Substrate Cycling in Energy Metabolism

NCT00361751 | Completed Phase 2

• 1 other identifier: DK34817 (completed)
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Insulin resistance and hyperglycemia contribute to negative outcomes in burned patients. We will assess insulin sensitivity in traditional terms of glucose metabolism, and with regard to the responsiveness of both muscle and liver protein metabolism, in severely burned patients. Plasma free fatty acid (FFA) and tissue TG levels will be manipulated via inhibition of peripheral lipolysis with nicotinic acid or activation of plasma lipoprotein lipase activity with heparin, stimulation of tissue fatty acid oxidation and thus reduction of tissue TG with the peroxisome proliferate-activated receptor (PPAR) alpha agonist fenofibrate. Methodological approaches will include stable isotope tracer techniques to quantify kinetic responses of protein, glucose and lipid metabolism in vivo, quantification of intracellular stores of TG and glycogen by means of magnetic resonance spectroscopy (MRS), as well as quantitative analysis of tissue levels of active products of fatty acids, key intermediates of the insulin signaling pathway, glycogen, the enzyme activities of citrate synthase and glycogen synthase and the activity of the muscle mitochondria. These studies will clarify the physiological and clinical significance of the alterations of tissue lipid metabolism that occur after burn injury, thereby forming the basis for new therapeutic approaches not only in this specific clinical condition but in other clinical circumstances in which hepatic and/or muscle TG is elevated. We will investigate the general hypothesis that the accumulation of intracellular TG in liver and muscle either directly causes insulin resistance in those tissues or serves as an indictor of the intracellular accumulation of active fatty acid products, such as fatty acyl CoA and diacylglycerol, which in turn disrupt insulin action. The following specific hypotheses will be investigated:

1. 1.Intracellular TG is elevated in both muscle and liver in severely burned patients. The reduction of the fat in the liver and the insulin resistance will improve clinical outcomes, glucose and protein metabolism.
2. 2.The insulin signaling pathway, as reflected by phosphoinositol-3-kinase (PI3K) and PKC activity, is impaired in tissues with elevated TG.
3. 3.Fatty acids, or their active intracellular products, are the direct inhibitors of insulin action, rather than the tissue TG itself.

Conditions

Burns; Insulin Resistance

Keywords

Glucose metabolism; Fat Metabolism; Insulin Resistance; Protein Metabolism; Tracer Methodology

Outcome Measures

Primary Outcomes (4)

• Daily Plasma Glucose

• Insulin stimulated glucose uptake

• Hepatic fat concentration

• Muscle fat concentrations and species

Secondary Outcomes (9)

• Muscle insulin signalling

• Muscle mitochondrial function

• Muscle mitochondrial enzyme activity

• Hepatic protein production

• Muscle protein balance

Interventions

fenofibrate DRUG

Eligibility Criteria

• Age: 4 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• We will study male and female burned patients from 20 KG (based on blood requirement) in weight. Patients will be studied between days 12-15 after the initial surgery and will have burns constituting \>40% of the body surface. Volunteers will be determined as healthy utilizing history, physical examination and screening laboratory values assessing liver and renal function, coagulation and platelet function.

You may not qualify if:

• Sulfide or iodide allergies 2.Respiratory Insufficiency 3.Multiple Fractures 4.History of Cancer in the last 5 years 5.Diabetes Mellitus 6.Bilirubin \>3.0 mg/dl 7.Associated head injuries requiring specific therapy 8.Associated injuries to chest or abdomen requiring surgery 9.Serum creatine \> 3.0 mg/dl after fluid resuscitation 10.Receipt of any experimental drug other than ones supplied with two months of this study 11.Any metal in body including rods, neurofibrilators, pacemakers, etc. 12.Orthopedic casting which would prevent placement in MRI 13.Hepatitis 14.Abnormal EKG 17. Bruits over the femoral artery 18. Electrical burn 19. Patients unable to lie still without heavy sedation will not be used for the MRS portion of the study.

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead
• Shriners Hospitals for Children: collaborator

Study Sites (1)

Shriners Hospital for CHildren

Galveston, Texas, 77550, United States

Location

Related Publications (1)

• Cree MG, Zwetsloot JJ, Herndon DN, Qian T, Morio B, Fram R, Sanford AP, Aarsland A, Wolfe RR. Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate. Ann Surg. 2007 Feb;245(2):214-21. doi: 10.1097/01.sla.0000250409.51289.ca.

  PMID: 17245174 DERIVED

MeSH Terms

Conditions

Burns; Insulin Resistance

Interventions

Fenofibrate

Condition Hierarchy (Ancestors)

Wounds and Injuries; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Fibric Acids; Isobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Phenyl Ethers; Ethers; Benzophenones; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenols; Ketones

Study Officials

• Robert R Wolfe, PhD

  UTMB/University of Arkansas

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH

Study Record Dates

• First Submitted: August 7, 2006
• First Posted: August 9, 2006
• Study Start: May 1, 2003
• Study Completion: May 1, 2005
• Last Updated: February 15, 2010

Record last verified: 2010-02

Locations

US (1)