Nutrition, Infection and Hepatic Carbohydrate Metabolism

描述(申请人提供)：肝脏对持续营养支持(NS)有独特的适应性反应。肝脏从适度的葡萄糖摄取和糖原储存转变为有效地将葡萄糖转化为乳酸的器官(即增强的糖酵解能力)。由于肝脏代谢流量的这种变化，我们假设在急性环境中肝脏葡萄糖摄取和处置的正常调节器(葡萄糖和胰岛素水平以及葡萄糖输送途径)在适应环境中不再发挥同样程度的控制。我们认为，在NS期间，胰高血糖素的下降是允许这种适应发生的关键。在适应环境中观察到的增强的肝脏葡萄糖处置减少了外周组织去除的外源性葡萄糖的比例，同时仍然保留了外周组织对总碳水化合物的摄取(葡萄糖+乳酸)。慢性NS后，超过1/3的外周碳水化合物摄取以乳酸形式存在。由于乳酸比葡萄糖更有效地清除，对胰岛素的依赖较少，外周组织对葡萄糖的绝对摄取率降低，胰岛素和葡萄糖浓度也降低。感染损害了这种适应性反应，尽管存在代偿性高胰岛素血症，肝脏会恢复到类似于不适应(即急性)状态的状态。未能适应将葡萄糖清除的责任转移到外周组织。当与感染引起的外周胰岛素抵抗相结合时，发生高血糖的风险增加。我们认为，感染诱导的胰高血糖素升高有助于这种受损的适应性反应，并加剧外周胰岛素抵抗。此外，虽然代偿性高胰岛素血症和/或高血糖或肠内(或门静脉)葡萄糖输送可以明显纠正肝脏葡萄糖摄取的损害，但我们假设这是不可持续的，因为它们不能克服肝脏糖酵解能力的缺陷。我们将解决的问题是。胰升糖素分泌的抑制是否在促进NS的代谢反应中起重要作用？在感染期间其抑制作用的失败是否导致肝脏和外周代谢的异常？感染过程中的代偿性高胰岛素血症和高血糖能维持对NS的适应性反应吗？感染期间释放的细胞因子是否改变了对NS的适应性反应？在NS期间，感染是否损害了门静脉和肠内葡萄糖输送促进肝脏葡萄糖摄取和抑制外周葡萄糖摄取的能力？实验将在接受持续营养支持的慢性导尿管清醒狗身上进行。肝脏葡萄糖代谢(单向肝脏葡萄糖摄取和产生，葡萄糖氧化)将使用示踪剂和动静脉差示技术相结合的方法进行评估。此外，我们还将同时评估肢体葡萄糖的摄取和处置。虽然以前的工作研究了全身葡萄糖代谢对感染的反应，但我们的模型提供了独特的能力，可以直接检查单个器官(肝脏和肌肉)在感染诱导的营养代谢调节中所起的作用，以及导致损害的因素和发生这些损害的机制。

DESCRIPTION (provided by applicant): The liver has a unique adaptive response to continuous nutritional support (NS). The liver switches from a site of modest glucose uptake and glycogen storage to an organ that efficiently converts glucose to lactate (i.e. enhanced glycolytic capacity). As a consequence of this shift in hepatic metabolic flux we hypothesize the normal regulators of liver glucose uptake and disposition in the acute setting (glucose and insulin levels and route of glucose delivery) no longer exert the same degree of control in the adapted setting. We believe the fall in glucagon during NS is essential to allowing the adaptation to occur. The enhanced hepatic glucose disposition observed in the adapted setting decreases the fraction of the exogenous glucose removed by peripheral tissues, while still preserving total carbohydrate uptake (glucose + lactate) by peripheral tissues. Following chronic NS greater than 1/3 of the peripheral carbohydrate uptake is as lactate. Since lactate is more efficiently cleared than glucose and less dependent upon insulin for its removal and the absolute rate of glucose uptake by peripheral tissues is diminished, the insulin and glucose concentrations are decreased as well. Infection impairs this adaptive response despite compensatory hyperinsulinemia with the liver reverting back to a state similar to the un-adapted (i.e. acute) state. The failure to adapt shifts the responsibility of glucose removal to peripheral tissues. When combined with the infection induced peripheral insulin resistance the risk of developing hyperglycemia increases. We believe the infection induced rise in glucagon contributes to this impaired adaptive response and aggravates the peripheral insulin resistance. Moreover, while the presence of compensatory hyperinsulinemia and/or hyperglycemia or enteral (or portal vein) glucose delivery can acutely correct the impairment in liver glucose uptake, we hypothesize this can not be sustained because they can not overcome the deficit in hepatic glycolytic capacity. The questions we will address are. Does the suppression of glucagon secretion play an essential role in facilitating the metabolic response to NS and does its failure to suppress during infection contribute to the abnormal hepatic and peripheral metabolism? Are the compensatory hyperinsulinemia and hyperglycemia during infection able to sustain the adaptive response to NS? Do cytokines released during infection modify the adaptive response to NS? Does infection impair the ability of portal and enteral glucose delivery to facilitate liver glucose uptake and inhibit peripheral glucose uptake during NS? Experiments will be carried out in chronically catheterized conscious dogs receiving continuous nutritional support. Hepatic glucose metabolism (unidirectional hepatic glucose uptake and production, glucose oxidation) will be assessed using a combination of tracer and arterio-venous difference techniques. In addition we will simultaneously assess limb glucose uptake and disposal. While previous work has examined the response of whole body glucose metabolism to infection, our model provides the unique ability to directly examine the role that individual organs (liver and muscle) play in the infection-induced modulation of nutrient disposition and the factors responsible for the impairment and the mechanisms by which they occur.