Type 2 Diabetes is a Delayed Late Effect of Whole-Body Irradiation in Nonhuman Primates.
Type 2 Diabetes is a Delayed Late Effect of Whole-Body Irradiation in Nonhuman Primates.
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DOI：
10.1667/rr13916.1
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发表时间：
2015-04
影响因子：
3.4
通讯作者：
Cline JM
中科院分区：
文献类型：
--
作者：
Kavanagh K;Dendinger MD;Davis AT;Register TC;DeBo R;Dugan G;Cline JM
新认识到的辐射暴露的一个后果可能是糖尿病和代谢性疾病的延迟发展。我们记录了一个独特的非人类灵长类猴子队列中2型糖尿病的发展，这些猴子在5-9年前接受了高剂量(6.5-8.4GY)的全身照射。我们在这里报道，与年龄匹配的未受辐射的猴子相比，受辐射的猴子的2型糖尿病患病率更高。这些受辐射的糖尿病灵长类动物表现出胰岛素抵抗和高甘油三酯血症，然而，它们缺乏灵长类中年糖尿病发生的典型肥胖表现。令人惊讶的是，计算机断层扫描的身体成分分析表明，先前的照射会导致特定的内脏脂肪质量损失。先前的照射导致骨骼肌中胰岛素信号有效性的降低和单核细胞趋化蛋白1水平的升高，这表明炎症加剧。然而，先前在动物和人类研究中已有文献证明，在辐射暴露下，胰腺功能没有大的缺陷。在辐射后的几年里，保持健康且没有患糖尿病的猴子明显更瘦、更小，而且在照射时通常更小、更年轻。与未接受辐射的年龄匹配的对照组相比，辐射也导致糖尿病和非糖尿病猴子的身高变小。我们的研究表明，放射后糖尿病的发生不是(全身性或异位储存库)脂肪堆积中断的结果，也不是全身性胰腺衰竭的结果，但表明周围组织，如肌肉系统，对胰岛素暴露的反应受到损害。这些动物持续的炎症似乎是辐射暴露的结果，可能会干扰胰岛素信号。目前尚不清楚一些动物因辐射的后遗症而免于患糖尿病的原因，但可能与身体大小有关。这些结果的翻译相关性表明，肌肉可能是全身照射延迟延迟效应的一个重要的、被低估的靶器官，导致胰岛素抵抗和糖尿病发展的风险增加。
One newly recognized consequence of radiation exposure may be the delayed development of diabetes and metabolic disease. We document the development of type 2 diabetes in a unique nonhuman primate cohort of monkeys that were whole-body irradiated with high doses (6.5–8.4 Gy) 5–9 years earlier. We report here a higher prevalence of type 2 diabetes in irradiated monkeys compared to age-matched nonirradiated monkeys. These irradiated diabetic primates demonstrate insulin resistance and hypertriglyceridemia, however, they lack the typical obese presentation of primate midlife diabetogenesis. Surprisingly, body composition analyses by computed tomography indicated that prior irradiation led to a specific loss of visceral fat mass. Prior irradiation led to reductions in insulin signaling effectiveness in skeletal muscle and higher monocyte chemoattractant protein 1 levels, indicative of increased inflammation. However, there was an absence of large defects in pancreatic function with radiation exposure, which has been documented previously in animal and human studies. Monkeys that remained healthy and did not become diabetic in the years after irradiation were significantly leaner and smaller, and were generally smaller and younger at the time of exposure. Irradiation also resulted in smaller stature in both diabetic and nondiabetic monkeys, compared to nonirradiated age-matched controls. Our study demonstrates that diabetogenesis postirradiation is not a consequence of disrupted adipose accumulation (generalized or in ectopic depots), nor generalized pancreatic failure, but suggests that peripheral tissues such as the musculature are impaired in their response to insulin exposure. Ongoing inflammation in these animals appears to be a consequence of radiation exposure and can interfere with insulin signaling. The reasons that some animals remain protected from diabetes as a late effect of irradiation are not clear, but may be related to body size. The translational relevance for these results suggest that muscle may be an important and underappreciated target organ for the delayed late effect of whole-body irradiation, leading to increased risk of insulin resistance and diabetes development.