Study: Most-used diabetes drug works in different way than previously thought

Proposed model: Metformin enters the cell and acts on the mitochondria, causing increased AMP. Elevated cellular AMP levels inhibit membrane bound adenylyl cyclase, causing a reduction in cellular cAMP levels and decreased PKA activation and target phosphorylation. Credit: Morris Birnbaum, M.D., Ph.D., Perelman School of Medicine, University of Pennsylvania; Nature

A team, led by senior author Morris J. Birnbaum, MD, PhD, the Willard and Rhoda Ware Professor of Medicine, with the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, found that the diabetes drug metformin works in a different way than previously understood. Their research in mice found that metformin suppresses the liver hormone glucagon's ability to generate an important signaling molecule, pointing to new drug targets. The findings were published online this week in Nature.

For fifty years, one of the few classes of therapeutics effective in reducing the overactive associated with diabetes has been the biguanides, which includes metformin, the most frequently prescribed drug for type 2 diabetes. The inability of insulin to keep liver glucose output in check is a major factor in the of type 2 diabetes and other diseases of .

"Overall, metformin lowers blood glucose by decreasing liver production of glucose," says Birnbaum. "But we didn't really know how the drug accomplished that."

Imperfectly Understood

Despite metformin's success, its mechanism of action remained imperfectly understood. About a decade ago, researchers suggested that metformin reduces glucose synthesis by activating the enzyme AMPK. But this understanding was challenged by genetic experiments in 2010 by collaborators on the present Nature study. Coauthors Marc Foretz and Benoit Viollet from Inserm, CNRS, and Université Paris Descartes, Paris, found that the livers of mice without AMPK still responded to metformin, indicating that were being controlled outside of the pathway.

Taking another look at how glucose is regulated normally, the team knew that when there is no food intake and glucose decreases, glucagon is secreted from the pancreas to signal the liver to produce glucose. They then asked if metformin works by stopping the glucagon cascade.

The Nature study describes a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. The team showed that metformin leads to the accumulation of AMP in mice, which inhibits an enzyme called adenylate cyclase, thereby reducing levels of cyclic AMP and protein kinase activity, eventually blocking glucagon-dependent glucose output from liver cells.

From this new understanding of metformin's action, Birnbaum and colleagues surmise that adenylate cyclase could be a new drug target by mimicking the way in which it is inhibited by metformin. This strategy would bypass metformin's affect on a cell's mitochondria to make energy, and possibility avoid the adverse side effects experienced by many people who take metformin, perhaps even working for those patients resistant to metformin.

add to favorites email to friend print save as pdf

Related Stories

Metal binding important for metformin action

Apr 14, 2012

(HealthDay) -- The ability of metformin to bind mitochondrial copper may be essential to its mechanism of action, according to a study published online April 9 in Diabetes.

Imeglimin beneficial as add-on to metformin in T2DM

Dec 14, 2012

(HealthDay)—For patients with type 2 diabetes inadequately controlled by metformin alone, addition of the new oral anti-diabetes agent imeglimin improves glycemic control with good tolerability and safety, ...

Old diabetes drug teaches experts new tricks

May 14, 2009

Research from the Johns Hopkins Children's Center reveals that the drug most commonly used in type 2 diabetics who don't need insulin works on a much more basic level than once thought, treating persistently elevated blood ...

Recommended for you

Screening for diabetes at dental visits using oral blood

Feb 26, 2015

It is estimated that 8.1 million of the 29.1 million Americans living with diabetes are undiagnosed and many who have diabetes have poor glycemic control. Given that each year many Americans visit a dental provider but not ...

CBT, sertraline insufficient in diabetes and depression

Feb 26, 2015

(HealthDay)—For patients with diabetes and depression, improvements in depression are seen with cognitive behavioral therapy (CBT) or sertraline, with a significant advantage for sertraline, but glycemic ...

Early signs in young children predict type 1 diabetes

Feb 26, 2015

New research shows that it is possible to predict the development of type 1 diabetes. By measuring the presence of autoantibodies in the blood, it is possible to detect whether the immune system has begun to break down the ...

Daily menu plan reduces blood sugar significantly

Feb 25, 2015

A large group of people with diabetes who followed a menu plan created by University of Alberta nutrition researchers for just three months significantly reduced their blood sugar levels.

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.