Meducator: McMaster researchers unlock secrets of diabetes drug

Avril-Lynn Ding
The Meducator
In an era where overweight, obesity, and physical inactivity are increasing health concerns, diabetes is emerging as a global epidemic. Type 2 diabetes accounts for about 90 per cent of diabetes cases. One of the world’s most commonly prescribed drug for type 2 diabetes is metformin. Approximately 120 million people worldwide, including two million in Canada, use the medication to control their disease. Although the drug has been in use for over 50 years, its mechanism of action remained a mystery. While doctors knew it needed to interact with insulin in order to be effective and it couldn’t lower blood sugar levels on its own, how and why the process occurs had remained unexplained.

Researchers at McMaster University were the first to propose an answer with the discovery that metformin operates on fat metabolism in the liver. The study, published in Nature Medicine on Nov. 4, was led by Dr. Gregory Steinberg, an associate professor in the Department of Medicine. Rather than assuming the drug directly reduced glucose levels, the researchers formed their hypothesis based on the principle that excess fat in insulin-sensitive organs, such as the liver and skeletal muscle, is associated with insulin resistance.

From previous studies, researchers know that metformin activates the metabolic sensor AMP-activated protein kinase (Ampk), an enzyme involved in fat metabolism. Ampk can deactivate two forms of the protein acetyl-CoA carboxylase (Acc), which increase fat production and reduce fat breakdown in their active forms.

In their study, the research team examined mice with a mutation in Acc that causes the proteins to become “immune” to deactivation by Ampk. However instead of becoming obese, the mutant mice were found to exhibit signs of fatty liver and pre-diabetes. This indicates that inactivity of Ampk results in high blood sugar, or alternatively, metformin’s activation of the Ampk pathway is linked to the drug’s role in diabetes.

For further experimentation, the researchers fed a group of normal and mutant mice with a high-fat diet to induce obesity. They then treated both groups with a daily metformin dose of 50 mg per kg of body weight, equivalent to therapeutic metformin doses for humans. While the drug was effective in reducing blood glucose levels in normal mice, it failed to have an effect on obese mutant mice. The observation that metformin was unable to lower blood sugar without reducing fat concentration in obese mice demonstrates that the drug does not directly affect sugar metabolism.

"The key is that metformin doesn't work to lower blood glucose by directly working on the glucose,” said Steinberg. “It works on reducing harmful fat molecules in the liver, which then allows insulin to work better and lower blood sugar levels.”

The study’s findings have great implications in the treatment of type 2 diabetes by pinpointing the biological process through which metformin lowers blood glucose level. As the drug remains the main therapeutic option for treating type 2 diabetes, understanding its precise mechanism of action and flaws will allow researchers to develop combination therapies and personalized treatments.

Further research is required to translate the results from rodents to humans, as not all clinical trials demonstrate metformin has a clear lipid-lowering effect in humans.