In this cross-sectional study of 116 survivors of childhood ALL, leptin levels were higher among females and those who had received CRT. Adiponectin closely mirrored insulin resistance, while leptin reflected insulin resistance as well as anthropomorphic, DXA, and CT measures of body fat. Furthermore, insulin resistance was nearly uniformly present regardless of gender or treatment variables and was found in non-obese, non-overweight subjects.
In a series of recent papers, Moschovi and colleagues described leptin and adiponectin levels during diagnosis and treatment of childhood leukemia and lymphoma.[17
] In their study of children with acute lymphoblastic leukemia, nine patients with ALL aged 2 to 7 years were found to have low adiponectin and high leptin levels at diagnosis; adipokines gradually moved towards non-cancer control levels during treatment.[18
] When 121 subjects with Non-Hodgkin Lymphoma subjects were examined, higher adiponectin levels at baseline was associated with worse prognosis.[17
] No prior study, however, has examined adipokines and their relationship to insulin resistance and measures of body fatness in survivors of acute leukemia.
Our findings contribute to a better understanding of how insulin resistance develops in long-term survivors of childhood ALL. Female gender and history of treatment with CRT were associated with higher leptin levels, lower adiponectin levels, and increased body fat as measured by BMI, waist circumference, DXA and abdominal CT, when compared to male gender and those without a history of treatment with CRT. Leptin, which communicates primarily with the brain regarding energy usage, was strongly correlated with insulin resistance in our overweight and obese subjects. We hypothesize that ALL or its therapy may result in a form of central leptin resistance so that, instead of processing a signal to burn energy, these subjects inappropriately store energy. Central leptin resistance in this population could be caused by damage to the hypothalamus itself, disruption of communication between the blood and the hypothalamus, or down-regulation of hypothalamic leptin receptors.
Our results support a mechanism for insulin resistance in this population that is in some part independent of BMI. Among subjects with BMI less than 25 (non-obese, non-overweight subjects), mean HOMA-IR was above normal levels, but leptin levels did not differ by HOMA-IR. While survivors of ALL are overweight and obese, on average, and are insulin resistant, on average, these two findings may not be completely interdependent. Further research among lean ALL survivors is needed.
Our study has some limitations. As noted, we conducted a cross-sectional analysis, so that causality cannot be inferred. Additionally, we do not have measures of body fatness and insulin resistance that pre-date the diagnosis of ALL in this population. Prior study of this population of ALL survivors has shown them to be more obese and more insulin resistant than non-cancer controls, however.[7
] Furthermore, our population of long-term ALL survivors is one of the largest that has been studied, and no prior examination of adipokines and insulin resistance in ALL survivors has been reported.
In conclusion, in this study of 116 survivors of childhood ALL, we have shown derangements in adipokines which may help explain the body composition changes and insulin resistance commonly seen in this population. Furthermore, we describe insulin resistance and serum leptin changes even among non-overweight, non-obese subjects. Our findings suggest that anthropomorphic and metabolic changes many years after ALL treatment remain a major health problem facing survivors and may be related to central leptin resistance.