Losartan prevents life-threatening insulin resistance in burn injuries

SAN FRANCISCO– 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.

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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 Mayer Resnick at 301.332.4402 (cell) or 301.634.7209 (office).

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The American Physiological Society was founded in 1887 to foster basic and applied bioscience. The Bethesda, Maryland-based society has more than 10,500 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.


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