From this large and diverse cohort of young adult survivors of childhood cancer, we report an almost two-fold increased risk of self-reported DM, primarily of probable type 2, in comparison with their siblings. This risk was most evident for AML, neuroblastoma, Wilms tumor, and Hodgkin lymphoma survivors who were treated with TBI or abdominal irradiation. Importantly, this risk was independent of obesity and physical inactivity. Survivors of ALL who were treated with cranial irradiation were also more likely to be diabetic than the siblings, but this was in part related to increased BMI and physical inactivity. The relationship between cranial irradiation and insulin resistance has been well described 7, 22–24
and is an expected outcome of the increased prevalence of obesity following CRT in this population.13,25
Further, Mohn and colleagues suggest that impaired β-cell function may persist following chemotherapy for ALL.26
Thus, the following discussion focuses on the less well characterized association between DM and abdominal and total body irradiation. Indeed, the diabetes observed among this irradiated cancer population may represent a form of therapy induced diabetes and be the result of an impairment of insulin release and specific β-cell lesions.27
Diabetes following abdominal irradiation for neuroblastoma has not previously been reported. Neuroblastoma survivors who were treated with abdominal irradiation had a nine-fold increased likelihood of being diabetic in comparison with siblings, after adjusting for BMI. In contrast, those who were not treated with abdominal irradiation did not have an elevated risk of DM. This pattern was also seen in the two other groups of survivors commonly exposed to abdominal irradiation. For both Wilms tumor and Hodgkin lymphoma survivors, a significantly increased risk of DM in comparison with siblings was observed only in those who were treated with abdominal irradiation. To date, there are a few studies that have assessed the risk of DM following abdominal irradiation. In a small retrospective chart review of 121 Wilms tumor survivors, 8 (6.6%) developed DM, 6 of whom were controlled on either diet or oral medication.11
Conversely, among 4387 childhood cancer survivors who were a median age of 29.8 years, Hawkins et al did not find an increased prevalence of DM associated with abdominal irradiation.28
There are several mechanisms by which abdominal irradiation may lead to DM. The pancreas is in the field of left-sided (or bilateral) abdominal irradiation. Small animal studies suggest that following radiation, the pancreatic islet cells show evidence of degranulation, vacuolization, mitochondrial destruction, and impaired insulin secretion.29,30
Pancreatic insufficiency, relative or absolute, may result following irradiation. Of note, however, most survivors in our study who had DM following abdominal irradiation were either on oral medication or combination therapy, suggesting that if they have β-cell dysfunction, it is not absolute. Thus, there are likely other mechanisms by which abdominal irradiation leads to DM. Alterations in adipose-derived hormones following radiation may lead to insulin resistance. Adipose tissue, originally thought only to have an energy storage function, is now recognized as an endocrine organ, producing and secreting a variety of factors including leptin, resistin and adiponectin.31,32
Perhaps the production of adiponectin or other adipose-derived hormones are radiosensitive processes and decreased levels may be a late effect of therapeutic abdominal irradiation.
Our finding of an association between TBI and DM confirms other recent studies.4–9
Generally, these studies suggest that DM following TBI is secondary to hyperinsulinemia rather than B-cell insufficiency.6,7,9
It is likely that the development of DM following TBI is multifactorial. Needless to say, the mechanisms described above with abdominal irradiation may apply also to patients who have been treated with TBI. Notably, though, the radiation dose to the abdomen is lower with TBI (12–15 Gy) than with abdominal irradiation in neuroblastoma or Wilms tumor treatment (20–30 Gy). Growth hormone deficiency (GHD) is common among childhood cancer survivors who are treated with TBI, particularly those treated at a young age.33,34
In non-cancer populations, GHD is associated with insulin resistance.35,36
GHD is likely one of the primary pathways by which ALL survivors become insulin resistant.22,37
Neville et al did not find an association between GHD and insulin resistance.7
Rather, they found that untreated hypogonadism and abdominal obesity were predictive of insulin resistance or hyperinsulinemia. The relationship of hypogonadism and insulin resistance among childhood cancer survivors has been reported by others.6,9
In the general population, men with androgen insufficiency have increased prevalence of insulin resistance and metabolic syndrome.38–40
However, this has not been reported in women with ovarian failure.
Interestingly, both GHD and androgen deficiency contribute to abdominal obesity.38,40
Abdominal obesity, particularly an increase in visceral adipose tissue, is strongly associated with the development of insulin resistance.41–43
It is thought that visceral fat is the more metabolically active fat and its ability to challenge the liver directly with free fatty acids (FFA) may play a crucial role in insulin resistance.41,44
Elevated levels of intrahepatic FFAs delivered directly through the portal system can lead to increased hepatic glucose production and reduced insulin sensitivity. Of note, recent studies within the HIV-infected population reported redistribution of adipose tissue in patients on a protease inhibitor. In these patients with HIV-associated adipose redistribution syndrome (HARS), there is an increase in visceral adipose tissue that is strongly correlated with insulin resistance and dyslipidemia.45
When interpreting the findings of this study, there are several limitations that need to be recognized. Diabetes was attributed to subjects who stated they were on a medication commonly used to treat DM or hyperinsulinemia. Misclassification resulting from reporting medications for DM is likely low. There is, however, a greater probability of misclassification resulting from undiagnosed DM. In addition, survivors who are aware of their increased risk for chronic health problems might be more likely to seek medical care than their siblings and therefore more likely to be diagnosed with a condition such as DM, leading to potential ascertainment bias and overestimates of risk. The sibling cohort is intended to represent a general, non-cancer population. While some outcomes may be different between siblings and the general population, we previously did not find any difference between the siblings and age- and gender-matched participants in national surveys with respect to BMI or meeting the CDC recommendations for physical activity.46–48
Non-participation may have introduced a selection bias in the study; 19% of the eligible survivors did not participate in this survey. Notably, participants did not differ from non-participants by diagnosis, original cancer treatment, or age at cancer diagnosis. Lastly, the cross-sectional design of this study precludes inferences of temporality, causality, and risk.
In summary, the prevalence of DM was almost twice as high in childhood cancer survivors compared to siblings, with risk being markedly elevated in those who were treated with either TBI or abdominal irradiation. It is likely that this additional chronic disease in childhood cancer survivors, who frequently also sustain damage to the heart, kidneys, and endocrine system,1
will lead to further morbidity and premature mortality. Thus, it is imperative that clinicians recognize this risk, screen for diabetes and pre-diabetes when appropriate, and approach survivors with aggressive risk-reducing strategies. Moreover, further research is warranted to understand the pathways by which these two modes of radiation therapy lead to diabetes.