Metformin mechanism found in gut cells
Scientists discovered metformin's main mechanism: it makes intestinal cells burn extra glucose by inhibiting mitochondrial complex I.
Scientists have pinpointed how the diabetes drug metformin works. The drug, first used in patients in the 1990s, forces gut cells to absorb and burn extra glucose by targeting their mitochondria.
Research published in May in the journal Nature Metabolism clarifies a long-standing debate. "Every year there's a new mechanism for metformin that says last year's mechanism was wrong," said study co-author Navdeep Chandel, a biochemist at Northwestern University. The source is a report from Live Science.
The search for a mechanism
Metformin affects several organs, complicating the search for a single explanation. Some past studies suggested the drug causes intestinal cells to use up glucose. An animal study released last year proposed it moves glucose into the intestines for gut bacteria to break down. Other research pointed to the liver, proposing metformin inhibits gluconeogenesis, the liver's process of making glucose.
Early theories focused on the liver. Scientists found metformin interacts with mitochondrial complex I, a key protein complex for generating cellular energy. However, this theory was dismissed because the drug's concentration in the liver is too low to exert an effect, according to pharmacology researcher Manuel Vázquez Carrera of the Sant Joan de Déu Research Institute.
Evidence from the gut
The new study led by Chandel found metformin does target mitochondrial complex I, but in the intestines where it builds up to higher concentrations. The first clue came from analyzing blood metabolites in people taking the drug. They observed a significant drop in citrulline, a metabolite produced almost exclusively by mitochondria in intestinal cells.
In experiments with genetically modified mice, the team provided intestinal cells with a backup enzyme for complex I that metformin cannot affect. When given metformin, these mice showed a much smaller drop in blood citrulline. The genetic tweak also reduced metformin's blood sugar-lowering effects by 80%, Chandel said.
How the mechanism lowers sugar
Blocking mitochondrial complex I forces cells to compensate. Normally, mitochondria generate about 30 ATP molecules from one glucose molecule. When blocked, cells switch to a less-efficient process called glycolysis, which yields only two ATP molecules per glucose. The researchers argue metformin forces intestinal cells to sequester and burn through large amounts of glucose using this inefficient strategy, thereby lowering blood sugar.
Lab tests showed glucose accumulated in the intestinal cells of normal mice but not in mice with the backup enzyme. "Much of the mechanistic evidence comes from male mice, so it remains unclear how well the findings translate to humans and whether there are sex-specific effects," Vázquez Carrera noted.
While about 80% of metformin's sugar-lowering activity involves complex I, the drug likely has additional targets. Chandel and his colleagues aim to explore its effects on other areas, such as the liver or gut microbiome, in future work.
