Malaria drug may treat metabolic syndrome's many symptoms

A drug used for decades to treat and prevent malaria might also fight the many symptoms of metabolic syndrome, a potentially disabling condition that is estimated to affect as many as a quarter of American adults. The findings appear in the November 2006 issue of the journal Cell Metabolism, published by Cell Press.

Researchers, led by Clay F. Semenkovich of Washington University School of Medicine and Michael B. Kastan of St. Jude Children's Research Hospital, found in studies of mice that the antimalaria drug chloroquine improved symptoms of metabolic syndrome; the drug reduced atherosclerosis, lowered blood pressure, and improved blood sugar tolerance. Chloroquine works by activating a particular stress pathway that mediates susceptibility to the syndrome, they found.

"In animals, activating this pathway with extremely low doses of chloroquine counteracted many of the features of metabolic syndrome," said Semenkovich. Semenkovich said he expects to begin a clinical trial of the drug's utility for curbing metabolic syndrome in human patients very soon.

Often associated with insulin resistance, metabolic syndrome can include five components: high triglycerides, low "good" cholesterol, high blood pressure, high blood sugar, and central obesity--characterized in men by a pants waist size of 40 or greater, Semenkovich said. Patients who exhibit three of the five components fit the criteria for metabolic syndrome.

The condition is also associated with atherosclerosis, leaving patients at increased risk of death from cardiovascular disease, the researchers said.

Rather than representing "a unique entity," some have suggested that the metabolic syndrome may simply reflect the cumulative contribution of its components to atherosclerotic risk, the researchers said. An alternative view is that atherosclerosis, insulin resistance, and the component clinical features of the metabolic syndrome share a common unifying mechanism, they added.

Evidence hinting at a unified mechanism came a few years ago with the discovery that people with the rare genetic condition called ataxia telangiectasia exhibit signs of insulin resistance. The disease is caused by ATM (Ataxia Telangiectasia Mutated), and those with one copy of the mutant gene are also at greater risk of vascular disease.

In the current study, the researchers set out to further explore the connection between ATM deficiency, insulin resistance, and heart disease.

They found that mice deficient for ATM, when fed a high-fat, "Western diet," develop symptoms that resemble metabolic syndrome. Cells lacking ATM also showed greater amounts of an enzyme known as JNK, which has been linked to insulin resistance, they reported.

They then found that treatment with a low dose of the ATM activator chloroquine reversed symptoms of metabolic syndrome in vascular disease-prone mice on a high-fat diet. The mice had a normal complement of ATM genes, which enabled them to respond to the drug, the researchers explained. Chloroquine also led to a decline in JNK activity in immune cells.

The results uncover a potential role for ATM deficiency in the development of the metabolic syndrome, they said. They also "provide proof of principle that modulating ATM-dependent signaling with low doses of chloroquine, comparable to 40 milligrams per week in a 70 kilogram human, reduces vascular disease." By comparison, Semenkovich said, physicians typically prescribe 250 milligrams of chloroquine each day for the treatment of malaria.

The findings could lead to significant changes in the approach toward treating metabolic syndrome, he said.

Treatment today is generally "limited to therapies for the disparate components of the syndrome: hypertension, hyperglycemia, obesity, and dyslipidemia," he added. While many of those individual drugs may be beneficial, Semenkovich said, drugs like chloroquine that activate the ATM pathway may offer a "unifying treatment to address a central process of the disease."

While he cautioned patients against taking chloroquine for metabolic syndrome just yet, the findings do suggest "that modulation of ATM-dependent signaling with chloroquine represents a potential treatment" for the condition. The results should also encourage a search for other small molecules that might target ATM without the malaria drug's potential side effects.

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Schneider et al.: "ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome." Publishing in Cell Metabolism 4, 377389, NOVEMBER 2006 DOI 10.1016/j.cmet.2006.10.002 www.cellmetabolism.org

The researchers include Jochen G. Schneider, Brian N. Finck, Jie Ren, Kara N. Standley, Carlos Bernal-Mizrachi, Anthony J. Muslin, and Clay F. Semenkovich of Washington University School of Medicine in St. Louis, MO; Masatoshi Takagi, Kirsteen H. Maclean, and Michael B. Kastan of St. Jude Children's Research Hospital in Memphis, TN. This work was supported by the National Institutes of Health (P50 HL083762, AG20091, HL57278, CA71387, CA21765, ES05777), the Clinical Nutrition Research Unit (DK56341), the Diabetes Research and Training Center (DK20579), a Burroughs Wellcome Clinical Scientist Award in Translational Research, and by the American Lebanese Syrian Associated Charities (ALSAC) of the St. Jude Children's Research Hospital.


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