August 30, 2000
Studies in mice show that a drug used to treat diabetes, called metformin, may be helpful in combating a common and potentially fatal liver disorder. The discovery, reported in the September issue of Nature Medicine, may lead to the development of the first drug to treat people who suffer from the condition known as fatty liver, the researchers say.
"We found that the drug completely cured fatty liver in mice. We didn't expect results this good," says Anna Mae Diehl, M.D., a professor of medicine at Johns Hopkins and principal investigator of the study. "Our results indicate that metformin may help treat fatty liver disease in patients with obesity-related insulin resistance. This is a large majority of patients with the disorder, perhaps as many as 30 to 50 percent."
Almost a quarter of adults in many industrialized countries suffer from excessive fat accumulation in the liver, a condition associated with obesity and type 2 diabetes. The disorder can lead to chronic liver disease, and once liver disease develops, it becomes one of the most common causes of death in this population. Currently, no drug treatments exist, and marginally useful therapies rely on dieting and exercise.
For several years, researchers have known that high levels of insulin and insulin-resistance are associated with fatty liver but it remained unclear whether or not these alterations played a direct role in the development of the liver disorder. Taking its possible role as a cue, however, Diehl and her colleagues wondered whether the drug metformin, which sensitizes the body to the effects of insulin, might prove effective against fighting the condition. To find out, they gave the drug to obese, insulin resistant mice who had fatty livers and studied them in comparison with similar mice who did not receive the drug.
The researchers discovered that mice who took the metformin were cured of their fatty liver completely. Although the drug is known to decrease appetite and over-eating has been shown to encourage the formation of fatty liver, the researchers found that modestly restricting calorie intake did little to improve the fatty liver problem in these mice.
To investigate how metformin worked, Diehl and her colleagues examined tissue and blood samples collected post mortem and discovered that mice who had taken the drug had lower levels of tumor necrosis factor alpha (TNF alpha) in their livers than those who had not. TNF alpha is a protein produced by the body during inflammation. It also promotes insulin-resistance. The scientists speculate that the drug works by inhibiting liver production of TNF alpha, thus improving liver insulin resistance and its consequences, including lipid accumulation in the liver.
"Although these studies are preliminary, our data justify cautious evaluation of metformin as a treatment for fatty liver disease," says Diehl. "And although one of the side effects of this drug is lactic acidosis, a build up of lactic acid, which is more serious in people with liver disease, we found no evidence of toxicity in the mice we studied." The researchers next plan to test the drug in other animal models.
To learn more about gastrointestinal disorders, visit http://www.hopkins-gi.org. Other authors of the study include Hui Zhi Lin, Shi Qi Yang, Christine Chuckaree, Francis Kuhajda, and Gabriele Ronnet from Hopkins.