Drug Prevents
Life-Threatening Insulin Resistance In Burn Injuries
SAN FRANCISCO (April 5, 2006) – Researchers have found
a way to prevent insulin resistance in burn-injured rats, a finding that,
while still quite preliminary, could eventually save burn victims’ lives and
speed their recovery.
The researchers honed in on the renin-angiotensin
system (RAS) as the key to preventing insulin resistance -- a unique line of
inquiry in burn research, according to lead author Sherry O. Kasper. About
70% of serious burn victims develop insulin resistance, a condition marked
by elevated levels of glucose and insulin.
Reversing the condition has the potential to reduce
mortality, length of stay in intensive care and infection rates among severe
burn patients, Kasper said. The American Physiological Society (APS)
awarded Kasper a Caroline tum Suden/Frances A. Hellebrandt Professional
Opportunity Award in recognition of the exemplary research. Kasper also
received the Mead Johnson Research Award in Endocrinology and Metabolism for
the best abstract in endocrinology and metabolism by a graduate student,
resident or postdoctoral fellow.
*Paper presentation: “Thermal injury
induced insulin resistance is associated with the renin-angiotensin system
(RAS)” 12:45 p.m.-3 p.m. Wednesday, April 5, Metabolism During Stress and
Trauma 928.2/board #D407. On view 7:30 a.m. – 3:30 p.m. Research was by
Sherry O. Kasper, Scott M. Castle, Brian J. Daley, Blaine L. Enderson,
Michael D. Karlstad, University of Tennessee Graduate School of Medicine,
Knoxville, TN.
Drug blocks RAS
Insulin resistance occurs when the body senses glucose
overload and attempts to reduce it by producing more insulin. When the
additional insulin is unable to moderate the glucose, the body releases even
more insulin. The result: elevated levels of both glucose and insulin.
Burn-related insulin resistance can last for months, Kasper said.
Kasper became interested in RAS while studying the
system as it relates to diabetes, blood pressure and aging. Karlstad, a
physiologist, is an expert in trauma and burn. Knowing that RAS plays an
important role in the development of insulin resistance in diabetic
patients, they theorized that blocking the RAS might prevent the condition
in burn patients.
“Our study shows that keeping blood glucose levels
normal can be done by treating the insulin resistance rather than by giving
more insulin, which opens the possibility for faster recoveries and improved
outcomes,” Karlstad said. The researchers used a simple but untried method
of preventing insulin resistance: they administered losartan, a drug which
blocks the RAS, to rats that received an insensate third-degree burn. An
insensate burn is one that damages nerves and prevents pain signals from
reaching the brain.
“Losartan treatment completely reversed the insulin
resistance of burn injury, returning it back to normal levels,” Kasper said
the study found. Burn-injured rats that did not receive the losartan showed
a 124% increase in insulin resistance while burn-injured rats that received
the treatment showed no evidence of insulin resistance. “This suggests that
insulin resistance caused by burn injury is due in part to the
renin-angiotensin system,” she said.
Glucose once thought
necessary to healing
Physiologists have long known that burn victims have
elevated blood glucose levels. Until recently, they thought the body needed
the additional glucose to heal the wounds. However, a recent study showed
that maintaining glucose at normal levels can decrease mortality and
diminish other negative outcomes of severe burns.
When glucose is not properly metabolized by the body,
it causes muscle breakdown, increases the chance of septicemia, and can harm
the lungs and kidneys, Kasper said. As a result of high glucose levels, burn
patients can suffer massive organ injury and organ failure.
“During burn injury, many changes occur in the body,
including changes in blood pressure and in the fluid inside the cells”
Kasper explained. “This activates the renin-angiotensin system.” The RAS
plays an important role in restoring blood pressure following hemorrhage and
plays a role in replenishing fluids to the body by increasing feelings of
thirst and fluid reabsorption by the kidneys, she said.
Too much glucose and
insulin
To test out the theory that blocking the RAS would
prevent insulin resistance, the researchers divided rats into three groups.
Two groups received an insensate burn. The third group served as a control
and did not receive a burn.
One burn group was given the losartan for three days;
the other burn group was given a placebo. The researchers gave all three
groups an oral glucose tolerance test on the third day and then monitored
blood glucose and insulin levels over 90 minutes.
The burn-placebo group showed insulin resistance rise
124%, Kasper said. The burn-losartan group showed no evidence of insulin
resistance and, in fact, the glucose and insulin levels for this group were
the same as the control group, which did not receive a burn.
“This is an extremely exciting finding with many
clinical possibilities for the future of burn injury treatment,” Kasper
said. The finding is still very preliminary, but if further studies bear it
out, the drug could eventually be given to burn patients to promote
healthier and speedier healing.
Another good thing, Kasper noted, is that losartan has
a clinical track record and its side effects are already known. The drug is
commonly prescribed to treat hypertension and has been particularly useful
with patients suffering both diabetes and hypertension.
Next steps:
Researchers want to get a more detailed molecular
picture of how the losartan works. They plan to look at how burns change
insulin signaling and how losartan corrects that change, Kasper said.
Funding: Merck & Co., Inc. and DuPont Co.
provided losartan potassium.
Editor’s Note: For
further information or to schedule an interview with a member of
the research team, please contact Christine Guilfoy at the APS newsroom @
415.905.1024 (March 31-April 5); or 978.290.2400 (cell) or after EB at
301.634.7253 (office) or
cguilfoy@the-aps.org; or Donna Krupa at (703) 967-2751 (cell) or
(301) 634-7209 (office).
Go to
http://www.faseb.org/meetings/eb2006/call/ and click on “Searchable
Program Planner and Itinerary Builder” to find the searchable online program
for EB.
* * *
The
American Physiological Society was founded in 1887 to foster basic and
applied bioscience. The Bethesda, Maryland-based society has more than
10,000 members and publishes 14 peer-reviewed journals containing almost
4,000 articles annually.
APS
provides a wide range of research, educational and career support and
programming to further the contributions of physiology to understanding the
mechanisms of diseased and healthy states. In May 2004, APS received
the Presidential Award for Excellence in Science,
Mathematics and Engineering Mentoring (PAESMEM).
# # #
Experimental Biology is an annual
scientific meeting convened by the Federation of American Societies of
Experimental Biology, including the American Physiological Society (APS)
and other biomedical societies. The meeting features “nominated” lectures,
symposia, research presentations, awards, a job placement center, and an
exhibit of scientific equipment, supplies, and publications. This year’s
participating Societies are APS, American Association of
Anatomists, American Society for Biochemistry and Molecular Biology,
American Society for Investigative Pathology, American Society for
Nutritional Sciences, and the American Society for Pharmacology and
Experimental Therapeutics.
