Insulin Resistance in Chronic Kidney Disease

描述(申请人提供)：慢性肾脏疾病(CKD)影响多达2600万美国人，或13%的美国人口。中-重度CKD(3-4期，肾小球滤过率15-59毫升/分钟/1.73平方米)对公众健康的影响尤其大，因为它是最常见的，而且它有可能放大心血管疾病的风险。具体地说，患有中重度CKD的患者有重要的心血管疾病“非传统”危险因素，而为普通人群制定的风险降低策略没有充分解决这些危险因素。胰岛素抵抗是慢性肾脏病引起心血管疾病的一种“非传统”机制。在慢性肾脏病中，骨骼肌对胰岛素作用的受体后抵抗通常是由于独特的代谢异常而获得的，包括肾脏骨化三醇合成受损、代谢性酸中毒和尿毒症毒素的积聚。反过来，胰岛素抵抗可能会通过损害内皮功能、增加活性氧物种和加剧全身炎症来促进心血管疾病。CKD特有的代谢异常从根本上改变了胰岛素抵抗的病理生理和确定，并为治疗干预提供了新的潜在靶点。这项赠款申请的总体目标是全面描述中重度CKD患者的胰岛素抵抗特征。首先，我们建议使用金标准方法(高胰岛素正葡萄糖钳夹试验、静脉葡萄糖耐量试验、口服葡萄糖耐量试验)来确定胰岛素抵抗的严重程度、胰岛β细胞的代偿反应以及对糖耐量的净影响，这些目前还知之甚少。其次，我们建议开发和验证估计胰岛素抵抗的公式，用于未来的流行病学研究和临床试验。第三，我们建议测试胰岛素抵抗与内皮功能、氧化应激和炎症的相关性。为了实现这些目标，我们组建了一个多学科团队，拥有CKD生物学、新陈代谢、胰岛素敏感性和β细胞功能的定量评估、营养和生物统计学方面的专业知识。作为这一创新合作方法的一部分，这项研究将利用华盛顿大学和西雅图肾脏研究所的现有资源。这些机构包括转化健康科学研究所临床研究中心、营养和身体成分核心中心和生物医学统计中心。 公共卫生相关性：中-重度慢性肾脏病是一个重要的公共卫生问题，因为它的高患病率和糟糕的健康结果。改善这一人群长期健康状况的关键是预防心血管疾病。患有中重度CKD的患者发生心血管事件的风险很高，死亡的可能性高达11倍，主要是由于心血管疾病，而不是进展为肾衰竭。一旦完成，建议的研究将提供可靠的经验基础，支持未来针对慢性肾脏病胰岛素抵抗的大型流行病学研究和临床试验的设计。这项工作的最终目标是降低中重度CKD患者的高发病率和死亡率。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) affects up to 26 million Americans, or 13% of the United States population. Moderate-severe CKD (stage 3-4, defined by glomerular filtration rate 15-59 mL/min/1.73m2) has a particularly large public health impact because it is most prevalent and because it potently amplifies risk of cardiovascular disease. Specifically, individuals with moderate-severe CKD have important "non-traditional" risk factors for cardiovascular disease which are not adequately addressed by risk reduction strategies developed for the general population. Insulin resistance is one "non-traditional" mechanism through which CKD may cause cardiovascular disease. In CKD, post-receptor resistance to insulin action in skeletal muscle is commonly acquired due to unique metabolic abnormalities, including impaired renal calcitriol synthesis, metabolic acidosis, and accumulation of uremic toxins. In turn, insulin resistance may promote cardiovascular disease by impairing endothelial function, increasing reactive oxygen species, and exacerbating systemic inflammation. The metabolic abnormalities unique to CKD fundamentally alter the pathophysiology and ascertainment of insulin resistance and offer novel potential targets for therapeutic intervention. The overall goal of this grant application is to comprehensively characterize insulin resistance in moderate- severe CKD. First, we propose to define the severity of insulin resistance, the compensatory response of the pancreatic beta cell, and net effects on glucose tolerance, which are currently poorly understood, using gold standard methods (hyperinsulinemic euglycemic clamp, intravenous glucose tolerance test, oral glucose tolerance test). Second, we propose to develop and validate formulae estimating insulin resistance for use in future epidemiologic studies and clinical trials. Third, we propose to test associations of insulin resistance with endothelial function, oxidative stress, and inflammation. To accomplish these goals, we have assembled a multidisciplinary team with expertise in the biology of CKD, metabolism, quantitative assessment of insulin sensitivity and beta-cell function, nutrition, and biostatistics. As part of this innovative collaborative approach, this study will take advantage of existing resources at the University of Washington and the Kidney Research Institute in Seattle. These include the Institute for Translational Health Sciences Clinical Research Center, Nutrition and Body Composition Core, and Center for Biomedical Statistics. PUBLIC HEALTH RELEVANCE: Moderate-severe CKD is an important public health problem due to its high prevalence and poor health outcomes. The key to improving long-term health outcomes in this population is prevention of cardiovascular disease. Persons with stage moderate-severe CKD are at high risk of cardiovascular events and are up to 11 times more likely to die, mostly due to cardiovascular disease, than to progress to kidney failure. Once completed, the proposed studies will provide a sound empirical basis to support the design of future large epidemiologic studies and clinical trials targeting insulin resistance in CKD. The ultimate goal of this work is to reduce the high morbidity and mortality in the large group of patients with moderate-severe CKD.