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Collaborative Grants 
Department of Medicine
| Researchers Seek the Heart of Diabetes heart and diabetes researchers explore common link between two diseases |
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“I would say these patients account for as many as 50 percent of those admitted by my team,” says Dr. Tabas. “They were not always admitted for their heart disease, but it is astounding how many patients in the hospital have diabetes and also suffer from heart disease.”
Cardiovascular disease is a potent killer in the United States, claiming the lives of one out of every three people. But heart disease is doubly dangerous for people with diabetes, killing two out of three Americans with diabetes. People with type 2 diabetes develop heart disease about eight years before the average American – and lose about eight years of life as a consequence.
Joining Forces
Now a unique trio of researchers at CUMC is delving more deeply into what underlies the connection. The partnership – Dr. Tabas, Alan Tall, M.D., professor of medicine, and Domenico Accili, M.D., professor of medicine – is one of the first that combines the expertise of atherosclerosis and diabetes researchers. It is supported by the National Heart Lung and Blood Institute.
People with diabetes tend to have types of “bad” cholesterol (apoB-containing lipoproteins, like LDL) that are particularly damaging to the arterial wall as well as low levels of “good” cholesterol (high density lipoproteins, or HDL). There also appear to be perturbations in the arterial wall itself that make diabetics more susceptible to lipoprotein problems. For example, an LDL of 100 mg/dl is associated with a relatively low risk of heart disease in most people without diabetes. But because diabetes renders someone so susceptible to atherosclerosis, a “low” LDL of 70 mg/dl may still be high enough to cause atherosclerosis. Some with diabetes are probably not protected from heart disease until their LDL is below 40 mg/dl.
“What really accelerates heart disease is insulin resistance, but we don’t know why,” Dr. Tabas says. “Though there has been a great deal of interest in understanding the role of insulin resistance in atherosclerosis, surprisingly little work has been done because the area falls between two distinct fields of research.”
The group’s cooperative efforts have already led to one possible explanation for the way insulin resistance speeds atherosclerosis. An atherosclerotic plaque is most dangerous when it ruptures and a clot forms over the lesion. Plaque rupture is thought to accelerate the death of macrophages, leading to dangerous necrosis of the plaque. Dr. Tall noticed reports in the literature that macro-phages are normally studded with insulin receptors that tend to keep the macrophages alive and healthy. The researchers discovered that in diabetes the macrophages have less active receptors and thus should be more susceptible to cell death.
“It piqued our interest because autopsies show more macrophage death and plaque necrosis than average,” Dr. Tabas says. “We wondered if insulin resistance in macrophages leads to the death of these cells.”
With the help of Dr. Accili, who developed a mouse model with insulin-resistant macrophages, the group found these mice had more macrophage death and plaque necrosis than normal mice. This work was published in the April 2006 issue of Cell Metabolism.
“The idea that insulin resistance of macrophages may be crucial in raising the risk of heart disease in diabetes is completely new and would not have been possible without collaboration between atherosclerosis and diabetes researchers,” Dr. Tabas says.
The new grant allows the researchers to continue to unravel the molecular details between insulin resistance and macrophage death, as well as ways insulin resistance leads the liver to produce an unfavorable mix of lipoproteins.
“The goal is to find a drug to slow the atherosclerotic process in diabetes patients,” Dr. Tabas says. “Once we combine a therapy directed at the plaque with lowering LDL, we should get a big effect on lowering heart disease in this susceptible and ever-increasing population.”
—Susan Conova
