Mitochondrial Oxidation and Insulin Resistance in Burn Patients Treated With Fenofibrate
Major burn injury causes significant insulin resistance on glucose and protein metabolism that persists for up to 6 months after the acute injury
This project proposes to answer the following questions:
- Will fenofibrate given to burn patients with insulin resistance restore their insulin sensitivity?
- What is the relationship between mitochondrial dysfunction in muscle tissue as the causative mechanism of burn related insulin resistance?
- To what extent will the restored insulin sensitivity affect glucose and protein metabolism in muscle, regenerating wounds and the liver, i.e. ameliorate burn related hyperglycemia and protein catabolism?
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||The Role of Mitochondrial Oxidation on Insulin Resistance in Burn Patients Treated With Fenofibrate|
- Insulin sensitivity on glucose and protein metabolism [ Time Frame: From admission to burn unit to 6 months post burn ] [ Designated as safety issue: No ]
- Systemic glucose homeostasis [ Time Frame: Admission to 6 months post burn ] [ Designated as safety issue: No ]
- Muscle protein balance [ Time Frame: Admission to 6 months post burn ] [ Designated as safety issue: No ]
- Wound protein balance [ Time Frame: Admission to 6 months post burn ] [ Designated as safety issue: No ]
|Study Start Date:||August 2008|
|Estimated Study Completion Date:||December 2013|
|Estimated Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
|Active Comparator: Fenofibrate||
Fenofibrate, PO, 5 mg/kg/day from admission to 6 months post burn
|Placebo Comparator: Placebo||
Placebo, sugar pill, from admission to 6 months post burn
The following specific hypotheses will be investigated:
- Following severe burn injury in human patients the mitochondrial fat oxidation capacity is decreased in muscle. This is associated with a corresponding progression in the severity of the resistance to the action of insulin on glucose disposal and protein synthesis and breakdown in muscle, regenerating wound and liver.
- Fatty acids, or their active intracellular products (e.g., DAG, acyl-CoenzymeA (Co-A), or acylcarnitine), are the direct inhibitors of insulin action, rather than tissue triglycerides (TG) itself. In other words, impaired mitochondrial fatty acid oxidation is the mechanism that causes altered lipid metabolism that ultimately contributes to insulin resistance.
- Accumulation of active fatty acid products, such as DAG, acyl-CoA, or acylcarnitine esters in muscle cells is due to the rate of uptake of plasma free fatty acid (FFA) exceeding the rate of oxidation within muscle due principally to a reduced capacity of mitochondria to oxidize fatty acids.
- Decreased insulin sensitivity in muscle is related to impaired insulin signaling. This will be reflected by increased activity of protein kinase C (PKC). Because PKC is thought to exert its regulatory effect primarily on either tyrosine kinase activity on the insulin receptor or downstream kinase insulin receptor substrate (IRS) phosphorylation, these elements of the insulin signaling cascade will be decreased. In turn, elements of insulin signaling related to the response of muscle glucose (PI3 kinase) and protein (P70S6k) metabolism will be reduced. We propose that increased tissue PKC activity will be associated with increased tissue concentration of DAG, acyl-CoA, or acylcarnitine.
- Treatment of patients with the peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate will improve mitochondrial capacity to oxidize fatty acids.
- Insulin sensitivity in muscle, skin and liver in terms of both glucose and protein metabolism will be improved by fenofibrate treatment.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00732485
|Principal Investigator:||David Herndon, MD||University of Texas Medical Branch, Galveston|