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Receptor Implicated in Diabetics’ Increased Risk of Heart Disease

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Duke Health News 919-660-1306

DURHAM, N.C. -- Duke University Medical Center researchers believe
that increased levels of a receptor and an inhibitory protein in the
heart may explain why heart disease patients with diabetes are at a
much greater risk of cardiovascular disease or heart attacks than
patients without diabetes.

The researchers found that while
levels of the protein, called Gαi, gradually increase with age, this
increase is almost twice as high in diabetic patients. This finding is
important, the researchers said, because elevated levels of this
receptor protein can lead to dilated cardiomyopathy, in which the heart
loses its ability to pump blood effectively throughout the body.
Untreated, this condition often leads to congestive heart failure.

Heart
disease is a major complication of diabetes, with about 70 percent of
deaths in patients with diabetes due to cardiac complications,
researchers said.

"We see an increase in the levels of
Gαi-coupled receptor in the heart as we age, but the increase is not
significant," said Duke pharmacologist Madan Kwatra, Ph.D., principal
investigator of a study whose results were published Aug. 26, 2004, in
the journal Diabetes. "However, when the effects of aging are combined
with the presence of diabetes, the increase becomes significant. In
addition, the study also found an increase in Gαi in atrium from
diabetic subjects.

"The results of our studies suggest a
molecular explanation for the increased risk of cardiac disease in
patients with diabetes, since increased activity of Gαi has been shown
to lead to the development of dilated cardiomyopathy," Kwatra said.
"This is the first demonstration of a diabetes-induced increase in Gαi
in the human heart."

Gαi mediates signaling through a family of G
protein-coupled receptors (GPCR), which are molecules on the cell
surface that respond to external hormones to affect cardiac function.
For example, beta-adrenergic receptors (βAR) -- which respond to the
hormones epinephrine and norepinephrine in the so-called
"fight-or-flight" response to increase cardiac output -- are also
members of this family. Gαi is one of a number of similar proteins that
can prevent these hormones from "coupling" to βARs, thereby decreasing
the heart's ability to contract.

Kwatra's team, which for years
has been studying the effects of age on GPCR signaling in the heart,
collected samples of human atria, the upper chambers of the heart, from
51 patients between the ages of 41 and 85, 95 percent of whom had Type
II diabetes. The patients had undergone surgery that required the use
of the heart-lung machine. In order to hook up the circulatory system
to the heart-lung machine, a small "plug" of atrial tissue must be
removed to attach the tubing.

For their experiments, the
researchers focused on cardiac muscarinic acetylcholine receptor
(mAChR), which works through Gαi to help regulate the autonomic
functioning of the heart. They measured the "density," or amount of
these receptors, in the atrial tissue of the patients with diabetes and
compared these findings to the levels of age-matched patients without
diabetes.

"We found that the cardiac mAChR density does increase
with age, but that the increase is statistically significant only in
the patients with diabetes," Kwatra explained. "These findings are
consistent with previous studies which have shown that the induction of
diabetes in animals enhanced the effects of mAChR on heart function."

Kwatra
added that evidence from other studies also shows that an increase
mAChR density in heart muscle cells can lead to arrhythmias, especially
atrial fibrillation, which can be life-threatening. People with
diabetes are known to have an increased incidence of atrial
fibrillation, he said.

Based on his research on human tissue and
animal models, Kwatra believes that changes in Gαi should be considered
when studying the underlying biochemical causes of heart disease.

Kwatra
plans further research to determine whether or not Gαi levels taken
from blood samples can be correlated with levels in the atria, as well
as studies of the ventricles, the other two pumping chambers of the
heart. In collaboration with Duke endocrinologist Mark Feinglos, M.D.,
the team will soon begin a study to measure levels of Gαi in the blood
cells of the patients with Type II diabetes.

"Beta-blockers,
which have been quite effective in improving the heart function of
patients with congestive heart failure, would seem to be a likely
candidate to reduce the risk of heart disease in people with diabetes
because these drugs have been shown to decrease cardiac Gαi levels,"
Kwatra said. "That class of drugs is already very well understood and
has very few side effects."

By blocking the stimulatory effects
of epinephrine and norepinephrine, beta-blockers reduce heart rate and
blood pressure. The drugs have been used for 20 years for different
ailments, but are primarily used to help treat high blood pressure,
chest pain, and heartbeat irregularities.

Kwatra's research was
supported by the National Institute of Aging, part of the National
Institutes of Health. Other Duke team members were Mark Richardson,
Ph.D., and Jason Kilts, Ph.D.

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