21st Century Syndrome

Little exercise. Unhealthy foods. Poor lifestyle choices propagate a complex metabolic disorder. One drug shows promise to stem the tide of this growing problem.



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"Investigating the causes of rare diseases ... can contribute to understanding the mechanisms of more common diseases."
Michael B. Kastan, MD, PhD

Driven by high-fat diets and low-exercise lifestyles, metabolic syndrome is spreading rapidly across continents, age groups and ethnic lines, leaving millions at significantly increased risk of potentially life-threatening problems such as diabetes and heart disease.

The multiple risks associated with this 21st century syndrome make treatment complex: Various drugs can alleviate individual symptoms such as high cholesterol or blood pressure. But now researchers see potential for one drug to provide overall control by engaging the beneficial effects of a single protein.

Left: A greasy burger in one hand and the remote control in the other — both unhealthy choices. The impact of this "western lifestyle" is studied by (below on left) Clay F. Semenkovich, MD, and laboratory manager Trey Coleman, PhD, using mouse models.

"As a physician who sees many patients with metabolic syndrome and pre-diabetes conditions, modifying diet and lifestyle are going to continue to be the cornerstone of any therapeutic regimen," notes Clay F. Semenkovich, MD, the Herbert S. Gasser Professor and chief of the Division of Endocrinology, Metabolism and Lipid Research at Washington University and Barnes-Jewish Hospital. "But additional medications will certainly help."

The new treatment's discovery began in the laboratory of Michael B. Kastan, MD, PhD, director of the Cancer Center at St. Jude Children's Research Hospital in Memphis TN. Kastan, a medical school classmate of Semenkovich at Washington University, is a specialist in the treatment of the rare genetic disorder ataxia-telangiectasia (A-T).

A-T causes children to have markedly increased risk of tumors, immunological problems and severe progressive deterioration of a part of their brain that controls muscle function and coordination. When researchers linked A-T to a mutated gene, they named the protein made by the gene ataxia-telangiectasia mutated, or ATM.

Kastan has been investigating the function of ATM for years, and he and others have shown that it is activated by and helps repair DNA damage. Kastan began to suspect it might have links to insulin, because A-T causes a highly unusual form of diabetes in some cases.

"There were reports for years of kids with A-T who were small and thin and had diabetes syndromes that resembled those seen in patients who were obese," Semenkovich recalls. "Mike rediscovered this in the old literature, where it had never been explained, and started to do some studies to try to learn what was happening."

To test if the ATM-insulin connection means ATM plays a role in metabolic syndrome, Semenkovich and Kastan studied a mouse model with reduced levels of ATM and a genetic predisposition to heart disease. When they fed the mice a high-fat diet, the animals developed increased insulin resistance, atherosclerosis and higher levels of a signaling molecule linked to inflammatory processes—a close match for many of the symptoms seen in human metabolic syndrome.

From earlier research, Kastan knew that ATM's activities — helping cells survive stress and damage — could be increased by the anti-malarial drug chloroquine. Kastan and Semenkovich wondered if that meant chloroquine could prevent or delay metabolic syndrome in their mouse model. Their hunch paid off. In a paper published in Cell Metabolism last fall, they reported that a small dose of chloroquine, equivalent to about 40 milligrams given once a week for humans, reduced blood pressure, decreased hardening and narrowing of the arteries and improved blood sugar tolerance in mice.

Chloroquine has been in use for more than a century as an anti-malarial drug, and physicians already know it is safe and well-tolerated. That allowed Semenkovich to quickly begin the first human trials. With funding from the National Institutes of Health, he has started enrollment for a year of testing to see if small doses of chloroquine reduce damage to the arteries in human adults with metabolic syndrome.

Because this treatment could involve putting patients on regular chloroquine doses for extended periods, Semenkovich is conducting further mouse research to see if an even lower dose still provides beneficial effects.

He also wants to see whether ATM's connections to metabolic syndrome can be used to better understand the links between obesity, diabetes and autoimmune conditions.

"It's intriguing that chloroquine has been used in the past to treat autoimmune conditions like lupus and arthritis," he says. "Our data further suggest that there are links we don't fully understand between the metabolic dysfunctions triggered by obesity and the inflammatory processes that go awry in autoimmune disorders."

He expresses confidence that obtaining more details, such as how ATM fits into and enhances insulin signaling pathways, will pay off in insights into other conditions.

"ATM might be involved in multiple important metabolic diseases that we haven't even thought about yet," he notes.

Finally, Semenkovich also wants to follow up on prior studies conducted elsewhere that suggested another link between ATM and heart disease. The studies found that as many as one in every 50 to 100 people lacks one copy of the ATM gene. They also suggested that this genetic variation could expose carriers to increased risk of heart attack.

"We're looking into the possibility of screening for the loss of one copy of ATM in humans and are planning studies in animals to see if chloroquine can help reduce this risk," he says.

According to Kastan, "Our studies show 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."

"It's an amazing thing," Semenkovich says. "We started with the study of a disease that affects one birth in thousands, and that led us to insights into one of the most pervasive health problems of modern industrialized society."