Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate

Abstract

Objective: 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.

Summary background data: Hyperglycemia following trauma, especially burns, is well documented. However, the underlying insulin resistance is not well understood, and there are limited treatment options.

Methods: 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.

Results: 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).

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT00361751.

FIGURE 1. A, Overall study design. OR, operation. B, Infusion study design.

FIGURE 2. A, Mean daily plasma glucose concentrations in mg/dL before and after treatment. The change between FEN and PLA was significant (*P = 0.004). B, Glucose infusion rate in mg/kg per minute during a hyperinsulinemic-euglycemic clamp is shown before and after treatment. The infusion rate, and thus insulin sensitivity, was significantly (*P = 0.003) increased after fenofibrate treatment. C, Suppression of hepatic glucose output during hyperinsulinemia as compared with basal. The percent suppression of endogenous glucose output was almost greater after fenofibrate treatment (P = 0.06). D, Total glucose uptake (endogenous and exogenous) during the hyperinsulinemia in mg/kg per minute. Uptake was significantly greater after fenofibrate (*P = 0.002).

FIGURE 3. A, Change from pretreatment to posttreatment in the ability of muscle citrate synthase to metabolize acetyl-CoA (μmol acetylCoA/μg protein per minute) (*P = 0.01). B, Change in the capacity of cytochrome C oxidase to metabolize cytochrome C (μmol cytochrome C/μg protein per minute) (*P = 0.01). C, State 3 coupled muscle mitochondria maximal pyruvate oxidative capacity (μmol O₂ /mg protein per minute) There was a significant increases in ATP production after fenofibrate treatment (*P = 0.001), whereas there was a decrease in the PLA group (*P = 0.006).

FIGURE 4. A, Change in phosphorylation of muscle insulin receptor from basal to clamp on the study days before and after either placebo of fenofibrate treatment, expressed as arbitrary band absorption measurements. Insulin stimulated phosphorylation was significantly increased following fenofibrate (*P = 0.04). B, Change in phosphorylation of muscle insulin receptor substrate: 1 from basal to clamp on the study days before and after either placebo off fenofibrate treatment expresses as arbitrary band absorption measurements. Insulin-stimulated phosphorylation was significantly increased following fenofibrate (*P = 0.04).

FIGURE 5. Glucose enters the mitochondria as pyruvate, and typically becomes acetyl CoA before entering the TCA cycle, where carbons are released for entry into the electron transport chain. Here either ATP or H free radicals are made. In burns, it may be that more free radicals are made relative to ATP primarily to generate more heat through uncoupling protein 1 (UCP-1), but that also creates reactive oxygen species (ROS), that in turn cause TNF-α production, and activation of protein kinase C (PKC), which inhibits insulin signaling. Further, if the TCA cycle is decreased, acetyl CoA can leave the mitochondrial and become malonyl CoA, which also activates PKC. Fenofibrate may work by increasing the ratio of glucose turned into ATP, thereby decreasing PKC activity though decreasing TNF-α and malonyl CoA.