January 7, 2013
Research Sheds New Light On How Popular Diabetes Drug Metformin Works
redOrbit Staff & Wire Reports - Your Universe Online
Metformin, the drug most frequently prescribed by doctors to treat Type 2 Diabetes, works differently than previously believed -- a discovery which could lead to new treatments that have fewer side effects.
Lead researcher Dr. Morris J. Birnbaum, a professor at the University of Pennsylvania's Institute for Diabetes, Obesity, and Metabolism (IDOM), and an international team of scientists have discovered that, in mice, metformin suppresses the liver hormone glucagon's ability to generate a key signaling molecule. Their findings have been published online in the journal Nature.
One of the main reasons that a diabetic's blood sugar levels become high is because of the inability of insulin to limit liver glucose output. Metformin lowers blood glucose by decreasing the liver's production, Birnbaum said, but until now the medical community was uncertain exactly how it was able to do so.
Previously, scientists believed that it reduced glucose synthesis by activating an enzyme known as AMPK. However, in 2010, Marc Foretz and Benoit Viollet from Inserm, CNRS and UniversitÃ© Paris Descartes -- both of whom also worked with Birnbaum on this latest study -- discovered that metformin still worked in mice that lacked AMPK, suggesting that the blood glucose levels were being impacted elsewhere.
"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 University of Pennsylvania said in a statement on Sunday.
They explained that the "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."
Thanks to these new insights into the processes behind metformin, the researchers believe that new diabetes drugs could be able to target the adenylate cyclase directly, bypassing the current medication's effect on a cell's mitochondria and potentially avoiding adverse side effects. Birnbaum and his colleagues also believe that such a treatment option could be used for those who are resistant to metformin.