Researchers have identified what appears to be the primary mechanism behind metformin’s effectiveness in treating type 2 diabetes, resolving decades of scientific uncertainty. The widely-used medication works by targeting mitochondrial complex I, a crucial energy-producing structure within intestinal cells, according to findings published in Nature Metabolism.
For years, scientists proposed various theories about how metformin lowers blood sugar, with explanations ranging from effects on the liver to impacts on gut bacteria. The challenge stemmed from metformin’s widespread influence across multiple organs and metabolic processes. A Northwestern University research team, led by biochemist Navdeep Chandel, conducted experiments using genetically modified mice to pinpoint the drug’s main action. When researchers equipped mice with backup enzymes that could compensate for complex I inhibition in the intestines, metformin’s effectiveness at reducing blood sugar levels dropped by approximately 80%.
The mechanism works through an elegant biological process: by blocking mitochondrial complex I in gut cells, metformin forces these cells to rely on a less efficient energy production pathway called glycolysis. This inefficiency causes intestinal cells to consume and burn through significantly more glucose than normal, ultimately reducing blood sugar levels throughout the body. Blood analysis revealed elevated citrulline levels—a metabolite produced almost exclusively by intestinal mitochondria—confirming the drug’s direct effects on gut cell energy production.
While the research provides substantial evidence that complex I inhibition accounts for roughly 80% of metformin’s acute effects, scientists acknowledge the drug likely has additional mechanisms. Future investigations will explore metformin’s broader impacts on liver function and gut microbiota.
Originally reported by Livescience →
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