Metformin Works Through the Gut, Not the Liver

For years, scientists thought they knew exactly how the world’s most popular diabetes drug worked, but it turns out they were looking at the wrong organ.

Researchers at Northwestern University have discovered that metformin targets mitochondrial complex I in the gut rather than the liver. Their findings demonstrate that the drug turns the intestines into a glucose “sink” to lower blood sugar levels.

The long-standing mystery of how metformin works

Prescribed to millions, metformin is considered the gold standard for treating type 2 diabetes; however, its exact mechanism has remained a subject of intense debate. 

Historically, scientists and physicians assumed the drug primarily targeted the liver, but this liver-centric view has always faced a hurdle known as the concentration problem. When an individual takes metformin, the drug reaches very high levels in the gut but only reaches much lower levels in the liver—often, levels are too low to switch off the liver’s glucose production effectively.

Previous research from the laboratory of Dr. Navdeep Chandel, a professor at Northwestern Medicine, established that metformin works by blocking mitochondrial complex I, a key part of the cell’s energy-making machinery. Despite this discovery, the specific tissue where this process mattered most remained unconfirmed.

Clinical observations have also added to the confusion. In many patients, metformin does not actually reduce the liver's glucose output, yet their blood sugar levels still drop.

The new study aimed to understand this further by testing whether inhibiting the energy machinery specifically in the gut is enough to control blood sugar.

Mapping metformin's action in the gut

Chandel and the team used a yeast enzyme called NDI1, which mimics mitochondrial function in mice but is completely resistant to metformin. By engineering mice to express NDI1 only in their intestinal cells, the researchers created a model where the gut was shielded from the drug’s effects while the rest of the body remained susceptible.

In the shielded mice, metformin lost its ability to lower blood sugar.

When the drug inhibits the mitochondria in the intestine, it forces those cells to find alternative ways to survive, leading them to consume vast amounts of sugar from 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,” said Chandel.

Once the gut consumes the extra glucose, the cells convert it into lactate and lactoyl-phenylalanine, a molecule recently identified for its role in suppressing appetite.

The study found that metformin increases levels of GDF15, a hormone that signals the brain to reduce appetite, and lowers the levels of citrulline, a marker produced only by healthy gut mitochondria. This explains the several hormonal changes often seen in patients.

Earlier theories suggested that metformin needed to build up in the system over time to change how the liver works. However, the team found that the gut only needed a temporary hit of the drug to inhibit mitochondria. This matches the clinical observation that metformin is most effective at reducing the blood sugar spike individuals get right after a meal.

Future implications of a gut-centered metformin mechanism

“Our study suggests that revisiting assumptions about metformin’s mechanism may offer a more detailed understanding of how it works,” said first author Dr. Zach Sebo, a postdoctoral fellow at Northwestern University.

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If the gut is the primary driver of the drug's success, future treatments could be designed to target the intestines directly. This might allow for effective blood sugar control with fewer systemic side effects, as the drug wouldn't need to circulate through the entire body.

The study also found parallels with the popular supplement berberine. Often marketed on social media as “nature’s Ozempic,” berberine was found to use the exact same intestinal pathway as metformin.

However, Chandel warns against swapping a proven medication for an over-the-counter alternative: “Metformin has decades of clinical evidence behind it, whereas supplements like berberine are far less rigorously tested. If you're going to use berberine, you may as well use the real deal.”

 The study was conducted in mice, and further human validation is needed. However, the implications for understanding the drug's multi-tool nature are vast.

“People have always wondered how one drug can do 10 things,” said 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.”

Reference: Sebo ZL, Chakrabarty RP, Grant RA, et al. Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control. Nat Metab. 2026. doi: 10.1038/s42255-026-01530-y

This article is a rework of a press release issued by Northwestern University. Material has been edited for length and content.