Metformin changes blood metal levels in humans, offering further insight into its mechanism of action

The widely used diabetes drug metformin changes blood metal levels in humans. The Kobe University study is an important step in understanding the drug’s many actions and designing better ones in the future.

Metformin is the most widely prescribed diabetes drug in the world. Apart from lowering blood sugar levels, it is also known to have a broad range of beneficial side effects such as against tumors, inflammation and atherosclerosis. However, although it has been used for more than 60 years now, its mechanism of action is still not clear, hampering the development of even better drugs against these conditions.

Kobe University endocrinologist Ogawa Wataru says, “It is known that diabetes patients experience changes in the blood levels of metals such as copper, iron and zinc.

“In addition, chemical studies found that metformin has the ability to bind certain metals, such as copper, and recent studies showed that it is this binding ability that might be responsible for some of the drug’s beneficial effects. So, we wanted to know whether metformin actually affects blood metal levels in humans, which had not been clarified.”

To do so, Ogawa and his team enlisted about 200 diabetes patients at Kobe University Hospital, half of whom took metformin and half of whom did not, in a study to analyze their blood serum levels for those metals and various metal deficiency indicators.

In the journal BMJ Open Diabetes Research & Care, the Kobe University team has published the first clinical evidence of altered blood metal levels in patients taking metformin. They showed that drug-taking patients have significantly lower copper and iron levels and heightened zinc levels.

Ogawa says, “It is significant that we could show this in humans. Furthermore, since decreases in copper and iron concentrations and an increase in zinc concentration are all considered to be associated with improved glucose tolerance and prevention of complications, these changes may indeed be related to metformin’s action.”

Recently, Japan has approved the use of imeglimin, a new diabetes drug that is a derivative of metformin but that should not be able to bind metals the same way as its parent.

“Imeglimin is thought to have a different method of action, and we are already conducting studies to compare the effects the two drugs have,” says Ogawa.

It is not just about understanding the current drugs, however. Ogawa explains the bigger picture, saying, “We need both clinical trials and animal experiments to pinpoint the causal relationship between the drug’s action and its effects. If such studies progress further, they may lead to the development of new drugs for diabetes and its complications by properly adjusting the metal concentrations in the body.”