Metformin Revisited: Brain Pathway Underlies Its Antidiabetic Effect

Although metformin has been the mainstay of treatment for type 2 diabetes for more than 60 years, researchers still don't have a full understanding of exactly how it works.

Scientists at Baylor College of Medicine, together with international colleagues, have discovered a previously unknown player that mediates the clinically significant effects of metformin: the brain. By identifying the involvement of the brain pathway in metformin’s antidiabetic action, the researchers have opened up new possibilities for more effective and precise diabetes treatment.

The study is published in the journal Science Advances.

"Metformin has long been thought to lower blood glucose levels primarily by inhibiting its production in the liver. Some studies have suggested an effect through the gut," said lead author Dr. Makoto Fukuda, an assistant professor of pediatrics (division of nutrition) at Baylor College of Medicine.

"We decided to study the brain because it is recognized as an important regulator of glucose metabolism throughout the body. We wanted to find out whether and how the brain is involved in the anti-diabetic effects of metformin."

The team focused on a small protein called Rap1, which is found in a specific region of the brain called the ventromedial hypothalamus (VMH). The researchers found that metformin’s ability to lower blood sugar at clinically relevant doses depends on deactivating Rap1 in this brain region.

To test this, Fukuda and his colleagues used genetically modified mice that lacked Rap1 in the VMH. These mice were fed a high-fat diet to mimic type 2 diabetes. When given low doses of metformin, the drug did not lower glucose levels. However, other diabetes drugs, such as insulin and GLP-1 agonists, continued to work.

To further confirm the brain's role, the researchers injected microdoses of metformin directly into the brains of diabetic mice. The result was a significant reduction in blood sugar levels — even at doses thousands of times lower than those typically taken orally.

"We also looked at which cells in the VMH are involved in the action of metformin," Fukuda said. "We found that SF1 neurons are activated when metformin enters the brain, indicating that they are directly involved in the drug's mechanism of action."

Using brain slices, the scientists recorded the electrical activity of these neurons. Metformin activated most of them, but only in the presence of Rap1. In mice that lacked Rap1 in these neurons, metformin had no effect, showing that Rap1 is necessary for metformin to “turn on” these brain cells and lower glucose levels.

"This discovery changes the way we think about metformin," Fukuda says. "It works not only in the liver and intestines, but also in the brain. We found that while the liver and intestines require high concentrations of the drug, the brain responds to very low doses."

While few antidiabetic drugs affect the brain, this study shows that the widely used metformin did so all the time.

“These findings open the door to new diabetes treatments that directly target this brain pathway,” Fukuda says.
“In addition, metformin is known to have additional beneficial effects, such as slowing brain aging. We plan to study whether the same Rap1 signaling pathway in the brain is responsible for these effects.”