Malaria drug for metabolic syndrome?

WASHINGTON, Nov. 13 (UPI) -- New research suggests metabolic syndrome, a disorder that affects one in four American adults, may be treatable with a malaria drug called chloroquine.

The drug's potential was discovered during animal studies of the rare genetic condition ataxia-telangiectasia (AT). The results are in the November issue of Cell Metabolism.

Researchers from Washington University School of Medicine in St. Louis and St. Jude Children's Research Hospital in Memphis found that a small amount of chloroquine relieved symptoms of the syndrome in mice. It worked by reducing blood pressure, decreasing hardening and narrowing of the arteries and improving blood-sugar tolerance.

"This research is significant because what began as the study of a rare disease, insulin resistant diabetes in children, has led to insight on a syndrome that affects a large portion of the population," said lead researcher Dr. Clay F. Semenkovich, professor of cell biology and physiology at Washington University.

The origins of the discovery go back six years, when Dr. Michael Katsan, director of the Cancer Center at St. Jude, and colleagues were investigating the type of diabetes that children with AT tend to have. This type of diabetes resembles metabolic syndrome because it is insulin resistant.

The genetic disorder, AT, is characterized by the deficiency or inactivation of the ATM enzyme. Both Katsan's and Semenkovich's labs found that a deficiency of ATM causes increased insulin resistance and atherosclerosis.

In the study, both mice with ATM and ATM-deficient mice, all of which had metabolic syndrome, were fed according to a typical, high-fat Western diet. When given chloroquine, mice with ATM had their symptoms reversed, while ATM-deficient mice showed no response to the drug. This, according to Semenkovich, suggests chloroquine had an effect on ATM.

They then found that chloroquine activates ATM. For more than 100 years, chloroquine has been used as a treatment for inflammatory diseases such as lupus and rheumatory arthritis. Because the symptoms of metabolic disease are also inflammatory, they decided to try the drug on mice that were ATM deficient.

"We're not trying to push chloroquine because it hasn't been proven yet in people, but our work suggests that the activation of ATM could prove to be a novel way to treat the disparate symptoms of metabolic syndrome," said Semenkovich.

Semenkovich noted that the biggest limitation of the study was that the results were tested on mice, which does not prove anything about humans. However, the researchers have tested small doses of chloroquine in a trial of five people with metabolic syndrome. The results were similar to those in mice: They proved to have enhanced insulin sensitivity after taking the chloroquine.

Although it is on the rise in industrialized countries, little is known about metabolic syndrome. Its symptoms include obesity, insulin resistance, high blood pressure, low levels of good cholesterol and high blood-sugar levels. Individuals with the syndrome are at higher risk for type 2 diabetes and heart disease.

"It's potentially interesting, and convincing data. The fact that there appears to be an interplay between ATM and insulin resistance is all new," Dr. Steven Shoelson, section head of cellular and molecular physiology at the Joslin Diabetes Center and professor of medicine at Harvard Medical School, said when asked to comment on the study.

He said since chloroquine is an approved drug it can be used in human trials, but in the long term it probably won't become the drug of choice for treating metabolic syndrome.

"While many adverse reactions have been attributed to chloroquine, perhaps the most disturbing is visual impairment. Retinopathy can be permanent and can continue to progress even after the drug has been discontinued. These points suggest that chloroquine could be used in clinical trials as a proof of principle, but it is less likely that chloroquine will find itself in the clinicians' armamentarium as a new treatment in patients with metabolic syndrome," Shoelson wrote in a separate article in this month's Cell Metabolism.

He speculated that further studies on chloroquine and ATM may lead to the development of a new, and hopefully better, drug to treat the syndrome.

A new clinical trial will be started pending approval from the National Institutes of Health. The trial will take a further look at chloroquine's effect on the hardening and narrowing of blood vessels.