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）都会发生积累。细胞内脂质的积累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肝脏TG和相关脂质的积累诱导了烧伤后肝脏胰岛素抵抗。我们将使用动物模型进一步研究肝脏TG积累的机制以及肝脏TG增加与胰岛素敏感性的关系。我们将研究肝脏TG积累的三个方面——TG的产生、VLDL的分泌和外周VLDL的清除。我们将特别关注饮食方法刺激VLDL的分泌和清除以及减少肝脏TG的产生。我们的假设是，低热量饮食加上增加的蛋白质摄入将减少肝脏储存的tg，从而改善胰岛素敏感性。我们认为这是一种相互作用，这意味着单独的低热量饮食和高蛋白饮食都不会产生与两者结合相同的效果。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上。研究将在长期使用仪器的猪中进行，使用稳定同位素示踪剂方法来量化适当的代谢参数。这些研究结果将直接应用于严重烧伤或损伤患者的营养护理。

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.