Metformin has been used for decades, but for a long time it was believed that it mainly worked in the liver and intestines. New research from Baylor College of Medicine shows that the brain plays a crucial role in its effectiveness. The drug works by suppressing a protein called Rap1 located in the ventromedial hypothalamus (VMH), a region that regulates metabolism. Metformin activates specific brain cells called SF1 neurons; researchers found that if Rap1 is missing, Metformin cannot activate these neurons and its ability to lower blood sugar levels fails. Interestingly, the brain responds to much lower doses of Metformin than the liver or intestines, indicating that the brain is very sensitive to the drug’s signals.
Experimental evidence
When scientists injected small amounts of Metformin directly into the brains of mice with diabetes, their blood sugar levels dropped significantly, even though the dose was thousands of times lower than that of a standard oral pill. Mice engineered to lack Rap1 in the VMH failed to respond to Metformin treatment, proving that this brain pathway is essential for the drug to function.
In this regard, the corresponding author Dr. Makoto Fukuda, associate professor of pediatrics-nutrition at Baylor, said: “We looked at the brain, because it is widely recognized as an important regulator of glucose metabolism throughout the body. We investigated whether and how the brain contributes to the antidiabetic effects of metformin.”
This discovery could lead to the development of new diabetes medications that specifically target brain pathways for better results with fewer side effects. In addition to diabetes, researchers think the same Rap1 signaling could explain why Metformin helps slow brain aging and provides other neuroprotective benefits.
