A new study finds that the metformin diabetes drug lowers blood sugar by acting on brain pathways, challenging long-held beliefs that it works mainly through the liver and gut.
Researchers Identify Brain Mechanism Behind Metformin
Metformin, a first-line treatment for type 2 diabetes for more than six decades, may regulate blood sugar through the brain, according to a study published in the journal Science Advances.
Researchers led by Makoto Fukuda examined how the drug interacts with the brain, which plays a key role in controlling whole-body glucose metabolism.
“It’s been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver,” Fukuda said. “We investigated whether and how the brain contributes to the anti-diabetic effects of metformin.”
The findings suggest that metformin influences brain pathways involved in regulating glucose, even though it has not traditionally been considered a brain-targeting drug.
Protein Rap1 Plays Key Role In Blood Sugar Control
The study focused on a protein called Rap1 protein located in the brain’s ventromedial hypothalamus, a region critical for sensing glucose levels and regulating appetite.
Researchers found that suppressing Rap1 activity in this brain region allowed metformin to reduce blood sugar effectively.
In experiments, genetically engineered mice lacking Rap1 in the ventromedial hypothalamus did not respond to low doses of metformin. However, other treatments, including insulin and GLP-1 agonists, remained effective.
When Metformin diabetes drug, was delivered directly to the brain, even at doses thousands of times lower than typical oral amounts, it significantly reduced blood sugar levels in the mice.
Findings May Lead To More Targeted Diabetes Treatments
The team also identified specific brain cells, known as SF1 neurons, that respond to metformin. These neurons showed increased activity when exposed to the drug, but only when Rap1 was present.
In mice lacking Rap1 in these neurons, metformin failed to activate the cells or regulate blood sugar, confirming the protein’s essential role.
“This discovery changes how we think about metformin,” Fukuda said. “It’s not just working in the liver or the gut, it’s also acting in the brain.”
He added that the brain responds to much lower concentrations of the drug compared with other organs, which could have implications for future therapies.
Researchers said the findings could open the door to new diabetes treatments that directly target brain pathways, potentially improving effectiveness and reducing side effects.
The study builds on decades of research into the metformin diabetes drug, first reported for diabetes treatment in 1957, and offers a new understanding of how the drug works in the body.
