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
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
7-Nov-2006