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 glucose production 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 high blood sugar of type 2 diabetes and other diseases of insulin resistance.
"Overall, metformin lowers blood glucose by decreasing liver production of glucose," says Birnbaum. "But we didn't really know how the drug accomplished that."
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 blood glucose levels were being controlled outside of the AMPK 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.
University of Pennsylvania School of Medicine: http://www.uphs.upenn.edu/news/
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
There's a new contender in the century-old quest for perfect, guiltless sweetness: allulose. It's sugar — but in a form that our bodies don't convert into calories. Perfect? Not quite.
Researchers say findings may have important public health implications as vitamin supplements are relatively safe and cost-effective
Sarcoptic mange can leave southern hairy-nosed and bare-nosed wombats blind and deaf before eventually killing them
Annual vaccinations could be a thing of the past as scientists have successfully tested vaccines on animals infected with different strains of influenza
Remember winter, when everything was cold and grey? Right now, when all around is lush and green, the contrast couldn’t be greater. But is everything really as it seems? New research shows that we see things differently in winter compared with summer.
We now know how to turn fat cells into ones that burn calories as heat rather than store them – raising the prospect of a gene therapy for obesity
A growing body of research suggests that doctors' racial biases and other prejudices continue to affect the care patients received. Medical educators say self-awareness is an important first step.
A new study renews questions about how aggressively doctors should treat a very early form of breast cancer or pre-cancer.
Addyi gains US marketing licence after third attempt, but questions remain about its effectiveness, potential side-effects and the true need for the drug
Increasingly taken by healthy people to improve focus before exams, after a comprehensive review researchers say modafinil is safe in the short-term