Metformin: This Diabetes Drug Works Directly in the Brain. What Are Its Effects?

Liputan6.com, Jakarta - A groundbreaking study published in March 2026 has transformed our understanding of one of the most common diabetes medications, Metformin.

For more than six decades, metformin has been known to be effective in lowering blood sugar, but its exact mechanism outside the liver and intestines has remained a mystery.

Now, researchers from Baylor College of Medicine, led by Dr. Makoto Fukuda, have discovered that this drug works directly in the brain.

This discovery opens a new dimension in how we view diabetes treatment and the potential of metformin beyond blood sugar control.

This significant finding, published in the journal 'Science Advances', not only explains metformin's unexpected pathway of action but also opens the door to the development of new types of diabetes medications that target the brain.

Fukuda said the team plans to investigate whether the same Rap1 signaling pathway is behind those effects as well.

“These findings open the door to developing new diabetes treatments that directly target this pathway in the brain,” he said.

This latest study specifically identifies that the drug metformin targets a small protein called Rap1, located in the ventromedial hypothalamus (VMH) of the brain.

This brain region is known to play a key role in regulating metabolism and appetite.

Metformin's ability to lower blood sugar at clinically relevant doses relies heavily on suppressing Rap1 activity in this brain area.

Furthermore, researchers observed that SF1 neurons in the VMH became active when metformin was administered to the brain, suggesting their direct involvement in the drug's action.

In a series of experiments in mice, metformin showed no effect on diabetes-like conditions if mice were bred without Rap1.

Beyond its role in blood sugar control, metformin has long been known to have other health benefits, including slowing brain aging.

Previous studies have also shown that metformin may reduce brain wear and tear and even lower the risk of long COVID.

Metformin has also shown beneficial effects in several neurological disorders, such as major depressive disorder, Alzheimer's disease, and Fragile X syndrome, although the exact mechanisms remain under investigation.

Its potential as a disease-modifying agent for Alzheimer's is further strengthened by its ability to activate the ubiquitin-binding protease rNGO/DDI2.

Long-term metformin use has also been associated with a reduced risk of dementia.

Metformin's neuroprotective mechanism involves reducing neuroinflammation by inhibiting microglial activation and suppressing proinflammatory cytokines.

Metformin also activates the Nrf2 pathway to combat oxidative stress, which is crucial for maintaining cognitive health.

To address the debate and broaden understanding of metformin's benefits beyond blood sugar control, several large trials are underway. One of these is the Targeting Aging with Metformin (TAME) trial.

The TAME trial will monitor 3,000 adults aged 65-79 for four years to investigate metformin's potential for slowing aging, including its effects on brain aging.

Furthermore, the Metformin in Alzheimer's Dementia Prevention (MAP) study is an ongoing Phase 2/3 prevention trial.

This study, involving 326 participants, assesses the effects of metformin on cognitive decline, offering new hope in Alzheimer's prevention.

Source:

https://www.newsnationnow.com/health/diabetes-metformin-affects-brain-study/ 

https://www.sciencealert.com/after-60-years-diabetes-drug-revealed-to-unexpectedly-affect-the-brain