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，严重烧伤后外周血和肝脏细胞内甘油三酯(TGS)都会积聚。这种细胞内脂质的积聚与肝脏和肌肉中胰岛素抵抗的发展及时相关。我们最重要的假设是烧伤后肝脏甘油三酯和相关脂质的积聚导致肝脏胰岛素抵抗。我们将利用动物模型进一步研究肝脏TG蓄积的机制以及肝脏TGS升高与胰岛素敏感性的关系。我们将研究肝脏甘油三酯蓄积的三个方面--甘油三酯的产生、作为极低密度脂蛋白的分泌和外周极低密度脂蛋白的清除。特别是，我们将重点介绍促进极低密度脂蛋白分泌和清除以及减少肝脏甘油三酯产生的饮食方法。我们的假设是，低热量饮食加上增加蛋白质摄入量将减少肝脏TGS的储存，从而改善胰岛素敏感性。我们认为这是一种交互作用，也就是说，无论是低卡路里饮食还是高蛋白饮食，都不会像两者结合那样产生同样的效果。我们进一步提出，胰岛素敏感性的改善将反映在伤口愈合的改善、瘦体重的维持和免疫功能的改善上。研究将在长期使用仪器的猪身上进行，使用稳定同位素示踪剂方法来量化适当的代谢参数。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：我们最重要的假设是烧伤后肝脏甘油三酯和相关脂质的积聚会导致肝脏胰岛素抵抗。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肝脏TGS的储存，从而改善胰岛素敏感性。我们进一步提出，胰岛素敏感性的改善将反映在伤口愈合的改善、瘦体重的维持和免疫功能的改善上。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.