Whole Body Irradiation Induces Diabetes and Adipose Insulin Resistance in Nonhuman Primates
Whole Body Irradiation Induces Diabetes and Adipose Insulin Resistance in Nonhuman Primates
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DOI：
10.1016/j.ijrobp.2019.11.034
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发表时间：
2020-03-15
影响因子：
7
通讯作者：
Kavanagh, Kylie
中科院分区：
文献类型：
--
作者：
Bacarella, Nicole;Ruggiero, Alistaire;Kavanagh, Kylie
目的：糖尿病是人类和非人类灵长类动物辐射暴露的延迟效应。糖尿病的特点是外周组织胰岛素抵抗，因此，辐照暴露可能导致胰岛素敏感组织（如肌肉和脂肪）发生重要变化。方法与材料：前瞻性研究了16只雄性恒河猴（全身照射4 Gy）对辐射反应的变化。我们评估了2年来身体成分和血糖控制的变化。在研究结束时评估胰岛素反应性、脂肪分解、炎症和纤维化。结果：随着时间的推移，受辐射的动物积累的脂肪更少，血红蛋白糖化的百分比显著增加，因此，40%的受辐射猴子在2年时的数值被定义为糖尿病。皮下（SQ）脂肪组织具有胰岛素抵抗性，胰岛素受体底物-1在胰岛素刺激下磷酸化降低，尽管与对照动物相比暴露于胰岛素，但皮下脂肪组织的基础脂肪分解增加。照射后SQ脂肪组织巨噬细胞浸润较多，脂肪细胞较大。观察到的肥大与血糖控制下降有关，巨噬细胞浸润与脂联素下降有关，表明炎症与健康恶化有关。未发现SQ脂肪纤维化的证据。结论：我们的研究首次前瞻性地说明了亚致死辐射暴露在没有肥胖的非人灵长类动物中直接传播代谢性疾病，并暗示SQ脂肪功能障碍是一个目标组织。(C) 2019 Elsevier Inc.版权所有。
Purpose: Diabetes mellitus is a delayed effect of radiation exposure in human and nonhuman primates. Diabetes mellitus 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.Methods and Materials: We prospectively investigated changes in response to irradiation (4 Gy whole body exposure) in 16 male rhesus macaques. We evaluated changes in body composition and glycemic control for 2 years. Insulin responsiveness, lipolysis, inflammation, and fibrosis were evaluated at study end.Results: Irradiated animals accumulate less fat and significantly increased percent glycation of hemoglobin A 1c over time, such that 40% of irradiated monkeys had values that define them as diabetic at 2 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.Conclusions: Our study is the first to prospectively illustrate that sublethal irradiation exposures directly propagate metabolic disease in the absence of obesity in nonhuman primates and implicate SQ adipose dysfunction as a target tissue. (C) 2019 Elsevier Inc. All rights reserved.