Association between Genetic Polymorphisms of β-Cell Differentiation Genes and Insulin Resistance (β-Cell Dysfunction) in Childhood Acute Lymphoblastic Leukemia (ALL) Survivors.

Background: The purposes of the study were to determine β-cell function and insulin sensitivity after ALL therapy cessation and the association between genetic polymorphisms of β-cell differentiation genes, TCF7L2 and PAX4, with insulin resistance (β-cell dysfunction) in childhood ALL survivors.

Methods: Childhood ALL patients diagnosed during 1997–2004 finished the treatment for at least 6 months. The oral glucose tolerance test and lipid screening were performed. Impaired glucose tolerance and diabetes mellitus (DM) were defined according to WHO criteria. β-cell function was estimated by homeostasis model assessment β-cell (HOMA β-cell) and insulinogenic index (IGI) and insulin sensitivity was estimated by whole body insulin sensitivity index (WBISI). The polymorphisms of TCF7L2 (rs12255372 and rs7903146) and PAX4 (A1186C) were genotyped and assessed for the association between these polymorphisms and the β-cell function and the insulin sensitivity.

Results: 126 patients were studied (52 females, 74 males and age at the time of study; 4–20 yrs). 116 patients (92%) had normal glucose tolerance (NGT) while the others 10 patients (8%) had impaired glucose tolerance (IGT). Comparing between IGT and NGT groups respectively, we found statistically significant differences in age at the diagnosis (7.5 and 5.2 yrs, p=0.041), age at the study (14 and 10.3 yrs, p=0.001), the duration of post ALL therapy cessation (43 and 26 months, p=0.015), and insulin sensitivity index (WBISI) (5.75 and 9.52, p<0.001). HOMA β-cell and IGI were not different between NGT and IGT group (190.8 and 139.5, p=0.332; 23.6 and 15.8, p=0.310, respectively). Moreover, 32 of 126 patients (25%) had insulin resistance (modified from the criteria of WBISI in obese children and adolescents). These 32 patients who had insulin resistance demonstrated significant pictures of metabolic syndrome i.e. hypertriglyceridemia (116.6 and 85.4 mg/dL, p=0.036), low HDL-C (43.0 and 48.3 mg/dL, p=0.015), obesity (BMI SDS 1.03 and 0.38, p=0.044) and were also older age at the study (12.8 and 9.9 yrs, p<0.001). The genotype frequencies and allele frequencies of polymorphisms of TCF7L2 and PAX4 genes between IGT and NGT groups and between insulin resistance and nonresistance were not difference (p>0.05).

Conclusion: The childhood ALL survivors who had IGT were associated with the longer duration of ALL therapy cessation, the older age at diagnosis and at the time of study, and insulin resistance while β-cell function was still relatively preserved. Long-term childhood ALL survivors have potential risks of IGT, insulin resistance and metabolic syndrome. Our findings with such small representatives are not yet applicable to associate TCF7L2 and PAX4 polymorphisms with the insulin resistance (β-cell dysfunction) in the childhood ALL survivors.