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VA RESEARCH MAY CAUSE RETHINKING OF TREATMENT
ON PATIENTS IN DIABETIC COMA -- Glucose
triggers
brain cell death in rats after hypoglycemic
coma.
Story here...
http://pub.ucsf.edu/
newsservices/releases/200704042/
Story below:
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Glucose triggers brain cell death in rats after
hypoglycemic coma
Brain damage that was thought to be caused by
hypoglycemic coma actually occurs when glucose is administered to treat
the coma, according to a study in rodents led by researchers at the San
Francisco VA Medical Center.
The results are surprising, say the authors, and may be of clinical
significance for the treatment of diabetics in hypoglycemic coma, though
they caution that the results cannot be immediately extrapolated to
humans.
Insulin is an essential hormone that moves glucose from the bloodstream
to individual cells, where it is broken down and used for energy.
Diabetics do not produce enough of their own insulin and must take it
several times a day.
A severe insulin overdose can reduce levels of glucose in the blood to
extremely low levels –– a condition known as hypoglycemia –– and cause
hypoglycemic coma, resulting in destruction of neurons in the
hippocampus and cerebral cortex, which are essential to memory and
cognition.
“This study tells us for the first time that, in rats, the brain damage
occurs not during the coma, but after it, when we give them glucose and
their blood glucose levels return to normal,” says principal
investigator Raymond A. Swanson, MD, chief of the neurology and
rehabilitation service at SFVAMC.
Furthermore, says Swanson, he and his fellow researchers have identified
the cause of the damage: the sudden return of glucose to the brain
activates the enzyme NADPH oxidase, which in turn initiates a process of
oxidative stress that is fatal to neurons.
Oxidative stress occurs when cells are poisoned by highly reactive forms
of oxygen. Previously, it had been assumed that oxidative stress in
neurons was initiated primarily by mitochondria, which process oxygen
for energy within cells.
The paper appears in the April 2007 issue of the Journal of Clinical
Investigation.
In their study, the researchers subjected rodents to a model of severe
hypoglycemic coma. “The rats could remain hypoglycemic without evidence
of significant oxidative stress for at least 60 minutes,” says Swanson,
who is also professor and vice-chair of neurology at the University of
California, San Francisco. “It was only when we gave them glucose to
reverse the hypoglycemia that the oxidative stress occurred. This was a
real surprise.”
The researchers then discovered that oxidative stress and neuron death
were prevented when the rats were given an inhibitor of NADPH oxidase,
indicating a key role for this enzyme.
“It is well-established that mitochondria can be a source of oxidative
stress,” says Swanson. “But in this setting, oxidative stress comes from
an entirely different source.” He adds that the normal role of NADPH
oxidase in the brain is “completely unknown.”
The authors also found that the degree of oxidative stress was directly
dependent upon the amount of glucose given. “We think that this stems
from a known link between glucose and NADPH oxidase,” Swanson says.
“Glucose is a precursor for NADPH, which in turn is used by NADPH
oxidase in generating oxidative stress.”
Swanson explains that the results have implications for both basic and
clinical science. For basic science, he says, “this calls for a
reconsideration of our concepts about the causes of oxidative stress in
other settings –– especially in ischemic stroke, where the blood supply
to the brain is diminished and there’s a big burst of oxidative stress
when the blood returns. That burst has always been blamed on oxygen, but
it may be that glucose is the culprit. And it may depend on how much
glucose is put in.”
In terms of clinical science, Swanson observes that “as clinicians, our
first reaction when we see a patient in hypoglycemic coma is to give
lots of glucose, fast. But our rodent model makes it clear that
overshooting glucose levels is very bad for rat brains. The way we treat
patients for hypoglycemia may have to be reevaluated.”
Swanson adds two strong cautions, however: “First, the work was done in
rodents, and it is not legitimate to immediately extrapolate these
findings to humans. Second, there are many ways to go wrong in humans by
not treating hypoglycemia aggressively enough. The results of this one
paper do not mean that clinicians should take an overly cautious
approach to hypoglycemic coma.”
In his own current research, Swanson is investigating the possible roles
of glucose and NADPH oxidase as agents of oxidative stress in a rodent
model of ischemic stroke. “So far, the results are very promising,” he
says.
Co-authors of the paper are Sang Won Suh, MD, PhD, Elizabeth T. Gum, MS,
and Aaron M. Hamby, BS, of SFVAMC and UCSF, and Pak H. Chan, PhD, of
Stanford University School of Medicine.
The research was supported by the Department of Veterans Affairs and by
grants from the Juvenile Diabetes Research Foundation (JDRF) and the
National Institutes of Health (NIH). The JDRF grant and the NIH grant to
Swanson were administered by the Northern California Institute for
Research and Education (NCIRE).
NCIRE - the Veterans Health Research Institute - is the largest research
institute associated with a VA medical center. Its mission is to improve
the health and well-being of veterans and the general public by
supporting a world-class biomedical research program conducted by the
UCSF faculty at SFVAMC.
SFVAMC has the largest medical research program in the national VA
system, with more than 200 research scientists, all of whom are faculty
members at UCSF.
UCSF is a leading university that advances health worldwide by
conducting advanced biomedical research, educating graduate students in
the life sciences and health professions, and providing complex patient
care.
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Larry Scott --
