Department of Pathology (Neuropathology), Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903 USA.
Mol Neurodegener. 2009 Dec 24;4:54. doi: 10.1186/1750-1326-4-54.
The current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases. Previous studies linked insulin resistance diseases to high fat diets or exposure to streptozotocin, a nitrosamine-related compound that causes T2DM, NASH, and AD-type neurodegeneration. We hypothesize that low-level exposure to nitrosamines that are widely present in processed foods, amplifies the deleterious effects of high fat intake in promoting T2DM, NASH, and neurodegeneration.
Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. Injection, and upon weaning, they were fed with high fat (60%; HFD) or low fat (5%; LFD) chow for 6 weeks. Rats were evaluated for cognitive impairment, insulin resistance, and neurodegeneration using behavioral, biochemical, molecular, and histological methods.
NDEA and HFD +/- NDEA caused T2DM, NASH, deficits in spatial learning, and neurodegeneration with hepatic and brain insulin and/or IGF resistance, and reductions in tau and choline acetyltransferase levels in the temporal lobe. In addition, pro-ceramide genes, which promote insulin resistance, were increased in livers and brains of rats exposed to NDEA, HFD, or both. In nearly all assays, the adverse effects of HFD+NDEA were worse than either treatment alone.
Environmental and food contaminant exposures to low, sub-mutagenic levels of nitrosamines, together with chronic HFD feeding, function synergistically to promote major insulin resistance diseases including T2DM, NASH, and AD-type neurodegeneration. Steps to minimize human exposure to nitrosamines and consumption of high-fat content foods are needed to quell these costly and devastating epidemics.
目前 2 型糖尿病（T2DM）、非酒精性脂肪性肝炎（NASH）和阿尔茨海默病（AD）的流行都代表了胰岛素抵抗性疾病。先前的研究将胰岛素抵抗性疾病与高脂肪饮食或接触链脲佐菌素（一种导致 T2DM、NASH 和 AD 型神经退行性变的亚硝胺相关化合物）联系起来。我们假设，广泛存在于加工食品中的低水平亚硝胺暴露会放大高脂肪摄入对促进 T2DM、NASH 和神经退行性变的有害影响。
长爪沙鼠幼崽通过腹腔注射接受 N-亚硝基二乙胺（NDEA）处理，断奶后，它们喂食高脂肪（60%；HFD）或低脂肪（5%；LFD）饲料 6 周。使用行为、生化、分子和组织学方法评估大鼠的认知障碍、胰岛素抵抗和神经退行性变。
NDEA 和 HFD +/- NDEA 导致 T2DM、NASH、空间学习缺陷以及肝和脑胰岛素和/或 IGF 抵抗的神经退行性变，以及颞叶中 tau 和胆碱乙酰转移酶水平降低。此外，暴露于 NDEA、HFD 或两者的大鼠的肝脏和大脑中促进胰岛素抵抗的前神经酰胺基因增加。在几乎所有的测定中，HFD+NDEA 的不良影响比单独任何一种处理都更严重。
环境和食物污染物暴露于低水平、亚致突变的亚硝胺，加上慢性 HFD 喂养，协同作用促进包括 T2DM、NASH 和 AD 型神经退行性变在内的主要胰岛素抵抗性疾病。需要采取措施减少人类对亚硝胺的暴露和减少高脂肪含量食物的摄入，以遏制这些代价高昂和毁灭性的流行。
