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Metformin is one of the most prescribed medicines in the U.S., primarily to treat or prevent type 2 diabetes. But how it works has been something of a mystery. Now researchers have discovered that the substance essentially transforms a person’s gut cells into a sugar sink, resulting in lowered levels of glucose.

Evidence of this mechanism stretches as far back as 1989, when French metabolic researcher Jean Girard and his colleagues published a paper describing how metformin increased the amount of glucose rats absorbed in their intestines. But when research picked up after the drug was finally approved by the U.S. Food and Drug Administration, in 1995, scientists mostly moved toward the theory that metformin reduced the liver’s production of glucose. “It was as if the preexisting science had never existed,” says University of Cambridge metabolism researcher Stephen O’Rahilly, who was not involved in the new study.

Later, radiologists discovered that metformin can cause patients’ guts to “light up like a beacon” during a positron-emission tomography scan, O’Rahilly says. (This version of the test used a tracer molecule that goes to tissues consuming sugar.) Gradually, metabolic scientists began to think this gut absorption of sugar could be important, and they revisited the old research. Not long after, University of Cambridge mitochondrial biologist Judy Hirst found that at very high levels, the drug blocks mitochondria from using oxygen.

For their new study, Northwestern University mitochondrial biologist Navdeep Chandel and his team wanted to figure out how these two ideas fit together: that metformin both causes the gut to absorb more glucose and blocks mitochondria’s oxygen use. Cell respiration, in which cells convert sugars into usable energy, happens inside mitochondria. So Chandel’s group complemented mitochondrial complex I, an enzyme necessary for cell respiration, with a yeast enzyme that isn’t affected by metformin and that they knew could perform some of the same functions in mice’s guts. In those mice, respiration continued as expected, but metformin didn’t reduce blood sugar levels. They concluded that when accumulated at high-enough levels, metformin, by blocking oxygen use, prompts gut cells to switch to a different metabolic pathway that uses much more sugar to produce energy.

This result is counterintuitive, especially considering metformin’s potential connection to antiaging effects. “All these people always say that for longevity, I want to boost my mitochondria,” Chandel says. “If anything, [metformin is] inhibiting mitochondria reversibly, transitively.”

“The broader lesson,” he adds, “is that inhibiting mitochondria may be beneficial when it is done in the right cells, for the right amount of time, without exposing the whole body to the broad toxicity of a mitochondrial inhibitor.” The new work was reported in Nature Metabolism.

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Thomas Fuchs

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