Background

One late effect of irradiation (IRRAD) exposure is type 2 diabetes mellitus (T2DM). Nonhuman primates (NHPs) exposed to variable IRRAD doses years prior demonstrated that diabetogenesis occurred in leaner, insulin resistant monkeys with altered skeletal muscle extracellular matrix and capillarization. T2DM is characterized by peripheral tissue insulin resistance, thus irradiation exposure may cause important changes in insulin-sensitive tissues such as muscle and adipose.

Methods

Here, we prospectively investigated changes in body composition, subcutaneous adipose character and metabolism in response to irradiation (4Gy whole body exposure) in 16 male rhesus macaques (N=10 IRRAD, N=6 controls (CTL)) two years post exposure. We evaluated changes in body composition and glycemic control over 2 years, and insulin responsiveness and lipolysis at study end.

Results

Body composition by computed tomography show IRRAD NHPs develop less fat and lower fat-to-lean mass ratios over time. IRRAD significantly increased percent glycation of hemoglobin A1c over time, and 40% of IRRAD monkeys had values that define them as T2DM at 2 years. Adipose was insulin resistant as evidenced by reduced phosphorylation of the insulin receptor substrate-1 in response to insulin challenge and had increased basal lipolysis despite comparable insulin exposures to CTL.

Conclusions

Our controlled study is the first to illustrate that sub-lethal irradiation exposures directly propagate metabolic disease in the absence of obesity in NHPs. We propose, and are quantitating, that irradiation-induced fibrosis and capillary rarefaction in adipose will be present.We believe structural and functional changes interfere with insulin receptor activation akin to that seen in muscle post-irradiation.