INSULIN RESISTANCE IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA UNDERGOING INDUCT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景：儿童急性淋巴细胞性白血病(LL)的治疗会引起高血糖，高血糖被认为是感染并发症、复发和死亡等不良后果的预测因子。高血糖的病因仍不清楚。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确诊之前就已经存在，并在治疗过程中恶化。此外，我们推测胰岛素抵抗水平最高的儿童在诱导治疗过程中会出现高血糖。 方法：我们计划在德克萨斯儿童癌症中心对40名新诊断的低风险儿童进行前瞻性临床研究，所有儿童都接受或根据AALLO331方案治疗。在诱导期间的三个时间点采集空腹血样：诱导治疗前(第1天)、诱导治疗2周(第15天)和诱导治疗结束时(第30天)。血样包括：葡萄糖、C-肽、HbA1C、胰岛素、糖尿病抗体(ICA 512和GAD 65)以及炎症标志物(CRP、TNF-α和IL-6)。我们将计算HOMA-IR测量的胰岛素抵抗，并比较一段时间的结果。此外，根据治疗前4天的血糖监测，患者将被分为高血糖组(血糖浓度在2或2以上)或正常血糖组进行比较。数据将使用学生t检验进行分析，以比较两组在三个时间点的胰岛素抵抗差异。我们将使用方差分析进行重复测量，比较每个个体患者S从确诊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，我们预计两组之间的HOMA-IR差异为1SD。我们预测出现高血糖的患者有更高的起始HOMA-IR值，该值在治疗过程中持续上升。我们希望我们的炎症标志物能模拟HOMA-IR的升高，并为高血糖对不良结局影响的潜在病理生理学提供解释。 假设 A.我们假设，在急性淋巴细胞白血病的儿童中，HOMA-IR测量的胰岛素抵抗在诊断时存在，并在诱导治疗期间恶化。 B.我们假设有一半的患者会出现高血糖，定义为2个或更多的血糖水平&140 mg/dL。 我们假设，与保持正常血糖的儿童相比，发生高血糖的儿童的胰岛素抵抗程度更高。 我们假设炎症标志物在诱导治疗过程中恶化。 我们假设，与正常血糖的儿童相比，高血糖儿童的炎症标志物会增加。 具体目标 本研究的目的是探讨胰岛素抵抗在儿童急性淋巴细胞白血病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。 通过空腹血糖和胰岛素测量测量胰岛素抵抗的HOMA-IR计算，并比较三个时间点的值：诊断日1，诱导中期15天和诱导结束30天。 在住院的前4天监测血糖浓度，并将患者分为正常血糖组或高血糖组。高血糖组将包括血糖水平在2 mg/dL或以上的所有患者。 高血糖组与正常血糖组HOMA-IR的比较 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 比较高血糖组和正常血糖组的炎症标志物。 背景和意义 众所周知，儿童急性淋巴细胞性白血病的治疗会导致高血糖。多项研究，包括我们自己的研究表明，化疗第一个月的高血糖，即所谓的诱导，预示着不良后果，如感染、住院、复发和死亡[1-3]。我们的初步回顾数据显示，55%的患者在治疗的第一个月内出现了高血糖，定义为2个或更多的血糖浓度为140 mg/dL。虽然高血糖的确切病因尚不清楚，但理论上认为，高血糖是由于使用类固醇导致的胰岛素抵抗状态，由于L-天冬酰胺酶等化疗药物对β细胞的损伤而导致的胰岛素分泌障碍，或者是胰岛素抵抗和β细胞损伤的组合。 我们认为胰岛素抵抗可能起到更大的作用，因为所有儿童幸存者在成年后都被发现比普通人群有更高的肥胖率、胰岛素抵抗和代谢综合征[4，5]。仍然没有答案的是，在诱导治疗期间是否已经存在胰岛素抵抗。我们希望证明胰岛素抵抗在高血糖的发生中起着重要的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Treatment for children with Acute Lymphocytic Leukemia (LL) 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 Children's 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 patient s 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 hyperglycemia's effect on adverse outcomes. 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. 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. 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. 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. Compare HOMA-IR among the hyperglycemic and euglycemic groups Measure inflammatory markers and compare values at two time points: diagnosis day 1and end of induction day 30 Compare inflammatory markers among the hyperglycemic and euglycemic groups. 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 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