Impaired Glucose Tolerance and Insulin Resistance in Survivors of Childhood Acute Lymphoblastic Leukemia: Prevalence and Risk Factors

Abstract

Survivors of acute lymphoblastic leukemia (ALL) are at increased risks of impaired glucose metabolism, insulin resistance, and metabolic syndrome. The aim of our study was to determine the prevalence of alterations in glucose metabolism and the predisposing factors of these disturbances in survivors of childhood ALL. In 131 ALL survivors, an oral glucose tolerance test was conducted to determine beta-cell function/insulin sensitivity. The particular risk factors were analyzed and 6 single nucleotide polymorphisms of diabetic predisposing genes: PAX4 and TCF7L2 were genotyped to evaluate the association between these factors and beta-cell function/insulin sensitivity. Ten out of 131 survivors (7.6%) had impaired glucose tolerance (IGT) whereas 40 out of 131 (30.5%) had insulin resistance (IR) and showed characteristics of the metabolic syndrome (hyperinsulinemia, hypertriglyceridemia, and low HDL-C). In the logistic regression analysis, the most important factor predicting IGT and IR was older age of survivors (P=0.014 and P<0.001, respectively) whereas the PAX4 R192H mutation (rs2233580) was significantly associated with IGT after adjustment for age (P=0.043) (adjusted OR 5.28, 95% CI 1.06-26.40). Existing evidence suggests that older age is an independent risk factor for developing IGT and IR in childhood ALL survivors, emphasizing the need for life-long metabolic screening. The PAX4 variant might impact individual susceptibility against IGT and diabetes. However, an identification of underlying risk(s) is the rational for future studies.