Featured Research

from universities, journals, and other organizations

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

Date:
January 6, 2013
Source:
University of Pennsylvania School of Medicine
Summary:
Researchers 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.

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 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."

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 Universitι 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.


Story Source:

The above story is based on materials provided by University of Pennsylvania School of Medicine. Note: Materials may be edited for content and length.


Journal Reference:

  1. Russell A. Miller, Qingwei Chu, Jianxin Xie, Marc Foretz, Benoit Viollet, Morris J. Birnbaum. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature, 2013; DOI: 10.1038/nature11808

Cite This Page:

University of Pennsylvania School of Medicine. "Most-used diabetes drug works in different way than previously thought." ScienceDaily. ScienceDaily, 6 January 2013. <www.sciencedaily.com/releases/2013/01/130106145741.htm>.
University of Pennsylvania School of Medicine. (2013, January 6). Most-used diabetes drug works in different way than previously thought. ScienceDaily. Retrieved July 29, 2014 from www.sciencedaily.com/releases/2013/01/130106145741.htm
University of Pennsylvania School of Medicine. "Most-used diabetes drug works in different way than previously thought." ScienceDaily. www.sciencedaily.com/releases/2013/01/130106145741.htm (accessed July 29, 2014).

Share This




More Health & Medicine News

Tuesday, July 29, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Deadly Ebola Virus Threatens West Africa

Deadly Ebola Virus Threatens West Africa

AP (July 28, 2014) — West African nations and international health organizations are working to contain the largest Ebola outbreak in history. It's one of the deadliest diseases known to man, but the CDC says it's unlikely to spread in the U.S. (July 28) Video provided by AP
Powered by NewsLook.com
$15B Deal on Vets' Health Care Reached

$15B Deal on Vets' Health Care Reached

AP (July 28, 2014) — A bipartisan deal to improve veterans health care would authorize at least $15 billion in emergency spending to fix a veterans program scandalized by long patient wait times and falsified records. (July 28) Video provided by AP
Powered by NewsLook.com
Two Americans Contract Ebola in Liberia

Two Americans Contract Ebola in Liberia

Reuters - US Online Video (July 28, 2014) — Two American aid workers in Liberia test positive for Ebola while working to combat the deadliest outbreak of the virus ever. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
Traditional African Dishes Teach Healthy Eating

Traditional African Dishes Teach Healthy Eating

AP (July 28, 2014) — Classes are being offered nationwide to encourage African Americans to learn about cooking fresh foods based on traditional African cuisine. The program is trying to combat obesity, heart disease and other ailments often linked to diet. (July 28) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins