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
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