Watson G Stennis, Craft Suzanne
Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
CNS Drugs. 2003;17(1):27-45. doi: 10.2165/00023210-200317010-00003.
An emerging body of evidence suggests that an increased prevalence of insulin abnormalities and insulin resistance in Alzheimer's disease may contribute to the disease pathophysiology and clinical symptoms. It has long been known that insulin is essential for energy metabolism in the periphery. In the past 2 decades, convergent findings have begun to demonstrate that insulin also plays a role in energy metabolism and other aspects of CNS function. Investigators reported 20 years ago that insulin and insulin receptors were densely but selectively expressed in the brain, including the medial temporal regions that support the formation of memory. It has recently been demonstrated that insulin-sensitive glucose transporters are localised to the same regions supporting memory and that insulin plays a role in memory functions. Collectively, these findings suggest that insulin may contribute to normal cognitive functioning and that insulin abnormalities may exacerbate cognitive impairments, such as those associated with Alzheimer's disease. Insulin may also play a role in regulating the amyloid precursor protein and its derivative beta-amyloid (Abeta), which is associated with senile plaques, a neuropathological hallmark of Alzheimer's disease. It has been proposed that insulin can accelerate the intracellular trafficking of Abeta and interfere with its degradation. These findings are consistent with the notion that insulin abnormalities may potentially influence levels of Abeta in the brains of patients with Alzheimer's disease. The increased occurrence of insulin resistance in Alzheimer's disease and the numerous mechanisms through which insulin may affect clinical and pathological aspects of the disease suggest that improving insulin effectiveness may have therapeutic benefit for patients with Alzheimer's disease. The thiazolidinedione rosiglitazone has been shown to have a potent insulin-sensitising action that appears to be mediated through the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma agonists, such as rosiglitazone, also have anti-inflammatory effects that may be of therapeutic benefit in patients with Alzheimer's disease. This review presents evidence suggesting that insulin resistance plays a role in the pathophysiology and clinical symptoms of Alzheimer's disease. Based on this evidence, we propose that treatment of insulin resistance may reduce the risk or retard the development of Alzheimer's disease.
越来越多的证据表明，阿尔茨海默病中胰岛素异常和胰岛素抵抗患病率的增加可能导致该疾病的病理生理过程和临床症状。长期以来，人们都知道胰岛素对外周能量代谢至关重要。在过去20年中，多项研究结果开始表明，胰岛素在中枢神经系统（CNS）的能量代谢及其他方面也发挥作用。20年前，研究人员报告称，胰岛素和胰岛素受体在大脑中密集但有选择性地表达，包括支持记忆形成的内侧颞叶区域。最近有研究表明，胰岛素敏感的葡萄糖转运体定位于支持记忆的相同区域，且胰岛素在记忆功能中发挥作用。总体而言，这些发现表明胰岛素可能有助于正常认知功能，而胰岛素异常可能会加剧认知障碍，比如与阿尔茨海默病相关的认知障碍。胰岛素在调节淀粉样前体蛋白及其衍生物β淀粉样蛋白（Aβ）方面可能也发挥作用，Aβ与老年斑有关，而老年斑是阿尔茨海默病的神经病理学特征。有人提出，胰岛素可以加速Aβ的细胞内运输并干扰其降解。这些发现与胰岛素异常可能会影响阿尔茨海默病患者大脑中Aβ水平的观点一致。阿尔茨海默病中胰岛素抵抗发生率的增加以及胰岛素可能影响该疾病临床和病理方面的众多机制表明，提高胰岛素有效性可能对阿尔茨海默病患者具有治疗益处。噻唑烷二酮类药物罗格列酮已被证明具有强大的胰岛素增敏作用，这一作用似乎是通过过氧化物酶体增殖物激活受体γ（PPAR-γ）介导的。PPAR-γ激动剂，如罗格列酮，也具有抗炎作用，这可能对阿尔茨海默病患者具有治疗益处。这篇综述提供的证据表明胰岛素抵抗在阿尔茨海默病的病理生理过程和临床症状中起作用。基于这一证据，我们提出治疗胰岛素抵抗可能会降低患阿尔茨海默病的风险或延缓其发展。
