Metabolic Syndrome in Childhood Cancer Survivors

随着许多曾经接受过儿童癌症治疗的人进入成年，临床和流行病学研究现在将重点放在癌症治疗的一系列长期影响上，以表征和理解“治愈的后果”。有证据表明，儿童癌症幸存者(CC)患代谢综合征(MS)的风险增加。该综合征由肥胖、胰岛素抵抗、血脂异常和高血压组成，是2型糖尿病和心血管疾病的预测因子。在健康人群中，肥胖在MS的发展中起着核心作用，然而，可以想象，在CCS中，肥胖以外的其他机制(例如内分泌异常、辐射暴露和抗肿瘤药物)可能在MS的发展中发挥关键作用。本建议的主要目的是在这些组成部分之间的关系变得复杂和疾病发展之前，评估胰岛素抵抗(通过正常血糖胰岛素钳)、生长激素缺乏和其他胰岛素抵抗介质与MS发展和心血管风险之间的关系。我们建议研究9-18岁的儿童和青少年的样本，他们在确诊后儿童癌症存活5年，以及他们的健康兄弟姐妹，他们将参加为期2天的临床评估。具体目标是：1)确定MS在CCS中的患病率，并与年龄和性别分布相似的健康对照组进行比较；2)评估胰岛素抵抗与MS其他组成部分以及心血管变化早期体征的关系；3)评估肥胖和胰岛素抵抗与生长激素分泌、脂肪因子和炎症介质的关系；4)评估与预防心血管疾病、糖尿病和肥胖有关的健康行为。这项建议解决了临床研究的需要，侧重于新发现的儿童癌症及其治疗的不良影响，特别是对于可预防/可改变的情况，并将提供关于潜在病因和干预途径的新数据。

As many individuals once treated for childhood cancer progress into adulthood, clinical and epidemiologic research is now focusing on an array of long-term effects from cancer treatment to characterize and understand the "consequences of cure". There is evidence to indicate that childhood cancer survivors (CCS) are at increased risk for the metabolic syndrome (MS). The syndrome is composed of obesity, insulin resistance, dyslipidemia and hypertension, and is a predictor of type 2 diabetes and cardiovascular disease. In healthy populations obesity has a central role in the development of the MS, however, it is conceivable that in CCS additional mechanisms other than obesity (e.g. endocrine abnormalities, exposure to radiation and antineoplastic agents) may play a critical role in the development of MS. The major objective of this proposal is to evaluate the relation between insulin resistance (by euglycemic insulin clamp), growth hormone deficiency and other mediators of insulin resistance, with the development of MS and cardiovascular risk early in life, before the relations between the components become complex and disease develops. We propose to study a sample of children and adolescents age 9-18 years, who survived childhood cancer for >5 years after diagnosis, and their healthy siblings, who will participate in a 2 day clinical evaluation. Specific aims are: 1) to determine the prevalence of MS in CCS and compare to healthy controls similar in age and gender distribution, 2) to assess the association of insulin resistance with other components of MS and with early signs of cardiovascular changes, and 3) to assess the relation between obesity and insulin resistance with growth hormone secretion,^adipokines and inflammatory mediators; 4) to evaluate health behaviors related to prevention of cardiovascular disease, diabetes, and obesity. This proposal addresses the need for clinical research focused on newly identified adverse effects of childhood cancer and its treatment, particularly for preventable/modifiable conditions, and will provide new data on potential etiologic factors and avenues for intervention.