How Metformin Lowers Blood Sugar: Study Points to the Intestines and Mitochondria
Scientists may have identified a key way that the diabetes medication metformin lowers blood sugar. New research suggests that the drug acts primarily in the intestines, where it changes the activity of mitochondria—the structures that produce energy inside cells.
Metformin is widely prescribed to help manage type 2 diabetes. Although the medication has been used clinically since the 1990s, researchers have not reached a consensus about exactly how it works.
“Every year, a new mechanism for metformin is published, which means that last year’s mechanism was wrong,” study co-author Navdeep Chandel, a biochemist at Northwestern University, said.
One reason the drug has been difficult to study is that metformin affects several organs and multiple parts of metabolism. “Metformin has a complex mechanism of action, affecting multiple organs and different aspects of metabolism, making it difficult to identify a single mechanism that explains all of its effects,” Manuel Vázquez-Carrera, a pharmacology researcher at the Instituto Sant Joan de Déu who was not involved in the study, told Live Science by email.
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Why metformin’s mechanism has been debated
Previous studies proposed several explanations for metformin’s blood-sugar-lowering effects. Some research suggested that the drug causes intestinal cells to take up and use more glucose. Other studies focused on the liver, where metformin may reduce gluconeogenesis—the process of producing glucose from other molecules during fasting and exercise.
Researchers have also investigated whether metformin changes the gut microbiome or moves glucose from the bloodstream into the intestines, where gut bacteria can metabolize it.
Studies examining the liver found that metformin can interact with mitochondrial complex I, a large protein complex involved in producing adenosine triphosphate, or ATP. ATP is the primary energy-carrying molecule in cells.
However, the idea that metformin primarily works by targeting mitochondrial complex I in the liver was questioned because the concentration of the drug in liver tissue may be too low to produce this effect.
Metformin may target mitochondria in intestinal cells
In a study published in Nature Metabolism, Chandel and his colleagues found evidence that metformin does inhibit mitochondrial complex I—but mainly in the intestines, where the drug can accumulate at relatively high concentrations.
The researchers first compared blood metabolites from people who were taking metformin with those from people who were not. They found that levels of a molecule called citrulline declined significantly after metformin treatment.
Citrulline is produced primarily by mitochondria in intestinal cells called enterocytes. The finding suggested that metformin could be affecting mitochondrial activity in the gut.
New research suggests that metformin changes mitochondrial activity in intestinal cells, causing them to use more glucose.
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How blocking mitochondrial complex I could lower blood glucose
To test the theory, the researchers genetically modified mice so their intestinal cells produced a backup enzyme that performs a similar function to mitochondrial complex I but is not affected by metformin.
When the mice received metformin, the drug had a much smaller effect on blood citrulline levels. This result supported the idea that metformin acts on mitochondrial complex I in intestinal cells.
The genetic modification also reduced metformin’s effect on blood sugar by approximately 80%, according to Chandel. This suggests that mitochondrial complex I inhibition may account for much of the medication’s short-term blood-sugar-lowering activity.
Mitochondria can produce approximately 30 ATP molecules from one glucose molecule. When mitochondrial energy production is reduced, cells may compensate by relying more heavily on glycolysis, a less efficient process that produces only two ATP molecules per glucose molecule.
The researchers propose that metformin forces intestinal cells to depend more on glycolysis. As a result, the cells draw in and use more glucose, which may help reduce the amount of glucose circulating in the bloodstream.
Experiments in mice supported this explanation. Metformin caused glucose to accumulate in the intestinal cells of normal mice, but not in mice carrying the backup enzyme.
More research is needed
The findings offer a possible explanation for how metformin lowers blood sugar, but important questions remain. Much of the mechanistic evidence came from male mice, so it is not yet clear how fully the results apply to humans or whether biological sex affects the drug’s activity.
Metformin may also influence other organs and biological systems, including the liver and the gut microbiome. Future research will need to determine how these effects interact with the intestinal mechanism identified in the study.
For now, the evidence suggests that metformin’s effect on intestinal mitochondria—and particularly its inhibition of mitochondrial complex I—could be a major reason the medication helps control blood glucose in people with type 2 diabetes.
This article is for informational purposes only and does not provide medical advice.
Sebo, Z. L., Chakrabarty, R. P., Grant, R. A., et al. (2026). “Metformin promotes glycemic control by inhibiting mitochondrial complex I in the intestinal epithelium.” Nature Metabolism.
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