Severe Insulin Resistance and Hypertriglyceridemia After Childhood Total Body Irradiation

Abstract

Objective To characterize the metabolic phenotype of 2 cases of normal weight young women who developed type 2 diabetes (T2D), severe insulin resistance (insulin requirement >200 units/day), marked hypertriglyceridemia (>2000 mg/dL), and hepatic steatosis beginning 9 years after undergoing total body irradiation (TBI) and bone marrow transplantation for childhood cancer. Methods Fasting plasma glucose, insulin, free fatty acids (FFAs), leptin, adiponectin, resistin, TNFα, and IL-6 were measured in each case and in 8 healthy women; Case 1 was also assessed after initiating pioglitazone. Coding regions and splice junctions of PPARG, LMNA, and AKT2 were sequenced in Case 1 and of PPARG in Case 2 to evaluate for familial partial lipodystrophies. Genotyping of APOE was performed in Case 1 to rule out type III hyperlipoproteinemia. Results Both cases had elevated plasma levels of insulin, leptin, resistin, and IL-6, high-normal to elevated TNFα, and low to low-normal adiponectin in keeping with post-receptor insulin resistance and adipose tissue inflammation. Case 1 experienced a biochemical response to pioglitazone. No causative mutations for partial lipodystrophies or type III hyperlipoproteinemia were identified. Conclusion Though metabolic derangements have previously been reported in association with TBI, few cases have described insulin resistance and hypertriglyceridemia as severe as that seen in our patients. We speculate that early childhood TBI may impede adipose tissue development leading to metabolic complications from an attenuated ability of adipose tissue to accommodate caloric excess, and propose that this extreme metabolic syndrome be evaluated for as a late complication of TBI.

Endocrine and Metabolic Disturbances in Survivors of Hematopoietic Stem Cell Transplantation in Childhood and Adolescence

“…TBI was associated with MetS in our patients. TBI in children can induce MetS via effects on hypothalamic integrity or by attenuating the ability of developing adipose tissue to accommodate caloric excess [43]. Importantly, our patients with MetS were not overweight or obese; high BMI is thus not a sensitive trigger for investigation of MetS after HSCT.…”

Late effects of childhood cancer treatment: severe hypertriglyceridaemia, central obesity, non alcoholic fatty liver disease and diabetes as complications of childhood total body irradiation

“…Our case had typical features of the metabolic syndrome despite a normal BMI, with diabetes developing 9 years after total body irradiation, both in keeping with what has been previously described . Her fasting serum triglycerides had been slightly increased for several years and her glycaemic control was slowly deteriorating prior to admission (Fig.…”

EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

“…This adds to the impression that some aspects of DNA damage repair or replication are critical to metabolic homeostasis. This notion gives further credence by the observation that childhood irradiation as part of cancer therapy predisposes to later DL and IR, which may sometimes be severe (52). Modelling of this phenomenon in leptin deficient, severely obese mice suggests that irradiation leads to adipocyte and preadipocyte death, effectively reducing adipose tissue expandability, leading to a worsened metabolic state if, rather than despite, a reduction in adipose gain after irradiation (53).…”