In contrast to previous reports of significant glucose tolerance abnormalities in children with FA prior to HCT, we found normal glucose tolerance and beta-cell function in the majority of FA children following HCT. FPIR was normal in more than half of the children, elevated in about a quarter, and reduced in about a quarter. Abnormal glucose tolerance was only found in one child and impaired fasting glucose in another child, both of whom had normal FPIR.
Two previous studies have identified low insulin levels during OGTT in children with FA [9
], and it has been suggested that this is pathologic and may lead to poor weight gain and growth[9
]. The current study more accurately assessed beta-cell function using the IVGTT and found 4 out of 17 children with lower than expected FPIR. These children were younger, less likely to have entered puberty, and more sensitive to insulin than those with greater FPIR. Importantly, they had completely normal fasting glucose levels and oral glucose tolerance. Thus it is difficult to ascribe any pathology to their relatively low insulin secretion.
Elevated FPIR was associated with insulin resistance, increased adiposity, and greater abnormalities in lipid levels in our FA participants. Previous studies have found an increased risk of hyperinsulinism and diabetes mellitus in long-term survivors of childhood HCT, even in the presence of normal BMI [2
], and in particular in association with a history of irradiation [2
]. Our data is consistent with these findings of hyperinsulinism in the face of normal BMI after HCT. However, there appears to be a synergistic effect of FA and HCT in some patients on insulin resistance, since three of our FA participants had significantly higher FPIR compared to FPIR in children without
FA after HCT [5
]. This group with elevated FPIR represented a minority of subjects in the current study, and we were unable to find any association with TBI history. Surprisingly, current steroid treatment did not appear to have a significant impact on insulin secretion or glucose metabolism either.
Wajnrajch reported genotype-phenotype correlations between complementation group and hyperinsulinism (FA-G, FA-A) and with insulinopenia (FA-C) [11
]. It is intriguing that the mutation for FA-C lies in the same region on chromosome 9 as the gene encoding the protein fructose-1,6-bisphosphatase, which is thought to be associated with Type 2 diabetes mellitus [19
]. There were no children with FA-C in this study. The children with lower FPIR were all FA-A, however two did not have mutation analysis performed. Unfortunately, our sample size is too small to determine any statistically significant genotype-phenotype correlations which could account for metabolic differences.
Elder et al. found a prevalence of abnormal glucose metabolism in 46% (n=16) of FA patients who had not been treated with HCT; 34% had impaired glucose tolerance and 11% had diabetes mellitus [9
]. After HCT, we found a prevalence of abnormal glucose metabolism of 17% (n=2), and no children had diabetes mellitus. Factors contributing to this lower prevalence may be the fact that our group had lower BMI Z-scores and fewer children who were SGA at birth. However, the difference in prevalence of abnormal glucose metabolism is surprising given that our population was slightly older on average, had received HCT, and some patients were being treated with steroids, whereas this was not the case in patients studied by Elder et al. We do not fully understand the difference in the prevalence of glucose intolerance before and after HCT. It would be premature to speculate that HCT itself might have had a positive impact on glucose metabolism in these patients. To clarify these differences, more prospective studies are needed assessing IVGTT and OGTT before and after HCT.
A major limitation of this pilot study is that we did not study the participants prior to their HCT. Thus, although published data have reported a high frequency of glucose tolerance abnormalities in FA children who have not undergone HCT, we cannot say for certain that the children in the current study had worse FPIR or oral glucose tolerance before their transplant. Also, we were obligated to use control data from the literature for FPIR levels since our IRB would not allow testing on non-FA children who had undergone HCT. We did not perform euglycemic clamp studies, but instead relied upon surrogate markers of insulin resistance.
In conclusion, the majority of children with FA had normal glucose tolerance and normal beta-cell function after HCT. Two small subsets of patients had lower than expected and higher than expected FPIR. The clinical significance of these differences is not yet known given the normal glucose tolerance and fasting glucose levels in these two groups. Future studies are needed to better delineate the impact of HCT on glucose metabolism, and the clinical significance of relative insulinopenia in children with FA who are underweight. We recommend OGTT assessment a minimum of every two years after HCT in children with FA. In addition, screening should be done prior to HCT in view of the high prevalence of abnormal glucose metabolism in FA patients who have not been treated with HCT, and the possible increased risk of infection during HCT reported by Derr et al. [20