Metformin lowers blood sugar: A new study has found that metformin, the widely used diabetes drug, may lower blood sugar through a brain pathway as well, challenging the long-held belief that its main action is limited to the liver and gut.
Metformin has been the first-line treatment for diabetes for more than six decades and is not generally thought of as a drug that acts on the brain. But researchers now say the brain may play a much more important role in how the medicine works than previously understood.
Also Read | BMI at age 10 may offer clues to future diabetes and heart risk, study finds
Makoto Fukuda, associate professor of paediatrics-nutrition at Baylor College of Medicine in the US, said metformin has traditionally been known to reduce blood glucose by lowering glucose production in the liver. Other research has also suggested that the gut is involved. His team decided to examine the brain because it is already known to be a major controller of the body’s glucose balance.
The study, published in Science Advances, identified a protein called Rap1 in the ventromedial hypothalamus, a part of the brain involved in glucose sensing and appetite regulation, as a key part of the process.
Researchers found that when Rap1 activity in that brain region was suppressed, metformin was able to lower blood sugar in a significant way. To test this further, they studied genetically modified mice that did not have Rap1 in the ventromedial hypothalamus.
Those mice were fed a high-fat diet to mimic type 2 diabetes and then given low doses of metformin. Unlike normal mice, they did not show an improvement in blood sugar levels. However, other diabetes treatments, including insulin and GLP-1 agonists, still worked.
The team then delivered metformin directly into the brains of diabetic mice. Even at doses far lower than those usually taken by mouth, the drug produced a clear drop in blood sugar, according to the researchers.
They also looked more closely at the brain cells involved and found that SF1 neurons in the ventromedial hypothalamus became active when metformin entered the brain. This suggested that these neurons were directly linked to the drug’s effect.
When the researchers measured electrical signals in brain tissue, they found that metformin increased the activity of most SF1 neurons, but only when Rap1 was present. In mice that lacked Rap1 in those neurons, metformin had no effect, showing that the protein is necessary for the drug to trigger this brain response and help regulate blood sugar.
Fukuda said the findings change the way scientists think about metformin. Rather than acting only through the liver or intestines, the drug also appears to work through the brain. He added that while the liver and gut need relatively high concentrations of metformin to respond, the brain seems to react at much lower levels.
The researchers said the discovery could help pave the way for new diabetes treatments designed to target this specific brain pathway more directly.