Revealing the secrets of how diabetes drug Metformin works

Researchers from McMaster University in Hamilton, Ontario have discovered how metformin, one of the world’s most commonly prescribed diabetes drugs, interacts with insulin in order to lower a person’s blood sugar.

According to the study authors, approximately 120 million people, globally, with Type 2 diabetes use the medication to control their disease, including two million in Canada. While doctors had known that metformin needed to interact with the hormone to be effective, the new study is the first to explain exactly how this process occurs.

“The key is that metformin doesn’t work to lower blood glucose by directly working on the glucose. It works on reducing harmful fat molecules in the liver, which then allows insulin to work better and lower blood sugar levels,” explained Greg Steinberg, an associate professor in the Department of Medicine of the Michael G. DeGroote School of Medicine.

Steinberg and colleagues from Alberta, Australia and Scotland wrote that the majority of people who take metformin have a fatty liver – a condition often linked to obesity. Fat is considered to be a trigger for pre-diabetes; it causes blood glucose to begin increasing because insulin cannot work efficiently enough to prevent sugar from coming from the liver.

In the study, published in the journal Nature Medicine, the team examined mice with a “genetic disruption” to a lone amino acid in a pair of proteins known as acetyl-CoA carboxylase (ACC). Those proteins, which are controlled by the metabolic sensor AMP-activated protein kinase, regulate both fat production and the ability to burn adipose tissue, and the researchers believe they may be associated with fatty liver.

Rodents with the mutated proteins developed signs of fatty liver and pre-diabetes, even if they were not obese, Steinberg and his associates said. However, when they gave metformin to obese mutant mice, they found that it failed to lower their blood sugar levels. Thus, the authors conclude that the drug works not by directly reducing sugar metabolism, but rather by reducing fat in the liver and enhancing the performance of insulin.

“Unlike the majority of studies using genetic mouse models, we haven’t deleted an entire protein; we have only made a very minor genetic mutation, equivalent to what might be seen in humans, thus highlighting the very precise way metformin lowers blood sugar in Type 2 Diabetes,” explained lead author Morgan Fullerton.

“This discovery offers a huge head start in finding combination therapies (and more personalized approaches) for diabetics for whom metformin isn’t enough to restore their blood sugar to normal levels,” Steinberg added.


The research was sponsored by the Canadian Institutes for Health Research and the Canadian Diabetes Association.

McMaster University


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