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Elizabeth Streich, 212-305-6535;
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Sept 17, 2007
NIH Awards $10.8 Million to
Investigating Connection between Diabetes & Heart Disease.
Cardiology, Endocrinology, Cell biology, Biostatistics Experts
Why Atherosclerosis Pervades Diabetic Arteries
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.
(Photo Credit: P. Constantinidis)
“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
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
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
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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