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

终末期肾病的营养、炎症和胰岛素抵抗

• 批准号: 8793728
• 负责人: TALAT Alp IKIZLER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793728
• 关键词: Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Catabolism; Chronic; Clinical; Complex; Data; Death Rate; Development; Diabetes Mellitus; Dialysis patients; Dialysis procedure; End stage renal failure; Enrollment; Epidemiologic Studies; Epidemiology; Etiology; Future; Goals; Healthcare; Hemodialysis; Hospitalization; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Intervention; Kidney Diseases; Kidney Failure; Knowledge; Laboratories; Lead; Link; Mediating; Mediator of activation protein; Metabolic; Mission; Muscle; Muscle Proteins; Nutritional; Obesity; Outcome; Pathogenesis; Patients; Physiological; Play; Proteins; Proteolysis; Protocols documentation; Research; Role; Signal Pathway; Skeletal Muscle; Techniques; Testing; Thiazolidinediones; Transplantation; United States; United States Department of Veterans Affairs; Veterans; anakinra; carbohydrate metabolism; clinical practice; cohort; cytokine; follow-up; improved; in vivo; insulin sensitivity; insulin sensitizing drugs; mortality; nutrition; patient population; protein metabolism; rosiglitazone; wasting

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.

描述（由申请人提供）： 在美国，有超过 300,000 名患者接受慢性血液透析 (CHD) 治疗，预计到 2010 年将增加到超过 400,000 名患者。在这些现有患者中，估计有 11,612 名退伍军人通过退伍军人管理局接受血液透析。不幸的是，接受长期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，蛋白质能量消耗（PEW）是一种独特且高度普遍的营养异常，其主要特征是先天性心脏病患者骨骼肌室中蛋白质分解增加，是导致这种不良结果的最重要的决定因素。尽管导致先心病患者发生光能波的病因和机制很复杂，而且大多不明确，但胰岛素抵抗和慢性炎症这两种众所周知且可能相互关联的营养异常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使用血糖正常的胰岛素钳夹技术进行了表征。多项体外和体内研究证明胰岛素的合成代谢作用超出了简单的碳水化合物代谢范围。在这种情况下，我们实验室的数据表明，胰岛素抵抗作为先心病患者蛋白质加速分解的主要介质至关重要。与这一假设一致，最近的体外数据表明，用胰岛素增敏剂（PPARg 激动剂罗格列酮）治疗可抑制肌肉蛋白水解。最近的流行病学数据进一步支持了这些体外和体内实验数据，这些数据显示，在服用噻唑烷二酮类药物（TZD）的非胰岛素糖尿病患者中，随访一年后，全因死亡率显着降低。慢性炎症是一种已知会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，慢性炎症与晚期肾病密切相关。已知慢性炎症也会诱发胰岛素抵抗，主要是通过诱导促炎细胞因子。此外，炎症和胰岛素抵抗在介导肌肉分解代谢时具有共同的信号通路。因此，有理由推测晚期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作用。在本申请中，我们假设先心病患者蛋白质能量消耗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先心病患者蛋白质能量消耗的机制。我们将通过以下具体目标来检验我们的假设： 具体目标 1：表征慢性炎症和胰岛素抵抗介导 CHD 患者肌肉蛋白分解的生理机制；具体目标 2：检验以下假设：通过施用 Interleukin-1 受体拮抗剂抑制炎症反应或通过施用 PPARg 激动剂增加胰岛素敏感性将改善净蛋白质代谢。如果成功，我们提出的研究将有很大潜力影响先心病患者的临床实践，因为提出的干预方案很容易获得，并最终可能导致住院率和死亡率的改善。因此，预计该提案的结果将对退伍军人的医疗保健产生重大影响，并为退伍军人管理部的研究任务做出重要贡献，提供终末期肾病代谢和营养方面的新知识患者。