After 60 years, researchers find hidden brain pathway behind metformin diabetes drug

For decades, doctors have relied on metformin to help people with type 2 diabetes bring high blood sugar back to earth. After years of debate about where and how metformin works, a new animal study points to a surprising place that matters more than many realized – the brain.

Researchers traced metformin’s action to a tiny control hub called the ventromedial hypothalamus and to a molecular switch named Rap1.

At clinically relevant exposures, turning that switch down in the brain was required for metformin to lower glucose, and tiny brain doses of the drug, in the microgram range, were enough to move blood sugar.

Metformin, blood sugar, and the brain

The hypothalamus sits deep in the brain and helps coordinate hormones and nerve signals that keep glucose in a safe range.

It receives information from the body and sends commands that change how the liver, muscle, and fat handle sugar.

“We looked into the brain as it is widely recognized as a key regulator of whole-body glucose metabolism,” said Dr. Makoto Fukuda of Baylor College of Medicine (BCM), associate professor of pediatric nutrition at Baylor and the study’s corresponding author.

Within that region, the team focused on Rap1, a small GTPase that modulates neuron activity and, in earlier work, was tied to changes in glucose balance.

The neurons of interest were SF1 neurons, a subpopulation in the ventromedial hypothalamus that are well known for shaping blood sugar responses.

How the study was done

The group used mice engineered to lack Rap1 in the forebrain or specifically in SF1 neurons.

When those animals received low doses of metformin, blood sugar did not fall, yet insulin and GLP-1 drugs still worked. This suggested that metformin needs Rap1 in this circuit, not just any glucose-lowering pathway.

To probe sensitivity, the team placed extremely small amounts of metformin directly into the brain ventricles of diabetic mice.

Even 1 to 10 micrograms cut glucose for hours, despite being thousands of times lower than standard oral doses used in rodent studies.

The brain effect did not depend on eating less, since glucose dropped even when food was removed and before appetite changed.

It also did not reflect drug leak into the blood, because the same tiny dose placed outside the brain did not lower glucose.

Electrophysiology added a mechanistic piece. In brain slices, metformin excited SF1 neurons, but only when Rap1 was present, and this cell-level activation fit the in vivo requirement for Rap1 to see a glucose effect.

Older ideas about metformin

For years, most explanations focused on the liver, where metformin slows down the amount of sugar the organ releases into the blood.

A major review pointed out several possible ways this happens, including changes to energy sensors in cells, effects on tiny energy-producing parts called mitochondria, and blocking certain chemical signals that normally raise blood sugar.

Those liver and gut routes remain important, especially at higher exposures where tissue concentrations reach the hundreds of micromolar in the liver and much higher in the intestine.

The new paper proposes that at lower, clinically relevant exposures, the brain pathway via Rap1 sits upstream and can drive glucose control without needing supraphysiologic peripheral drug levels.

“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,” said Dr. Fukuda.

The gut still plays a role

Multiple human and animal studies show that metformin boosts GDF15, a hormone that reduces appetite through a brainstem receptor and helps with weight control.

Those effects can contribute to better glycemic control over time by easing insulin resistance tied to excess weight.

The new brain Rap1 pathway does not erase those intestinal and hepatic actions. It reframes the picture by adding a central circuit that responds to lower exposures and can tip whole body glucose handling through nerve and hormonal outputs.

Why this matters

Understanding a brain circuit for metformin’s action could point to new drug targets.

If a medicine can dial down Rap1 signaling in the ventromedial hypothalamus, even modestly, it might lower glucose with fewer side effects elsewhere.

“These findings open the door to developing new diabetes treatments that directly target this pathway in the brain,” said Dr. Fukuda. That is a different strategy from flooding the liver or gut with high drug levels.

Clinicians will want human data before practice changes. The current work is in mice, and translation to people requires careful trials that measure brain exposure, glucose outcomes, and safety.

Metformin and future brain studies

A key issue is exposure. The blood-brain barrier (BBB) limits many drugs, yet metformin has been detected in cerebrospinal fluid and brain tissue at micromolar concentrations in animal models, levels that align with the neuronal responses reported in the new work.

Another open question is the relay from the ventromedial hypothalamus to peripheral organs.

Signals from SF1 neurons can shift liver glucose output and muscle glucose uptake, but mapping each step in living animals, then in people, will take time.

Since Rap1 is involved in chemical signaling inside cells and can also be found near structures called lysosomes, researchers wonder if it connects with how low doses of metformin affect energy sensors in those same areas.

This link could help explain why smaller amounts of the drug seem to act mainly through the brain, while higher doses work more in the liver and intestines.

The broader clinical picture matters too. People take metformin for years, not hours, and long term adaptations in the brain and gut can differ from acute responses.

Separating dose, timing, and tissue exposure in real world use will be important for any future labeling changes.

The study is published in Science Advances.

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