Studies of a rare genetic condition that increases cancer risk have unveiled a potential treatment for metabolic syndrome, a common disorder that afflicts as many as one in every four American adults and puts them at sharply increased risk of type 2 diabetes and clogged arteries.
Scientists know relatively little about metabolic syndrome, which is linked to a range of symptoms that include obesity, insulin resistance, high blood pressure, low levels of good cholesterol and high blood sugar levels. The number of adults and children with the condition is rising sharply in industrial countries, and diagnoses are also increasing in developing countries like India and China as they adopt Western standards of living.
In findings published in the November issue of Cell Metabolism, researchers at Washington University School of Medicine in St. Louis and St. Jude Children's Research Hospital in Memphis, Tenn. report that a small dose of the malaria drug chloroquine eased many symptoms of metabolic syndrome in mice, reducing blood pressure, decreasing hardening and narrowing of the arteries and improving blood sugar tolerance.
"We just received funding for a clinical trial, and we're very excited to see if the processes activated by chloroquine can effectively treat one of the most common health problems of modern industrialized society," says senior author Clay F. Semenkovich, M.D., professor of medicine and of cell biology and physiology at Washington University. "We already know that chloroquine is safe and well-tolerated, and our mouse results suggest we may only need very low and perhaps infrequent doses to achieve similar effects in humans."
Researchers elsewhere proposed recently that high doses of the anti-aging molecule resveratrol might similarly treat obesity and metabolic syndrome. However, it is unclear if such high doses are safe, and scientists know relatively little about how resveratrol is easing symptoms.
In contrast, the surprising chain of connections that led to the possibility of using chloroquine also has provided a fairly detailed sense for how the drug may be helping. That chain starts with a link between insulin and a protein known as ATM. Normally involved in the response to stress and repair of DNA, ATM is mutated in the rare genetic disorder ataxia-telangiectasia (AT). Individuals with this disease have markedly increased risk of tumors, immunological problems and severe progressive deterioration of a part of their brain that controls muscle function and coordination.
In the present study, the Washington University/St. Jude team demonstrated that the ATM enzyme is important for many of the beneficial effects of insulin and that loss of ATM worsens blood sugar control, high blood pressure and atherosclerosis.
"Our studies of ATM demonstrate how investigating the causes of rare diseases at a molecular level can contribute to understanding the mechanisms of more common diseases and point the way to new treatment options for those diseases," said Michael Kastan, M.D., Ph.D., director of the Cancer Center at St. Jude.
Kastan's laboratory discovered how ATM is activated in response to DNA damage. Six years ago, they were investigating an unusual type of diabetes that can occur in children with AT when they discovered that insulin can activate ATM. This observation led to studies in the Semenkovich lab showing the importance of ATM in metabolic syndrome. When the Kastan lab discovered that chloroquine can activate ATM, it provided a potential treatment intervention, the success of which is reported in this paper.
Prior studies done elsewhere had suggested that loss of one copy of the gene for ATM, a condition that could be present in one in every 50 to 100 people, increases risk of coronary artery disease and heart attack. The Kastan and Semenkovich labs found reduced ATM levels created a condition like metabolic syndrome in mice fed a high-fat diet and given a genetic predisposition to heart disease. Symptoms included increased insulin resistance and atherosclerosis and higher levels of a signaling molecule that activates a class of immune defensive cells known as macrophages.
"The data are starting to suggest that some of the metabolic dysfunctions triggered by obesity may be linked to the inflammatory responses that go awry in autoimmune disorders like arthritis," notes Semenkovich. "Chloroquine is sometimes used to treat autoimmune conditions like lupus and arthritis. Our studies provide further evidence for links between oxidative stress, inflammatory processes and common human diseases such as type 2 diabetes."
At low doses, chloroquine moderated many of the symptoms of metabolic syndrome in several mouse models of metabolic syndrome and type 2 diabetes. Researchers are still determining the exact details of how chloroquine and insulin signal through ATM, and those details could lead to additional treatment options for these disorders.
A pilot clinical trial at Washington University using low dose chloroquine in patients with symptoms of metabolic syndrome is showing promising results. A broader therapeutic trial that involves a year of low-dose chloroquine treatment will get under way soon. If it is successful, a multicenter trial will likely follow.
"We want to make sure we find the right dose--it may be possible to go even lower--and that it's safe and effective," Semenkovich says. "We're also looking into the possibility of screening for the loss of one copy of ATM in humans that unknowingly puts many at increased risk of heart attack and diabetes, and are planning studies in animals to see if chloroquine can help reduce this risk."
Schneider JG, Finck BN, Ren J, Standley KN, Takagi M, Maclean KH, Bernal-Mizrachi C, Muslin AJ, Kastan MB, Semenkovich CF. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. Cell Metabolism, November 2006.
This research was funded by the National Institutes of Health, the Burroughs-Wellcome Fund, and the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org.
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