We have previously shown that accumulation of both peripheral and hepatic intracellular triglycerides (TGs) occurs following severe burn injury in both human patients and in a porcine animal model. This accumulation of intracellular lipids is associated in time with the development of insulin resistance both at the liver and in the muscle. Our overriding hypothesis is that accumulation of hepatic TG and related lipids induce hepatic insulin resistance following burn injury. We will use the animal model to further examine the mechanisms responsible for hepatic TG accumulation and the relation of increased hepatic TGs to insulin sensitivity. We will investigate the three aspects of hepatic TG accumulation- TG production, secretion as VLDL, and peripheral VLDL clearance. In particular, we will focus on dietary approaches to stimulating VLDL secretion and clearance and reducing hepatic TG production. Our hypothesis is that a hypocaloric diet coupled with an increased protein intake will decrease hepatic storage of TGs, and thereby improve insulin sensitivity. We propose that this is an interactive effect, meaning that neither the hypocaloric diet nor high protein alone will have the same effect as the combination of the two. We further propose that improved insulin sensitivity will be reflected in improved wound healing, maintenance of lean mass and immune function. Studies will be performed in chronically instrumented pigs using stable isotope tracer approaches to quantify appropriate metabolic parameters. The results from these studies will have direct application in the nutritional care of severely burned or injured patients.

Public Health Relevance

Our overriding hypothesis is that accumulation of hepatic TG and related lipids induce hepatic insulin resistance following burn injury. Our central hypothesis is that a hypocaloric diet coupled with an increased protein intake will decrease hepatic storage of TGs, and thereby improve insulin sensitivity. We further propose that improved insulin sensitivity will be reflected in improved wound healing, maintenance of lean mass and immune function. The results from these studies will have direct application in the nutritional care of severely burned or injured patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK034817-27
Application #
8458976
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Laughlin, Maren R
Project Start
1984-12-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
27
Fiscal Year
2013
Total Cost
$315,146
Indirect Cost
$97,804
Name
University of Arkansas for Medical Sciences
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Zhang, Xiao-jun; Wang, Lijian; Tuvdendorj, Demidmaa et al. (2013) Acute hyperinsulinemia and reduced plasma free fatty acid levels decrease intramuscular triglyceride synthesis. Metabolism 62:44-51
Tuvdendorj, Demidmaa; Chinkes, David L; Herndon, David N et al. (2013) A novel stable isotope tracer method to measure muscle protein fractional breakdown rate during a physiological non-steady-state condition. Am J Physiol Endocrinol Metab 304:E623-30
Zhang, Xiao-Jun; Rodriguez, Noe A; Wang, Lijian et al. (2012) Measurement of precursor enrichment for calculating intramuscular triglyceride fractional synthetic rate. J Lipid Res 53:119-25
Fram, Ricki Y; Cree, Melanie G; Wolfe, Robert R et al. (2010) Impaired glucose tolerance in pediatric burn patients at discharge from the acute hospital stay. J Burn Care Res 31:728-33
Fram, Ricki Y; Cree, Melanie G; Wolfe, Robert R et al. (2010) Intensive insulin therapy improves insulin sensitivity and mitochondrial function in severely burned children. Crit Care Med 38:1475-83
Cree, Melanie G; Fram, Ricki Y; Herndon, David N et al. (2008) Human mitochondrial oxidative capacity is acutely impaired after burn trauma. Am J Surg 196:234-9
Fram, Ricki Y; Cree, Melanie G; Chinkes, David L et al. (2007) Recovery of labeled CO2 from acetate in severely burned children. Am J Physiol Endocrinol Metab 293:E1726-9
Ferrando, Arny A; Wolfe, Robert R (2007) Restoration of hormonal action and muscle protein. Crit Care Med 35:S630-4
Sun, Dayong; Cree, Melanie G; Wolfe, Robert R (2006) Quantification of the concentration and 13C tracer enrichment of long-chain fatty acyl-coenzyme A in muscle by liquid chromatography/mass spectrometry. Anal Biochem 349:87-95
Sidossis, Labros S; Magkos, Faidon; Mittendorfer, Bettina et al. (2004) Stable isotope tracer dilution for quantifying very low-density lipoprotein-triacylglycerol kinetics in man. Clin Nutr 23:457-66

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