diabetic mice that was thousands of times smaller than a typical oral dose. This tiny amount was enough to significantly reduce their hyperglycemia, or high blood sugar, confirming the brain’s high sensitivity to the drug.
“This discovery changes how we think about metformin,” said Dr. Makoto Fukuda, the study’s corresponding author and an associate professor at Baylor, in a college press release. “It’s not just working in the liver or the gut, it’s also acting in the brain.” The team also identified specific brain cells, known as SF1 neurons, that are activated by metformin through this Rap1 pathway. These findings open the door to developing new diabetes therapies that directly target this neural mechanism, potentially leading to more effective treatments with fewer side effects.
References
- Baylor College of Medicine. (2025, July 30). Study reveals brain pathway behind metformin’s blood sugar-lowering effects. Medical Xpress; Baylor College of Medicine. https://medicalxpress.com/news/2025-07-reveals-brain-pathway-metformin-blood.html
- Lin, H.-Y., Lu, W., He, Y., Fu, Y., Kaneko, K., Huang, P., De La Puente-Gomez, A. B., Wang, C., Yang, Y., Li, F., Xu, Y., & Fukuda, M. (2025). Low-dose metformin requires brain Rap1 for its antidiabetic action. Science Advances, 11(31), eadu3700. https://doi.org/10.1126/sciadv.adu3700
