Hyperinsulinemia, Impaired Glucose Tolerance, and T2DM in Cancer Survivors

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The occurrence of hyperinsulinism and type 2 diabetes mellitus (T2DM) has been identified in survivors of childhood malignancy, particularly after bone marrow transplantation (BMT). Only small numbers of patients had been studied and evaluated long-term. The recent study of Hoffmeister et al¹ dealing with a population of children followed after hematopoietic cell transplantation, showed a 3-fold increase rate for T1DM and T2DM. The study of Neville et al focused on the predisposing factors and early markers of DM, a critical issue for the development of prevention strategies. This group studied 248 survivors of childhood cancers; half of them were adults at the time of evaluation. The median duration after diagnosis was 12.9 years. They grouped hyperinsulinism (HI), impaired glucose tolerance (IGT), and T2DM together for analysis of potential risk factors. Body mass index (BMI) and abdominal adiposity were potential markers. In this population, which is often growth-retarded, the waist-to-height (W/H) ratio correlated well with the volume of visceral fat as measured by CT scan. A ratio of >0.5 was considered a good predictor of complications of obesity.

The mean BMIs of both prepubertal and pubertal subjects were similar compared with controls, but the mean W/H ratio was higher, with a doubling of the percentage in children with abdominal adiposity. In all groups, there was a tendency for accumulating abdominal fat. In pubertal and adult subjects, abdominal adiposity was predictive for the occurrence of biochemical markers for metabolic abnormalities (insulinemia and lipid profiles). Fasting insulin concentrations were higher in prepubertal and pubertal subjects, compared with their controls. Hyperinsulinism, IGT, or DM were detected in 18% of pubertal and adult subjects. Eleven percent of this group had IGT/DM (p<0.001). In the group with BMT, conditioning with total body irradiation (TBI) increased the risk (Table).

This study confirms the risk factors previously identified, with a strong focus on the BMT group. Total body irradiation turns out to be a major risk factor for metabolic abnormalities. Differences with previously reported studies could be accounted for by the prospective approach, the broad ranging diagnoses, and the grouping together of the 3 metabolic criteria. Interestingly, hypogonadism also emerged as an independent risk factor, and W/H ratio was a more important marker than BMI. In keeping with these data, it is suggested that the use of conditioning with TBI for BMT deserves reconsideration and underlines the need for regular and long-term clinical and metabolic follow-up.

Neville KA, Cohn RJ, Steinbeck KS, Johnston K, Walker JL. Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab. 2006;91:4401-7.

Editor’s Comment

Diabetes mellitus has not been considered a significant risk in the follow-up of cancer survivors. Initially, treatment with asparaginase suggested a rare immediate risk. Thereafter, the higher frequency of moderate—but significant—overweight observed in patients with leukemia suggested such a risk. In the present prospective study of a large group of etiologies, a new vision is emerging. Of note, some factors did not turn out to be significant: asparaginase-related hyperglycemia, diagnosis, small birth size, abdominal or testicular irradiation. The group at risk had BMT with TBI as conditioning, as opposed to busulfan conditioning, which had no significant effect on the metabolic outcome. The authors suggested that the pancreatic beta cell is an unlikely target, and instead focused on the effect of irradiation on the muscle mass by unknown mechanisms, one possibly being mitochondrial dysfunction. Little is known about the outcome of the irradiated adipose tissue and possible inflammatory processes.

This study provides some clinical clues such as early correction of hypogonadism and careful follow-up of W/H ratio. In the population at risk because of TBI, appropriate nutritional and lifestyle control may not be sufficient. More long-term studies are needed to help understand the mechanism(s) of these adipose—and possibly muscular—changes to help prevent metabolic syndrome and DM.

Raphaël Rappaport, MD

Reference - (linked to )

Hoffmeister PA, Storer BE, Sanders JE. Diabetes mellitus in long-term survivors of pediatric hematopoietic cell transplantation. J Pediatr Hematol Oncol. 2004;26:81-90.

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Last Updated: 04/30/2008