Metformin is a regularly prescribed medication for type 2 diabetes that has also been making the news for its ability to reduce levels of fat, but new research from Stanford Medicine and Harvard Medical School is uncovering the mechanism for how this actually works. It turns out that both metformin and physical exercise can both produce the same essential molecule.

Working with mice and human cohorts, scientists sought clarification on the way that metformin does its thing. There were more than 90,000 prescriptions for metformin issued in the United States in 2021, with that number thought to be far higher in 2024, since diabetes is still on the rise.  “Until now, the way metformin, which is prescribed to control blood sugar levels, also brings about weight loss has been unclear,” said Jonathan Long, PhD, who is an assistant professor of pathology. “Now we know that it is acting through the same pathway as vigorous exercise to reduce hunger. Understanding how these pathways are controlled may lead to viable strategies to lower body mass and improve health in millions of people.”

What is the Anti-Hunger Molecule?

Rather than being simply all about blood sugar levels, metformin produces the anti-hunger molecule; lac-phe. This molecule influences metabolism and is also made by those who are not on the drug, but undertake intense physical exercise instead. While the weight loss seen by metformin users tends to be around 2 to 3% in the first year, this is nowhere near the 15% dropped by semaglutide based drugs such as Ozempic or Wegovy, but the fact that metformin’s results are in large part owed to a natural physical process that can be mimicked without the drug offers an encouraging and safe way to develop these types of medications further.

Lac-phe, first discovered at Baylor University in 2022, is a byproduct of muscle fatigue and is a hybrid with the amino acid phenylalanine. The new research found that obese laboratory mice given Metformin had increased levels of lac-phe in their blood. They ate less than their peers and lost about 2 grams of body weight during the nine-day trial.

Dr Long and his colleagues also analyzed the stored blood plasma samples from humans with type 2 diabetes 12 weeks after they had taken metformin and saw significant increases in the levels of lac-phe. “It was nice to confirm our hunch experimentally,” said Dr Long. “The magnitude of effect of metformin on lac-phe production in mice was as great as or greater than what we previously observed with exercise. If you give a mouse metformin at levels comparable to what we prescribe for humans, their lac-phe levels go through the roof and stay high for many hours.”

These findings, still in the early stages, could eventually show that exercise may negate the requirement of drugs for type 2 diabetes, while also offering a lifeline for those who are physically unable to workout.