NEW YORK –A multidisciplinary team of researchers from Columbia University Medical Center has received a $10.8 million, five-year Program Project Grant (PPG) from the National Institutes of Health to investigate why people with type 2 diabetes are dangerously susceptible to heart disease, the leading cause of death for people suffering from diabetes.
In a 2006 Nature Medicine op-ed, Elizabeth (Betsy) G. Nabel, M.D., director of The National Heart Lung and Blood Institute (NHLBI) and Allen M. Spiegel, M.D., then director of The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), called for researchers from different disciplines to study the two top killers of Americans – diabetes and heart disease – in a more unified fashion and specifically to investigate the connection between insulin signaling and atherosclerosis.
Ira Tabas, M.D., Ph.D., professor and vice-chairman of research in the Department of Medicine at Columbia’s College of Physicians & Surgeons, Alan Tall, M.D., a professor of medicine in the Division of Molecular Medicine, and Domenico Accili, M.D., a professor of medicine and the co-director of research at CUMC’s Naomi Berrie Diabetes Center, answered that call. The three investigators bring distinctly unique expertise in their respective disciplines and years of experience to bear on the problem of atherosclerosis and its effects on diabetes.
“The worldwide epidemic of obesity has led to staggering rates of type 2 diabetes and, in turn, the deadly consequences of heart disease,” said Dr. Tabas, the grant’s principal investigator. “If we could better understand the role that insulin resistance plays in the progression of atherosclerosis, we may be able to develop therapies to prevent the serious consequences from both of these diseases.”
Expansion of Earlier Work on Macrophage Death’s Link to Atherosclerosis
The molecular and cellular mechanisms linking the insulin resistance found in diabetics to atherosclerosis are presently poorly understood. Columbia researchers will use this grant to identify pathways that contribute to accelerated atherosclerotic lesion progression in insulin-resistant states. They will focus on two cell types – macrophages and hepatocytes.
Earlier research led by Dr. Tabas explained what causes the death of macrophages, the white blood cells that accumulate in the cholesterol-laden plaques in arteries of patients with atherosclerosis. Those dead macrophages pile up to form what Dr. Tabas calls a “macrophage graveyard” or necrotic core causing plaque rupture. The rupture can stimulate the formation of clots that can block blood flow and cause heart attacks and strokes. According to Dr. Tabas, the biggest danger in atherosclerosis comes not so much from the plaque growing to a point that it blocks the artery, as is often believed, but rather from smaller plaques becoming unstable and prone to rupture. According to Dr. Tabas, it turns out that plaques from subjects with diabetes have larger necrotic cores, raising the possibility that amplified plaque macrophage death is an important factor in the higher rate of heart disease in diabetics.
Dr. Tall, working with Drs. Tabas and Accili, focused on the fact that macrophages ordinarily contain insulin receptors, but patients with type 2 diabetes are insulin-resistant, meaning these receptors function poorly. The Columbia researchers found in earlier research, published in Cell Metabolism in 2006, that more macrophage death and plaque necrosis occurred in a mouse model of macrophage insulin resistance. This suggests that in patients with type 2 diabetes, insulin resistance promotes macrophage death, which can lead to atherosclerosis.
Exploring Role of Lipoproteins, Insulin Action on Artery Degeneration
Dr. Tall’s laboratory uses molecular, genomic and cellular approaches to investigate basic aspects of the pathogenesis of atherosclerosis. In addition to working with Dr. Tabas on macrophage death pathways, Dr. Tall will work with Dr. Accili to investigate pathways involved in production of lipoproteins, such as very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL, often called bad cholesterol), in insulin–resistant states. This will offer clues as to how high atherogenic lipoprotein levels contribute to heart disease in people with diabetes.
Dr. Domenico Accili ’s research is focused on the pathogenesis of insulin action and resistance and its role in type 2 diabetes. He plans to use new mouse models to investigate potentially pro-atherogenic or plaque-causing insulin actions in the liver and macrophages as part of this NIH grant. Dr. Accili’s lab has recently shown that insulin action in liver, brain and beta cells is sufficient to confer insulin sensitivity onto the whole organism and protect against the development of diabetes in mice.
In addition, the lead investigators will call upon the biostatistical and mouse modeling expertise of Carrie L. Welch, Ph.D., associate research scientist, and Rajasekhar Ramakrishnan, Sc.D., research scientist and acting director of the division of biomathematics, to help with the design and analysis of mouse phenotype data and microarray experiments.
This program project grant is jointly funded by the NIDDK the NHLBI. The NIH program project grant mechanism is designed to support research in which the funding of several interdependent projects as a group offers significant scientific advantages over support of these same projects as individual regular research grants.
Heart Disease & Diabetes Stats
Chronic heart disease - usually caused by atherosclerosis or fatty deposits in the inner walls of the arteries that carry blood throughout the body from the heart - can lead to heart attacks, stroke and sudden death. Heart disease accounts for 65 percent of diabetic deaths each year, according to NIDDK. NIDDK estimates that adults with diabetes have heart disease death rates about two to four times higher than adults without diabetes. The risk for stroke is two to four times higher among people with diabetes.
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