Scientists discover popular diabetic drug's unexpected effect on the brain

For 60 years, metformin has been the go-to medication to manage type 2 diabetes. It is known for lowering blood sugar, however, there is no complete picture of how it really works. Scientists have now discovered its unexpected effect on the brain.

Metformin may affect the brain

Metformin works primarily by reducing glucose production in the liver and acting through the gut. However, scientists at Baylor College of Medicine and international collaborators have now recognised a new player mediating clinically relevant effects of metformin: the brain. The findings are published in the journal Science Advances.

“It’s been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver. Other studies have found that it acts through the gut. We looked into the brain as it is widely recognized as a key regulator of whole-body glucose metabolism. We investigated whether and how the brain contributes to the anti-diabetic effects of metformin,” corresponding author Dr. Makoto Fukuda, associate professor of pediatrics – nutrition at Baylor.

The role of Rap1

The reasearchers looked at a small protein called Rap1, during the study. This protein is found in a specific part of the brain known as the ventromedial hypothalamus (VMH). They found that metformin’s ability to lower blood sugar at clinically relevant doses depends on turning off Rap1 in this brain region.

To test this, the researchers used genetically modified mice that lacked Rap1 in their VMH. These test subjects were then fed a high-fat diet to mimic type 2 diabetes. The researched found that the drug failed to lower blood sugr, when given low doses of metformin. However, other diabetes medications like insulin and GLP-1 agonists still worked.

To further confirm that the brain is a key player in this drug’s effectiveness, the researchers injected tiny amounts of metformin directly into the brains of diabetic mice. They saw a significant drop in blood sugar, even with doses thousands of times smaller than what’s typically given by mouth.

“We also investigated which cells in the VMH were involved in mediating metformin’s effects. We found that SF1 neurons are activated when metformin is introduced into the brain, suggesting they’re directly involved in the drug’s action,” Fukuda said.

The observed used brain samples to measure how active the neurons were. They found that the metformin increased their activity, but only when Rap1 was present. The drug showed no impact in mice without Rap1. This confirmed that Rap1 is essential for metformin to “switch on” these brain cells and lower blood sugar.

“This discovery changes how we think about metformin. It’s not just working in the liver or the gut, it’s also acting in the brain. We found that while the liver and intestines need high concentrations of the drug to respond, the brain reacts to much lower levels,” Fukuda said.

Though a few anti-diabetic drugs act on the brain, this one shows that the commonly used metformin has been doing so all along. “These findings open the door to developing new diabetes treatments that directly target this pathway in the brain. In addition, metformin is known for other health benefits, such as slowing brain aging. We plan to investigate whether this same brain Rap1 signaling is responsible for other well-documented effects of the drug on the brain,” Fukuda added.