Insulin resistance and Alzheimer's disease.
Insulin resistance and Alzheimer's disease.
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DOI：
10.5483/bmbrep.2009.42.8.475
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发表时间：
2009-08-31
期刊：
影响因子：
3.8
通讯作者：
de la Monte SM
中科院分区：
文献类型：
--
作者：
de la Monte SM
新出现的数据表明，脑胰岛素抵抗和胰岛素缺乏作为认知障碍和神经退行性变，特别是阿尔茨海默病（AD）的介质的关键作用。胰岛素和胰岛素样生长因子（IGFs）调节神经元的存活、能量代谢和可塑性，这是学习和记忆所必需的。因此，胰岛素和IGF信号传导中的内源性脑特异性损伤占大多数AD相关异常。然而，认知障碍的第二个主要机制与肥胖和2型糖尿病（T2 DM）有关。人类和实验动物研究表明，与外周胰岛素抵抗相关的神经变性可能通过肝-脑轴实现，其中毒性脂质（包括神经酰胺）穿过血脑屏障并引起脑胰岛素抵抗、氧化应激、神经炎症和细胞死亡。本质上，脑胰岛素抵抗导致AD型神经变性的机制有两种：一种是由内源性CNS因子介导的;另一种是外周胰岛素抵抗伴过量细胞毒性神经酰胺产生。
Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer’s disease (AD). Insulin and insulin-like growth factors (IGFs) regulate neuronal survival, energy metabolism, and plasticity, which are required for learning and memory. Hence, endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities. However, a second major mechanism of cognitive impairment has been linked to obesity and Type 2 diabetes (T2DM). Human and experimental animal studies revealed that neurodegeneration associated with peripheral insulin resistance is likely effectuated via a liver-brain axis whereby toxic lipids, including ceramides, cross the blood brain barrier and cause brain insulin resistance, oxidative stress, neuro-inflammation, and cell death. In essence, there are dual mechanisms of brain insulin resistance leading to AD-type neurodegeneration: one mediated by endogenous, CNS factors; and the other, peripheral insulin resistance with excess cytotoxic ceramide production.