Scientists have long assumed metformin fights Type 2 diabetes by suppressing glucose production in the liver. A new Northwestern University study says the gut is actually where the action happens — and the findings could reshape how future blood sugar treatments are developed.
Metformin has been the go-to medication for Type 2 diabetes for decades, prescribed to hundreds of millions of people worldwide. Scientists believed they understood how it worked: the drug, they thought, traveled to the liver and told it to make less glucose. A new study from Northwestern University is overturning that assumption — and pointing to a different organ entirely.
The research, published May 8 in Nature Metabolism, found that metformin primarily targets the intestine, not the liver. Rather than reducing glucose production, the drug appears to prompt cells lining the gut to absorb and burn more glucose from the bloodstream — essentially transforming the intestine into a biological sponge for excess sugar.
The study was conducted in mice using a genetically engineered model in which gut cells were made resistant to metformin’s effects. When those cells could no longer respond to the drug, metformin lost much of its ability to lower blood glucose — strong evidence that the gut is a primary site of the drug’s action.
How It Works Inside the Cell
The key mechanism involves mitochondria, the energy-producing structures found in nearly every cell. Metformin works by inhibiting mitochondrial complex I, a critical enzyme in cellular respiration. When this enzyme is slowed in gut cells, those cells are forced to find energy elsewhere — and they turn to glucose circulating in the blood.
“Metformin essentially helps the intestine suck the glucose out of the bloodstream, which further highlights that the gut plays a major role in regulating blood sugar levels,” corresponding author Navdeep Chandel, a professor of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine, said in a news release.
Chandel’s lab had previously shown that metformin blocks mitochondrial complex I. The new study goes a step further by identifying which tissue that inhibition matters most in. According to the researchers, the findings suggest that targeting mitochondrial metabolism in the gut could be a promising strategy for developing new blood sugar treatments.
“Our study suggests that revisiting assumptions about metformin’s mechanism may offer a more detailed understanding of how it works,” added first author Zach Sebo, a postdoctoral fellow in the Chandel lab, who will soon launch his own research group at the University of Kansas School of Medicine.
What This Means for Berberine, ‘Nature’s Ozempic’
The findings also shed light on berberine, a plant-derived supplement that has exploded in popularity on social media under the nickname “nature’s Ozempic.” Berberine is sold over the counter and is frequently used to help manage blood sugar, though regulatory agencies have not approved it as a treatment for diabetes. The study found that berberine appears to engage the same intestinal pathway as metformin.
“Metformin has decades of clinical evidence behind it, whereas supplements like berberine are far less rigorously tested,” Chandel added. “If you’re going to use berberine, you may as well use the real deal.”
Experts have cautioned that while berberine shows some promise, the evidence base remains thin compared to pharmaceutical-grade medications, and it should not be used as a substitute for doctor-prescribed treatments.
Explaining Clinical Puzzles
Beyond reframing the drug’s basic mechanism, the study helps explain several observations that have long puzzled clinicians treating patients on metformin. People who take the drug tend to have lower blood sugar after meals, reduced levels of a molecule called citrulline in the bloodstream, and higher levels of a hormone called GDF15, which is associated with reduced appetite and weight loss.
All three patterns make sense through the lens of the new findings. If metformin inhibits mitochondria in intestinal cells, those cells produce less citrulline — a molecule made exclusively in the small intestine’s mitochondria. The energy stress in gut cells also triggers GDF15 release, which signals to the brain to reduce food intake and recalibrate metabolism.
“People have always wondered how one drug can do 10 things,” added Chandel. “Well, it can do that if the drug is hitting a big node in a cell, and hitting mitochondria in a cell is a big node. So, if you can get into those cells and inhibit mitochondria, it’s going to have huge effects.”
Why It Matters for Students and Young Adults
Type 2 diabetes is increasingly diagnosed in younger populations, and metabolic conditions once considered middle-age concerns are showing up in college-age adults. Understanding precisely how leading medications work opens the door to more targeted therapies with fewer side effects. It also raises important questions about the unregulated supplements many young people are turning to for health management — including berberine, which is widely available at campus health stores and online.
The study also highlights the gut as an underappreciated player in metabolic health, an area of growing scientific interest. Researchers are increasingly recognizing that the digestive system does far more than process food — it actively regulates hormones, appetite and blood sugar in ways that could eventually inform entirely new classes of treatments.
Additional Northwestern co-authors include Ram Chakrabarty, Rogan Grant, Karis D’Alessandro, Alec Koss, Jenna Blum, Shawn Davidson and Colleen Reczek. Chandel is also an investigator with the Chan Zuckerberg Initiative.
Source: Northwestern University