Insulin Sensitivity and Mitochondrial Function Are Improved in Children With Burn Injury During a Randomized Controlled Trial of Fenofibrate

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Abstract
To determine some of the mechanisms involved in insulin resistance immediately following burn trauma, and to determine the efficacy of PPAR-alpha agonism for alleviating insulin resistance in this population. Hyperglycemia following trauma, especially burns, is well documented. However, the underlying insulin resistance is not well understood, and there are limited treatment options. Twenty-one children 4 to 16 years of age with >40% total body surface area burns were enrolled in a double-blind, prospective, placebo-controlled randomized trial. Whole body and liver insulin sensitivity were assessed with a hyperinsulinemic-euglycemic clamp, and insulin signaling and mitochondrial function were measured in muscle biopsies taken before and after approximately 2 weeks of either placebo (PLA) or 5 mg/kg of PPAR-alpha agonist fenofibrate (FEN) treatment, within 3 weeks of injury. The change in average daily glucose concentrations was significant between groups after treatment (146 +/- 9 vs. 161 +/- 9 mg/dL PLA and 158 +/- 7 vs. 145 +/- 4 FEN; pretreatment vs. posttreatment; P = 0.004). Insulin-stimulated glucose uptake increased significantly in FEN (4.3 +/- 0.6 vs. 4.5 +/- 0.7 PLA and 5.2 +/- 0.5 vs. 7.6 +/- 0.6 mg/kg per minute FEN; pretreatment vs. posttreatment; P = 0.003). Insulin trended to suppress hepatic glucose release following fenofibrate treatment (P = 0.06). Maximal mitochondrial ATP production from pyruvate increased significantly after fenofibrate (P = 0.001) and was accompanied by maintained levels of cytochrome C oxidase and citrate synthase activity levels. Tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 in response to insulin increased significantly following fenofibrate treatment (P = 0.04 for both). Fenofibrate treatment started within 1 week postburn and continued for 2 weeks significantly decreased plasma glucose concentrations by improving insulin sensitivity, insulin signaling, and mitochondrial glucose oxidation. Fenofibrate may be a potential new therapeutic option for treating insulin resistance following severe burn injury.