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

Melanie G. Cree, Jennifer J. Zwetsloot, David Herndon, Ting Qian, Beatrice Morio, Ricki Fram, Arthur P. Sanford, Asle Aarsland, Robert R. Wolfe

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Abstract

OBJECTIVE: To determine some of the mechanisms involved in insulin resistance immediately following burn trauma, and to determine the efficacy of PPAR-α 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 ∼2 weeks of either placebo (PLA) or 5 mg/kg of PPAR-α 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.

Original languageEnglish (US)
Pages (from-to)214-221
Number of pages8
JournalAnnals of Surgery
Volume245
Issue number2
DOIs
StatePublished - Feb 2007

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Fenofibrate
Insulin Resistance
Randomized Controlled Trials
Wounds and Injuries
Insulin
Glucose
Placebos
Peroxisome Proliferator-Activated Receptors
Therapeutics
Insulin Receptor Substrate Proteins
Citrate (si)-Synthase
Glucose Clamp Technique
Body Surface Area
Liver
Insulin Receptor
Electron Transport Complex IV
Pyruvic Acid
Burns
Hyperglycemia
Tyrosine

ASJC Scopus subject areas

  • Surgery

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Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate. / Cree, Melanie G.; Zwetsloot, Jennifer J.; Herndon, David; Qian, Ting; Morio, Beatrice; Fram, Ricki; Sanford, Arthur P.; Aarsland, Asle; Wolfe, Robert R.

In: Annals of Surgery, Vol. 245, No. 2, 02.2007, p. 214-221.

Research output: Contribution to journalArticle

Cree, MG, Zwetsloot, JJ, Herndon, D, Qian, T, Morio, B, Fram, R, Sanford, AP, Aarsland, A & Wolfe, RR 2007, 'Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate', Annals of Surgery, vol. 245, no. 2, pp. 214-221. https://doi.org/10.1097/01.sla.0000250409.51289.ca
Cree, Melanie G. ; Zwetsloot, Jennifer J. ; Herndon, David ; Qian, Ting ; Morio, Beatrice ; Fram, Ricki ; Sanford, Arthur P. ; Aarsland, Asle ; Wolfe, Robert R. / Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate. In: Annals of Surgery. 2007 ; Vol. 245, No. 2. pp. 214-221.
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abstract = "OBJECTIVE: To determine some of the mechanisms involved in insulin resistance immediately following burn trauma, and to determine the efficacy of PPAR-α 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 ∼2 weeks of either placebo (PLA) or 5 mg/kg of PPAR-α 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.",
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AU - Cree, Melanie G.

AU - Zwetsloot, Jennifer J.

AU - Herndon, David

AU - Qian, Ting

AU - Morio, Beatrice

AU - Fram, Ricki

AU - Sanford, Arthur P.

AU - Aarsland, Asle

AU - Wolfe, Robert R.

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N2 - OBJECTIVE: To determine some of the mechanisms involved in insulin resistance immediately following burn trauma, and to determine the efficacy of PPAR-α 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 ∼2 weeks of either placebo (PLA) or 5 mg/kg of PPAR-α 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.

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