For half a century one of the most popular and most-prescribed classes of diabetes drugs has been biguanides, which includes the drug metformin. Metformin helps to keep liver glucose output in check, which, in turn, keeps blood sugar down in type 2 diabetes patients. Until now, however, doctors weren’t exactly sure how metformin, was accomplishing this feat.

“Overall, metformin lowers blood glucose by decreasing liver production of glucose,” said Dr. Morris Birnbaum, a researcher at the Institute for Diabetes, Obesity, and Metabolism at the University of Pennsylvania. “But we didn’t really know how the drug accomplished that.”

It was suggested in the past that metformin reduces glucose by activating an enzyme called AMPK. However, this hypothesis was shot down in 2010 when researchers found that mice without AMPK in their livers still responded to metformin, suggesting the drug works in a different way.

Birnbaum and his colleagues this week published the results of a new study in the journal Nature. Their research found that metformin antagonizes the action of glucagon, which reduces fasting glucose levels. Metformin was also shown to accumulate AMP in mice, which leads to the blocking of glucagon-dependent glucose output from the liver.

While the new discovery might be seen as an exercise in curiosity, the new study’s findings may lead to new drugs that work similarly to metformin. The study’s authors stated that new drugs could get around metformin’s affect on cell mitochondria, avoiding some of the side effects that go along with the drug.

(Image courtesy Morris Birnbaum, M.D., Ph.D., Perelman School of Medicine, University of Pennsylvania/Nature)