For decades, scientists believed that metformin, one of the world’s most widely used drugs for Type 2 Diabetes, mainly worked by targeting the liver to reduce sugar production.
But a new study from Northwestern University suggests the drug’s real power may actually come from the gut.
The study, published in Nature Metabolism, found that metformin lowers blood sugar by changing how cells in the intestine use energy.
Instead of focusing mainly on the liver, the drug appears to force gut cells to absorb and burn more glucose, helping remove excess sugar from the bloodstream.
Researchers say the findings could reshape how scientists think about one of the most commonly prescribed diabetes drugs in the world.
Glucose is the body’s main source of quick energy, but too much glucose in the blood can lead to insulin resistance and damage to blood vessels and organs over time. The researchers discovered that metformin slows down energy production inside tiny structures called mitochondria within gut cells. Mitochondria are often described as the “power plants” of cells because they produce energy needed for normal function.
By slowing this energy system, metformin pushes intestinal cells to consume more glucose themselves. According to study author Navdeep Chandel, the intestine essentially acts like a sponge, soaking up extra sugar from the blood.
The research builds on earlier studies from Chandel’s laboratory showing that metformin blocks a key part of mitochondrial activity called mitochondrial complex I. The new study helps identify the gut as the major location where this process matters most for blood sugar control.
To test the idea, the scientists used specially engineered mice whose intestinal cells were resistant to metformin’s effects. In these mice, the drug was much less effective at lowering blood sugar levels, strongly suggesting the gut plays a central role in metformin’s action.
The findings may also explain several unusual effects doctors have observed in people taking metformin. For example, many patients have lower blood sugar after meals, reduced appetite and mild weight loss. The study suggests these effects may happen because stressed gut cells release signals that influence metabolism and hunger.
One of these signals is a hormone called GDF15, which can tell the brain to eat less. Researchers also found changes in citrulline, a substance produced by mitochondria in the small intestine, further supporting the idea that metformin strongly affects gut cell energy production.
The study also uncovered similarities between metformin and berberine, a plant-based supplement sometimes promoted online as “nature’s Ozempic.” The researchers found that berberine appears to affect the same pathway in the intestine as metformin.
However, Chandel cautioned that metformin has decades of scientific evidence supporting its safety and effectiveness, while supplements like berberine have not been tested nearly as rigorously.
The researchers believe the findings could open the door to new diabetes treatments designed specifically to target the gut. Instead of focusing mainly on the liver, future therapies may work by helping the intestine remove extra sugar from the bloodstream more effectively.
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