Metformin has been the most widely prescribed medicine for type 2 diabetes for more than 60 years.
Millions of people take it every day because it helps lower blood sugar, is affordable, and has a long record of safety.
Even so, scientists have never completely understood how the medicine works inside the body.
A new study from Baylor College of Medicine now suggests that one of metformin’s most important targets may actually be the brain rather than only the liver or the gut. The findings were published in Science Advances.
For many years, researchers believed metformin mainly reduced the amount of sugar released by the liver.
Other studies suggested that the medicine also works through the intestines. Because the brain plays a major role in controlling hunger, energy use, and blood sugar, the research team wondered whether it could also be involved in metformin’s effects.
The scientists focused on a brain region called the ventromedial hypothalamus, which helps regulate the body’s metabolism. Inside this region they studied a protein called Rap1. Their experiments showed that metformin lowers blood sugar by reducing the activity of Rap1 in this part of the brain.
To test the idea, the researchers used mice that had been genetically modified so Rap1 was missing from this brain region. The mice were fed a high-fat diet to create a condition similar to type 2 diabetes. When these mice received low doses of metformin, the medicine no longer lowered their blood sugar. However, insulin and GLP-1 medicines still worked, showing that Rap1 appears to be important only for metformin.
The team then injected extremely tiny amounts of metformin directly into the brains of diabetic mice. Even though the doses were thousands of times smaller than those taken by mouth, blood sugar levels still fell significantly. This showed that the brain is highly sensitive to the medicine.
The researchers also identified special nerve cells known as SF1 neurons. Metformin increased the activity of these cells, but only when Rap1 was present. Without Rap1, the neurons did not respond, providing more evidence that this protein is a key part of the process.
The findings suggest the brain responds to much lower amounts of metformin than the liver or intestines.
This could explain why the drug has remained so effective for decades despite scientists not fully understanding its action. It also raises the possibility that future medicines could target the same brain pathway more directly.
If you care about diabetes, please read studies that not all whole grain foods could benefit people with type 2 diabetes, and green tea could help reduce death risk in type 2 diabetes.
For more information about health, please see recent studies about unhealthy plant-based diets linked to metabolic syndrome, and results showing Mediterranean diet could help reduce the diabetes risk by one third.
