Nutrition, Inflammation and Insulin Resistance in End-Stage Renal Disease

描述(由申请人提供)： 在美国，接受慢性血液透析(CHD)治疗的患者超过30万人，预计到2010年，这一数字将上升到超过40万人。在这些目前的患者中，估计有11612名退伍军人通过退伍军人管理局接受血液透析。不幸的是，接受慢性血液透析治疗的患者死亡率高得令人无法接受。流行病学研究表明，蛋白质能量浪费(PEW)是一种独特且高度普遍的营养异常，其主要特征是冠心病患者骨骼肌室内蛋白质分解增加，是导致这一不良结局的最重要决定因素之一。虽然导致CHD患者PEW的病因和机制复杂且大多不清楚，但两种公认的且可能相互关联的营养异常--胰岛素抵抗和慢性炎症--可能在这种疾病的发病机制中发挥关键作用。冠心病患者的胰岛素抵抗已通过正常血糖胰岛素钳夹技术进行了表征。多项体外和体内研究表明，胰岛素的合成代谢作用超出了简单的碳水化合物代谢。在此背景下，我们实验室的数据表明，胰岛素抵抗作为冠心病患者蛋白质加速分解的主要媒介具有至关重要的作用。与这一假设一致的是，最近的体外数据表明，胰岛素增敏剂(PPARg激动剂罗格列酮)的治疗抑制了肌肉蛋白分解。这些体外和体内实验数据进一步得到了最近的流行病学数据的支持，这些数据显示，需要服用噻唑烷二酮(TZD)的非胰岛素糖尿病患者在一年的随访中全原因死亡率显著降低。慢性炎症是一种在动物模型中引起肌肉分解代谢的疾病，在流行病学研究中与晚期肾脏疾病有很强的相关性。众所周知，慢性炎症也会导致胰岛素抵抗，主要是通过诱导促炎细胞因子。此外，炎症和胰岛素抵抗在调节肌肉分解代谢时共享共同的信号通路。因此，有理由推测进展性肾病的慢性炎症通过在生理和细胞水平上诱导蛋白质代谢的胰岛素抵抗来介导其蛋白质分解代谢效应。在这一应用中，我们假设冠心病患者蛋白质能量浪费的慢性炎症成分是由胰岛素抵抗介导的。这项拨款申请的首要目标是阐明慢性炎症和胰岛素抵抗影响冠心病患者蛋白质能量消耗的机制。我们将通过以下特定目标来验证我们的假设：特定目标1：描述慢性炎症和胰岛素抵抗介导冠心病患者肌肉蛋白质分解的生理机制；特定目标2：验证通过给予白细胞介素1受体拮抗剂抑制炎症反应或通过给予PPARg激动剂增加胰岛素敏感性将改善净蛋白质代谢的假设。如果成功，我们拟议的研究将极大地影响冠心病患者的临床实践，因为拟议的干预方案将很容易获得，并最终可能导致住院和死亡率的改善。因此，预计这项提案的结果将对退役军人的医疗保健产生重大影响，并为退役军人管理部的研究使命做出重要贡献，为终末期肾病患者的代谢和营养方面提供新的知识。

DESCRIPTION (provided by applicant): There are more than 300,000 patients receiving chronic hemodialysis (CHD) therapy in the United States, which is estimated to rise to over 400,000 patients by 2010. Of those current patients, an estimated 11,612 veterans receive hemodialysis through Veterans Administration. Unfortunately, patients receiving chronic hemodialysis therapy, suffer from unacceptably high death rates. Epidemiological studies indicate that protein energy wasting (PEW), a unique and highly prevalent nutritional abnormality primarily characterized by increased protein breakdown in the skeletal muscle compartment in CHD patients, is one most important determinants of this poor outcome. Although the etiology and mechanisms leading to PEW in CHD patients are complex and mostly ill-defined, two well-recognized and presumably interrelated nutritional abnormalities, insulin resistance and chronic inflammation, are likely to play critical roles in the pathogenesis of this condition. Insulin resistance in CHD patients has been characterized using euglycemic insulin clamp techniques. Multiple in vitro and in vivo studies demonstrate the anabolic effects of insulin that extend beyond simple carbohydrate metabolism. In this context, data from our laboratory indicate the critical importance of insulin resistance as a major mediator of accelerated protein breakdown in CHD patients. Consistent with this hypothesis, recent in vitro data indicate that treatment with an insulin sensitizer (PPARg agonist rosiglitazone) suppressed muscle proteolysis. These in vitro and in vivo experimental data are further supported by recent epidemiological data showing significantly lower rate of all-cause mortality at one year of follow up among incident CHD patients with non-insulin requiring diabetes on thiazolidinediones (TZD). Chronic inflammation, a condition known to cause muscle catabolism in animal models, has a strong association with advanced kidney disease in epidemiological studies. Chronic inflammation is also known to induce insulin resistance, primarily by the induction of pro-inflammatory cytokines. Further, inflammation and insulin resistance share common signaling pathways when mediating muscle catabolism. Thus, it is reasonable to speculate that chronic inflammation of advanced kidney disease mediates its protein catabolic effects by inducing insulin resistance of protein metabolism at both the physiological and cellular levels. In this application, we hypothesize that the chronic inflammatory component of protein energy wasting in CHD patients is mediated by insulin resistance. The overarching goal of this grant application is to elucidate the mechanisms by which chronic inflammation and insulin resistance influence the development of protein energy wasting in CHD patients. We will test our hypotheses by the following specific aims: Specific Aim 1: To characterize the physiological mechanisms by which chronic inflammation and insulin resistance mediate muscle protein breakdown in CHD patients; Specific Aim 2: To test the hypothesis that inhibiting inflammatory response by administration of an Interleukin-1 receptor antagonist or increasing insulin sensitivity by administration of a PPARg agonist will improve net protein metabolism. If successful, our proposed studies will have great potential to influence clinical practices in CHD patients because the proposed intervention protocol would be easily accessible and could ultimately lead to improvements in the hospitalization and death rates. Hence, it is expected that the results of this proposal will have a great impact on Veterans' Health Care and make important contributions to the research mission of the Department of Veterans Administration, providing new knowledge in metabolic and nutritional aspects of end-stage renal disease patients.