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
Details
Lead Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)