Substrate Cycling in Energy Metabolism

描述（由申请人提供）：我们之前已经证明，在人类患者和猪动物模型中，严重烧伤后外周和肝脏细胞内甘油三酯（TG）均发生蓄积。细胞内脂质的这种积累与肝脏和肌肉中胰岛素抵抗的发展及时相关。我们的主要假设是，肝脏TG和相关脂质的积累诱导烧伤后肝脏胰岛素抵抗。我们将使用该动物模型进一步研究肝脏TG蓄积的机制以及肝脏TG增加与胰岛素敏感性的关系。我们将研究肝脏TG蓄积的三个方面-TG产生、作为VLDL分泌和外周VLDL清除。特别是，我们将集中在饮食的方法来刺激VLDL的分泌和清除，并减少肝脏TG的生产。我们的假设是，低热量饮食加上增加蛋白质摄入量将减少TG的肝脏储存，从而改善胰岛素敏感性。我们认为这是一种相互作用的效应，也就是说，无论是低热量饮食还是高蛋白饮食，单独使用都不会产生与两者结合使用相同的效果。我们进一步提出，改善的胰岛素敏感性将反映在改善的伤口愈合，维持瘦体重和免疫功能。将在长期使用仪器的猪中进行研究，使用稳定同位素示踪剂方法定量适当的代谢参数。这些研究的结果将直接应用于严重烧伤或受伤患者的营养护理。 公共卫生相关性：我们的主要假设是，肝脏TG和相关脂质的积累诱导烧伤后肝脏胰岛素抵抗。我们的中心假设是，低热量饮食加上增加蛋白质摄入量将减少TG的肝脏储存，从而改善胰岛素敏感性。我们进一步提出，改善的胰岛素敏感性将反映在改善的伤口愈合，维持瘦体重和免疫功能。这些研究的结果将直接应用于严重烧伤或受伤患者的营养护理。

DESCRIPTION (provided by applicant): 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.