Metformin has been a mainstay in diabetes care for decades. Millions rely on it to manage blood sugar, and doctors prescribe it with great confidence.
Yet one basic question has remained unsettled for years. Where exactly does this drug do its job?
A new study now offers a clearer answer. It shifts attention away from the liver and toward a different organ. The gut may be doing most of the heavy lifting.
A trusted drug, unclear action
Metformin is the most widely used drug for type 2 diabetes. It lowers blood glucose and improves long-term outcomes.
Medical teaching has long linked its action to the liver. The idea is simple. The drug reduces glucose production in liver cells.
But real-world data has not always matched this view. In some patients, liver glucose output does not fall. In others, it may even rise.
At the same time, blood sugar still improves. This mismatch has puzzled researchers for years.
Clues from early medicine
The story of metformin goes back to plant-based remedies. It comes from a class of compounds found in French lilac (Galega officinalis), a medicinal herb that was historically used to treat diabetes.
These compounds were explored in the mid-20th century. Over time, metformin was developed as the safest option.
Even then, scientists struggled to pin down exactly how it worked. The liver explanation gained popularity because it fit early lab findings. But patient data kept raising questions.
A glowing hint in scans
One clue came from imaging studies. Doctors use PET scans to track glucose use in the body. These scans highlight tissues that absorb large amounts of sugar.
In people taking metformin, the gut lights up strongly. This effect became so consistent that patients often stop using the drug before scans.
Otherwise, the bright signal from the gut can interfere with results.
This pattern suggested something important. The gut was taking in large amounts of glucose during treatment.
Metformin builds up in gut
Another piece of the puzzle came from drug distribution. Metformin does not spread evenly across the body. Its concentration in the intestine is far higher than in the blood or liver.
In fact, Metformin levels in the gut can be hundreds of times greater than those in circulation. This means intestinal cells receive the strongest exposure. For years, this detail was known but not fully explored.
Target inside cells
The new study has brought these ideas together. It focused on an enzyme structure inside cells called mitochondrial complex I. This enzyme plays a key role in energy production.
Researchers have long suspected that metformin affects this complex. But earlier work dismissed the idea. The reasoning was simple. Blood levels of the drug seemed too low to block complex I.
The missing link was concentration. In the gut, levels are high enough to make this effect possible.
Mouse gut made insensitive to metformin
To test this, scientists designed a targeted experiment. They modified mice so that intestinal cells carried a special enzyme. This enzyme replaced complex I function but resisted metformin.
This made the gut cells insensitive to metformin. The rest of the body remained unchanged.
The results were clear. In normal mice, metformin improved glucose control. In modified mice, the effect largely disappeared. This showed that the gut plays a central role.
“Our study suggests that revisiting assumptions about metformin’s mechanism may offer a more detailed understanding of how it works,” said Zachary Sebo, the study’s first author.
With metformin, gut becomes glucose sink
What happens inside the intestine explains the effect. When complex I is blocked, cells cannot rely on their usual energy pathway. They switch to glycolysis instead.
This shift increases glucose uptake. Intestinal cells pull in sugar from the blood and convert it into lactate. The gut starts acting like a sink that absorbs excess glucose after meals.
“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 Navdeep Chandel, professor at Northwestern University’s Feinberg School of Medicine.
Lactate and side effects
This process also explains a known side effect of metformin use. The drug raises lactate levels in the blood. This comes directly from increased glycolysis in gut cells.
In rare cases, high lactate can cause complications. Understanding the source helps explain why this happens.
Citrulline levels fall
The study also explained another change. Levels of citrulline drop in people taking metformin. This molecule is produced mainly in the intestine.
Its production depends on healthy mitochondrial activity. When complex I is blocked, this process slows down. As a result, citrulline levels fall.
Why this matters
Citrulline links to nitric oxide production. Nitric oxide helps blood vessels relax and supports muscle function during exercise.
Lower citrulline may affect how the body responds to physical activity. Some studies show that metformin can reduce exercise benefits in older adults. This new finding may help explain why.
Researchers suggest that supplements could help restore this balance. More work is needed to confirm this idea.
Timing of metformin in gut matters
Another insight related to dosing. Continuous, low-level exposure to metformin does not produce strong effects in animal models. Instead, a single, higher dose works better.
This matches how people take the drug. A tablet creates a short spike in intestinal concentration. This spike is enough to trigger the glucose clearing effect.
Taking the drug with meals may also improve results. The timing aligns the drug action with rising blood sugar levels.
A natural compound link
The study also looked at berberine. This plant-derived compound has gained attention as a supplement for blood sugar control.
Berberine is poorly absorbed into the bloodstream. At first glance, this seems like a limitation. But the new findings suggested the opposite.
Because it stays in the gut, it reaches high local concentrations. It also blocks complex I, even more strongly than metformin.
Berberine shares mechanism
Experiments showed that its effect disappears when gut cells are protected from this mechanism. This places it in the same pathway as metformin.
“Metformin has decades of clinical evidence behind it, whereas supplements like berberine are far less rigorously tested,” Chandel said.
“If you’re going to use berberine, you may as well use the real deal.”
Liver still plays role
The liver is not completely out of the picture. Some effects of metformin still appear, even when gut action is blocked. This suggests that other pathways exist.
In advanced diabetes, liver processes may matter more. But for many patients, the gut appears to drive most of the benefit.
Rethinking drug design
These findings open new directions for treatment. Future drugs may focus on the intestine rather than the whole body.
A drug that acts only in the gut could reduce side effects. It could also improve safety by avoiding unwanted effects in other tissues.
A shift in perspective
For years, the gut was seen as a barrier in drug delivery. Now it looks like a key target. Metformin has been working in plain sight all along.
This new understanding brings clarity to a long-standing question. It also shows how much remains to be learned, even about the most familiar medicines.
The study is published in the journal Nature Metabolism.
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