International journal of radiation oncology, biology, physics | 2019
Whole Body Irradiation Induces Diabetes and Adipose Insulin Resistance in Non-human Primates.
Abstract
PURPOSE\nDiabetes mellitus (DM) is a delayed effect of radiation exposure in human and non-human primates. DM is characterized by peripheral tissue insulin resistance, and as a result, irradiation exposure may cause important changes in insulin-sensitive tissues such as muscle and adipose.\n\n\nMETHODS AND MATERIALS\nWe prospectively investigated changes in response to irradiation (4Gy whole body exposure) in 16 male rhesus macaques. We evaluated changes in body composition and glycemic control over two years. Insulin responsiveness, lipolysis, inflammation, and fibrosis were evaluated at study end.\n\n\nRESULTS\nIrradiated animals accumulate less fat and significantly increased percent glycation of hemoglobin A1c over time, such that 40% of irradiated monkeys had values that define them as diabetic at two years. Subcutaneous (SQ) adipose tissue 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 control animals. Irradiated SQ adipose tissue had more macrophage infiltration and adipocytes were larger. The observed hypertrophy was associated with decreased glycemic control and macrophage infiltration correlated with decreased adiponectin, signifying that inflammation is associated with worsening health. No evidence of SQ adipose fibrosis was detected.\n\n\nCONCLUSIONS\nOur study is the first to prospectively illustrate that sub-lethal irradiation exposures directly propagate metabolic disease in the absence of obesity in non-human primates and implicate SQ adipose dysfunction as a target tissue.