Therapeutic Management of Burn Induced Hyperglycemia with Insulin and Metformin

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Burn injury afflicts approximately 450,000 individuals annually in the United States. Despite efforts to decrease incidence via implementation of public awareness campaigns and drastic improvements in living conditions, nearly 11 million people worldwide required treatment at a major burn center or hospital in 2004. Sustained hypermetabolism and hypercatabolism are notorious changes associated with severe burn injury. Anchored within these pathophysiological changes is the development of hyperglycemia and insulin resistance. These perturbations in metabolism may persist for up to three years following burn injury and are well-established contributors to post burn morbidity and mortality. Accordingly, the implementation of tight glycemic control protocols in burn centers across the nation ensued. Insulin administration has been shown to attenuate the hyperglycemic response to burn injury. Moreover, it is thought that insulin may improve auxiliary components of hypercatabolism, indicative of insulin’s anabolic properties. However, a drawback associated with insulin administration is the development of hypoglycemia which has led to the search for alternative glucose modulating agents. Metformin, a well-known anti-hyperglycemic agent, has been shown to decrease burn induced hyperglycemia in adults. Relative euglycemia was attained by use of metformin exclusive of the adverse effects associated with insulin administration (hypoglycemia). However, the safety and efficacy of metformin in pediatric burn patients has not been investigated. Moreover, at large doses metformin is a known complex I inhibitor of the electron transport chain. Whether or not these alterations in mitochondrial respiration persist at clinically relevant dosages in pediatric burn patients remains unknown. We hypothesize that insulin attenuates hypercatabolism independent of glucose modulating effects, and that metformin will safely attenuate hyperglycemia and associated metabolic changes in severely burn injured children. We will test this hypothesis in two specific aims. By use of a prospective study design, in the first aim we will determine the clinical effects of insulin vs. no insulin therapy in children with severe burn injury. Patients will be divided into two groups: those who receive insulin to decrease serum blood glucose levels and those who did not require insulin administration. In the second aim, we will investigate the novel use of metformin or placebo in pediatric burn patients in a prospective, randomized control trial. This IRB-approved clinical trial will be the first of its kind in determining safety and efficacy profiles of metformin in pediatric burn patients. Outcomes to be collected in both aims include (but are not limited to) parameters pertaining to glucose homeostasis and insulin resistance, body composition, metabolic changes, growth, incidence of infections and sepsis, and mortality. Upon completion of this project, we will improve our understanding of glucose homeostasis and the therapeutic modulators which control the hyperglycemic response to burn injury in children. If metformin is found to safely improve clinical outcomes similar to insulin (barring hypoglycemia), we will implement the use of metformin in our pediatric patients to alleviate hyperglycemia following burn injury.

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Burn, Insulin resistance, Pediatrics, Insulin, Metformin
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