For several years, researcher have known that high levels of insulin and insulin-resistance are associated with fatty liver, an untreatable condition that can lead to chronic liver disease and death. But it remained unclear whether this insulin connection played a direct role in the development of the liver disorder. Taking its possible role as a cue, however, Hopkins researcher Anna Mae Diehl, M.D., wondered whether the drug metformin, a diabetes drug that sensitizes the body to the effects of insulin, might prove effective in fighting the condition. To find out, Diehl and colleagues in her lab gave the drug to obese, insulin resistant mice who had fatty livers and compared them with similar mice who did not receive the drug. The result? Mice given the metformin were fully cured of their fatty liver (nature Medicine, September 2000).
“We found that the drug completely cured fatty liver in mice, which we didn’t expect,” Diehl says. “That means metformin may help treat fatty liver disease in patients with obesity-related insulin resistance,” she adds, noting that 30 to 50 percent of diabetes patients have the liver disorder.
How did metformin work? Diehl discovered from postmortem blood samples that mice given the drug had lower levels of tumor necrosis factor alpha (TNF alpha) in their livers than those who were not. TNF alpha, a protein produced by the body during inflammation, also promotes insulin-resistance. So it appears that the drug works by inhibiting liver production of TNF alpha, thus improving liver insulin resistance.
“What if we had a treatment that will improve that insulin sensitivity in these animals? Will it get rid of the liver disease? It turns out metformin does,” says Diehl, who is planning human trials of the drug.