INSULIN RESISTANCE IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA UNDERGOING INDUCT

正在接受治疗的急性淋巴细胞白血病儿童的胰岛素抵抗

• 批准号: 8356701
• 负责人: Rona Yoffe Sonabend
• 金额: $ 1.42万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356701
• 关键词: Acute Lymphocytic Leukemia; Adult; Antibodies; Beta Cell; Blood Glucose; Blood specimen; Cancer Center; Cessation of life; Child; Childhood Acute Lymphocytic Leukemia; Clinical Research; Data; Development; Diabetes Mellitus; Diagnosis; Etiology; Failure; Fasting; Functional disorder; Funding; General Population; Glucose; Grant; Hospitalization; Hyperglycemia; Individual; Infection; Insulin; Insulin Resistance; Interleukin-6; Measurement; Measures; Metabolic syndrome; Methods; Monitor; National Center for Research Resources; Neoadjuvant Therapy; Newly Diagnosed; Obesity; Patients; Peptides; Play; Principal Investigator; Protocols documentation; Relapse; Research; Research Infrastructure; Resources; Risk; Role; Sample Size; Source; Steroids; Students; Survivors; Testing; Texas; Time; Tumor Necrosis Factor-alpha; United States National Institutes of Health; adverse outcome; asparaginase; base; cell injury; chemotherapeutic agent; chemotherapy; childhood cancer survivor; comparison group; cost; falls; fasting glucose; glucose monitor; human TNF protein; inflammatory marker; insulin secretion; prospective; treatment duration

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Background: Treatment for children with Acute Lymphocytic Leukemia (ALL) is known to induce hyperglycemia which has identified as a predictor of adverse outcomes such as infectious complications, relapse, and death. The etiology of hyperglycemia remains unknown. Based on survival data on obesity in survivors of childhood cancer, we hypothesize that insulin resistance exists prior to the diagnosis of ALL and worsens during therapy. Furthermore, we speculate that the children with the highest levels of insulin resistance will develop hyperglycemia during induction therapy. Methods: We plan to conduct a prospective clinical study at Texas Childrens Cancer Center on 40 newly diagnosed children with low risk ALL treated on or according to protocol AALLO331. Fasting blood samples will be collected at three time points during induction: pretreatment (day 1), 2 weeks into induction therapy (day 15), and at the end of induction therapy (day 30). The blood sample includes: glucose, c-peptide, HbA1C, insulin, Diabetes antibodies (ICA 512 and GAD 65), and inflammatory markers (CRP, TNF-alpha, and IL-6). We will calculate insulin resistance, as measured by HOMA-IR, and compare results over time. Additionally, patients will be divided into a hyperglycemia (2 or more blood glucose concentrations 140 mg/dL) or euglycemia group for comparison based on glucose monitoring done during the first 4 days of treatment. Data will be analyzed using a Students t-test to compare the difference in insulin resistance between the 2 groups at the three time points. We will use ANOVA for repeated measures to compare the degree of change in each individual patients insulin resistance from diagnosis to the end of induction. Results/Conclusions: Based on our preliminary data, we expect that 50% of the patients will fall into the hyperglycemia group. With the sample size we calculated, we expect to detect a difference of 1 SD for HOMA-IR between our two groups. We predict that patients who develop hyperglycemia have higher starting HOMA-IR values which continue to rise during the course of treatment. We hope that our inflammatory markers mimic the rise in HOMA-IR and offer an explanation for the underlying pathophysiology of hyperglycemias effect on adverse outcomes. I. HYPOTHESIS a. We hypothesize that, in children with Acute Lymphocytic Leukemia, insulin resistance, as measured by HOMA-IR, exists at diagnosis and worsens during induction therapy. b. We hypothesize that half of the patients will develop hyperglycemia, defined as 2 or more blood glucose levels 140mg/dL. c. We hypothesize that insulin resistance will be higher in the children which develop hyperglycemia compared to the children who remain euglycemic (primary hypothesis). d. We hypothesize that inflammatory markers worsen during induction therapy. e. We hypothesize that children with hyperglycemia will have increased markers of inflammation compared to their euglycemic counterparts. II. SPECIFIC AIMS The purpose of this study is to explore the role of insulin resistance in the development of hyperglycemia and the duration of insulin resistance during induction therapy in children treated with acute lymphocytic leukemia. a) Measure HOMA-IR (calculation of insulin resistance using fasting glucose and insulin measurements) and compare values at three time points: diagnosis (day 1), mid-induction (day 15), and end of induction (day 30). b) Monitor blood glucose concentrations during the first 4 days of hospitalization and categorize patients into the euglycemic or the hyperglycemic group. The hyperglycemia group will include all patients that have 2 or more blood glucose levels 140mg/dL. c) Compare HOMA-IR among the hyperglycemic and euglycemic groups d) Measure inflammatory markers and compare values at two time points: diagnosis (day 1) and end of induction (day 30) e) Compare inflammatory markers among the hyperglycemic and euglycemic groups. III. BACKGROUND AND SIGNIFICANCE Treatment for children with Acute Lymphoblastic Leukemia is known to induce hyperglycemia. Multiple studies, including those of our own, have shown that hyperglycemia during the first month of chemotherapy, known as induction, predicts adverse outcomes such as infections, hospitalizations, relapse, and death [1-3]. Our retrospective preliminary data reveals that 55% of patients (n= 135) developed hyperglycemia, defined as 2 or more blood glucose concentrations 140mg/dL, within the first month of therapy. While the exact etiology of hyperglycemia remains unknown, it is theorized that hyperglycemia results from either a state of insulin resistance due to steroid use, failure of insulin secretion due to beta cell damage from chemotherapeutic agents such as L-asparaginase, or a combination of insulin resistance and beta cell damage. We believe that insulin resistance may play the greater role as survivors of childhood ALL are found to have greater rates of obesity, insulin resistance, and metabolic syndrome in adulthood compared to the general population [4, 5]. What remains unanswered is whether insulin resistance is already present during induction therapy. We hope to show that insulin resistance plays a prominent role in the development of hyperglycemia

该子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 表示子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 摘要 背景资料：已知急性淋巴细胞白血病（ALL）儿童的治疗会诱导高血糖症，高血糖症已被确定为感染并发症、复发和死亡等不良结局的预测因子。 高血糖症的病因仍不清楚。 基于儿童癌症幸存者肥胖的生存数据，我们假设胰岛素抵抗在ALL诊断之前就存在，并且在治疗期间存在胰岛素抵抗。 此外，我们推测胰岛素抵抗水平最高的儿童在诱导治疗期间会出现高血糖。 研究方法：我们计划在德克萨斯州儿童癌症中心对40名新诊断的低风险ALL儿童进行前瞻性临床研究，这些儿童接受或根据方案AALLO331治疗。 将在诱导期间的三个时间点采集空腹血样：治疗前（第1天）、诱导治疗2周（第15天）和诱导治疗结束时（第30天）。 血液样本包括：葡萄糖、c肽、HbA1C、胰岛素、糖尿病抗体（ICA 512和GAD 65）和炎症标志物（CRP、TNF-α和IL-6）。 我们将计算胰岛素抵抗，通过HOMA-IR测量，并比较结果随时间的变化。 此外，根据治疗前4天进行的血糖监测，将患者分为高血糖（2个或以上血糖浓度140 mg/dL）或正常血糖组进行比较。 将使用Students t检验分析数据，以比较两组在三个时间点的胰岛素抵抗差异。 我们将使用ANOVA进行重复测量，以比较每个患者从诊断到诱导结束胰岛素抵抗的变化程度。 结果/结论：根据我们的初步数据，我们预计50%的患者将属于高血糖组。 根据我们计算的样本量，我们预计两组之间HOMA-IR的差异为1 SD。 我们预测，发生高血糖的患者具有较高的起始HOMA-IR值，并在治疗过程中持续升高。 我们希望我们的炎症标志物能够模拟HOMA-IR的升高，并为高血糖症对不良结局的潜在病理生理学影响提供解释。 I. 假设 a. 我们假设，在急性淋巴细胞白血病患儿中，胰岛素抵抗（HOMA-IR）在诊断时就存在，在诱导治疗期间也存在。 B. 我们假设有一半的患者会发生高血糖症，定义为2个或更多的血糖水平140 mg/dL。 C. 我们假设与血糖正常的儿童相比，发生高血糖的儿童的胰岛素抵抗会更高（主要假设）。 D. 我们假设炎症标志物在诱导治疗期间恶化。 e. 我们假设，与血糖正常的儿童相比，高血糖儿童的炎症标志物增加。 二. 具体目标 本研究的目的是探讨胰岛素抵抗在急性淋巴细胞白血病患儿诱导治疗期间高血糖发生和胰岛素抵抗持续时间中的作用。 a）、 测量HOMA-IR（使用空腹血糖和胰岛素测量值计算胰岛素抵抗）并比较三个时间点的值：诊断（第1天）、诱导中期（第15天）和诱导结束（第30天）。 B） 在住院的前4天监测血糖浓度，并将患者分为血糖正常组或高血糖组。高血糖症组将包括2个或以上血糖水平140 mg/dL的所有患者。 c）、 高血糖组与正常血糖组HOMA-IR比较 d）、 测量炎症标志物并比较两个时间点的值：诊断（第1天）和诱导结束（第30天） e）、 比较高血糖组和正常血糖组的炎症标志物。 三. 背景和意义 已知治疗儿童急性淋巴细胞白血病会诱发高血糖。包括我们自己的研究在内的多项研究表明，化疗第一个月（称为诱导期）的高血糖症可预测不良结局，如感染、住院、复发和死亡[1 - 3]。 我们的回顾性初步数据显示，55%的患者（n = 135）在治疗的第一个月内发生高血糖症，定义为2个或更多的血糖浓度140 mg/dL。 虽然高血糖症的确切病因仍然未知，但理论上高血糖症是由于类固醇使用导致的胰岛素抵抗状态、由于化疗剂如L-天冬酰胺酶的β细胞损伤导致的胰岛素分泌失败或胰岛素抵抗和β细胞损伤的组合引起的。 我们认为，胰岛素抵抗可能发挥更大的作用，因为发现儿童ALL幸存者成年后肥胖、胰岛素抵抗和代谢综合征的发生率高于一般人群[4，5]。目前尚不清楚的是，在诱导治疗期间是否已经存在胰岛素抵抗。我们希望表明胰岛素抵抗在高血糖的发展中起着突出的作用