Substrate Cycling in Energy Metabolism

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.

Conditions

• Burns
• Insulin Resistance

Interventions

DRUG

fenofibrate

Sponsors & Collaborators

• Shriners Hospitals for Children

  collaborator OTHER

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  lead NIH

Principal Investigators

• Robert R Wolfe, PhD · UTMB/University of Arkansas

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

4 Years

Max Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2003-05-31

Completion

2005-05-31

Countries

• United States

Study Locations