Substrate Cycling in Energy Metabolism

• Status: Completed
• Trial end date: 2005-05-01
• Target enrollment: 0
• Participant gender: All

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. 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. The insulin signaling pathway, as reflected by phosphoinositol-3-kinase (PI3K) and PKC activity, is impaired in tissues with elevated TG.

3. Fatty acids, or their active intracellular products, are the direct inhibitors of insulin action, rather than the tissue TG itself.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborator: Shriners Hospitals for Children
• Treatments: Fenofibrate

Criteria

Inclusion Criteria:

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.

Exclusion Criteria:

1.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.

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