IUPS/APS Newsroom March 29-April 6
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Pediatric Burn Victims’ Recovery, Diabetes Aided By Fenofibrate; Improved Mitochondrial Function Increases Glucose Metabolism

Treating insulin resistance directly could cut general trauma illness

San Diego (April 3, 2005) – One of the immediate serious results of sudden extreme trauma or stress, including burns and even surgery, is insulin resistance, or diabetes. As a result, healing is delayed, especially in the case of severe burns, and since the body is unable to fully use blood sugar for energy, muscle tissue is broken down as the body scavenges for other possible energy sources.

However, children with severe flame burns of more than 40% body surface area showed “significantly improved whole body glucose uptake -- almost to normal levels -- after a two-week course of treatment with fenofibrate,” according to lead researcher, Melanie Green Cree at the University of Texas Medical Branch, Galveston. (The UTMB trauma center last week treated about 20 adult victims, including several with burns from the British Petroleum refinery after an explosion that killed at least 15 workers and injured dozens more.)

Cree said trauma in children “seems to cause problems with fat metabolism, which in turn may cause insulin resistance. This insulin resistance can be ameliorated with 10-14 days of fenofibrate treatment, and it may significantly improve morbidity outcomes, healing rates, and decrease time spent in the intensive care unit.”

Going into the experiment, “we felt that the fat metabolism in the children may be deranged by their burns,” Cree said. “We hoped that improving fat metabolism with fenofibrate, which is traditionally used to lower plasma triglycerides, would improve the insulin sensitivity. There is conflicting data about the relationship between glucose and fat metabolism. However, acute burn trauma seriously affects both glucose and fat metabolism, and our results show that by increasing cell mitochondrial fat metabolism with fenofibrate (marketed as Tricor by Abbott Laboratories), glucose metabolism can also be improved,” Cree reported.

*Paper presentation: “Fenofibrate improves glucose metabolism in pediatric burns patients,” 12:30 p.m.-3 p.m. Sunday April 3, Physiology 361.2/board #A317. On view 7:30 a.m. - 4 p.m.  Cree is presenting the research at the 35th Congress of the International Union of Physiological Sciences in San Diego, March 31 - April 5, 2005. 

The entire research team includes: Melanie Green Cree, Alse Aarsland, David Chinkes, David N. Herndon and Robert R. Wolfe from the University of Texas Medical Branch and Shriners Hospital for Children, Galveston.

Surprising 70% of serious burn victims show high insulin resistance

Working with children at the Shriners Hospital for Children, Galveston, the team found that when the children were admitted, “a surprising 70% of children with greater than a 40% total body surface area flame burns have an insulin sensitivity almost half that of healthy children. We wanted to understand why this diabetes develops and to see if medication could reduce it,” Cree said.

The study involved 18 child burn victims ages 4 to 14 years of age who were admitted within four days of injury to the Shriners tertiary burn center in Galveston. They were studied four days after their first and third excision and grafting surgeries. The patients were randomly assigned either to placebo or fenofibrate treatment after the first procedure. The fenofibrate (FEN) patients received 5mg/kg of fenofibrate once daily for 11±2 days. Whole body insulin sensitivity was measured with a clamp technique; stable isotopes of glucose were used to measure liver glucose release and leg glucose uptake was calculated from arterial and venous samples. “Both the liver and the muscle in the leg were examined to try to understand which organs were responsible for the changes in insulin sensitivity, Cree explained.

After treatment, there was no change in the placebo group, but whole body glucose uptake during the clamp, the measure of insulin sensitivity, improved in the FEN group (p = 0.02). Insulin should prevent glucose release from the liver, but at one week following the burn, and before treatment, only 60% of release was prevented in either group. Following treatment, suppression of glucose release by the liver increased to over 70% of normal in the FEN group, whereas it dropped to 50% in the placebo group.  

Before treatment at one week post-burn, muscle did not respond much to insulin in terms of glucose uptake. After treatment with fenofibrate, insulin-stimulated glucose uptake improved in the FEN group, compared to no improvement in the placebo group.

Mode of operation and next steps, including non-burn trauma 

Results of the clinical experiment “lead to the conclusion that fenofibrate increases whole body glucose uptake in pediatric burn trauma patients, and appears to work by enhancing liver and muscle insulin sensitivity,” Cree said.

“Even greater implications would be to do similar studies in non-burn trauma patients or in surgical patents,” she added. “Currently, intensive care units nationwide have been instituting protocols to keep blood glucose levels normal during recovery. However, if the insulin resistance itself could be treated, rather than just the high glucose, the possibility exists for improved outcomes beyond the insulin treatment. This perhaps could mean faster recoveries and fewer deaths in many situations,” Cree said.

Already she said the research group is conducting “a high insulin protocol to tightly control blood glucose levels in the Shriners youth burn population, to see if the fenofibrate is more or less efficacious than this traditional high insulin treatment. At the same time, we are also partially blocking the stress response with a beta-blocker, and this also seems to improve insulin sensitivity,” Cree noted

Funding and background. Robert Wolfe, professor in the Department of Surgery and Anesthesia at UTMB, started studying the hypermetabolic effects of burns at the Shriners hospital for Children, Boston while at Harvard University. For the past 20 years he has worked with David Herndon at the Shriners Hospital for Children, Galveston.

This study was supported by an NIH grant.

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The 35th Congress of the International Union of Physiological Sciences is in San Diego, March 31 - April 5, 2005.  The Congress (http://www.iups2005.org/) is organized by the six member societies of the U.S. National Committee of the IUPS, the American Physiological Society, the Society for Neuroscience, the Microcirculatory Society, the Society of General Physiologists, the Biomedical Engineering Society, and the Society for Integrative and Comparative Biology, under the auspices of the U.S. National Academy of Sciences.

The IUPS conference, held every four years, runs concurrently this year with Experimental Biology 2005 at the San Diego Convention Center.

The American Physiological Society (APS), which is hosting IUPS, was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes nearly 4,000 articles every year in its 14 peer-reviewed journals. In May, APS received the Presidential Award for Excellence in Science, Mathematics and Engineering Mentoring (PAESMEM).

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Editor’s Note: For further information or to schedule an interview with a member of the research team, please contact Donna Krupa at the IUPS/APS newsroom @ 619.525.6228 (March 31-April 6), or (703) 967-2751 (cell) or (301) 634-7209 (office), or Stacy Brooks at 240.432.9697 (cell) or 301.634.7253 (office).

A searchable online program for IUPS and EB is at http://www.faseb.org/meetings/eb2005/call/default.htm

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