Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98108, USA.
Diabet Med. 2011 Dec;28(12):1463-75. doi: 10.1111/j.1464-5491.2011.03464.x.
Sir Harold Himsworth's prescient observations 75 years ago have recently been expanded to include a clear relationship between insulin resistance and central nervous system function. Insulin is a master regulator of corporeal ageing in all known species, determining the rate and expression of ageing in multiple body systems. Thus, it is not surprising that insulin also plays an important role in brain ageing and cognitive decline that is associated with pathological brain ageing. Brain ageing is accompanied by reduced insulin effectiveness, either by an inadequate cellular response to insulin or by insulin deficiency attributable to reduced insulin transport across the blood-brain barrier. Age-associated brain insulin abnormalities may contribute to cognitive decline in ageing, as have been documented in older adults with Type 2 diabetes mellitus and hypertension. With more extreme pathology, brain insulin resistance may be associated with neurogenerative diseases such as Alzheimer's disease, and the condition which precedes Alzheimer's disease, known as amnestic mild cognitive impairment. In the following review, we discuss the mechanisms through which insulin resistance may induce or potentiate pathological brain ageing and thereby create a neurobiological environment that promotes neurodegeneration and associated cognitive decline. This topic is timely, given that insulin resistance-associated conditions such as diabetes and obesity have reached epidemic proportions. The prevalence of such chronic conditions, in combination with a rapidly ageing population, may result in a corresponding increase in the prevalence of Alzheimer's disease and other cognitive disorders. Fortunately, insulin resistance-associated conditions are amenable to both pharmacologic and lifestyle interventions that may reduce the deleterious impact of insulin resistance on the ageing brain.
75 年前，哈罗德·希姆斯沃斯爵士（Sir Harold Himsworth）的远见卓识得到了扩展，他明确指出胰岛素抵抗与中枢神经系统功能之间存在着关联。胰岛素是所有已知物种中调节躯体衰老的主要物质，决定了多个身体系统衰老的速度和表现。因此，胰岛素在与病理性脑衰老相关的脑衰老和认知能力下降中发挥着重要作用也就不足为奇了。脑衰老伴随着胰岛素作用的降低，这可能是由于细胞对胰岛素的反应不足，也可能是由于血脑屏障对胰岛素的转运减少导致胰岛素缺乏。与年龄相关的大脑胰岛素异常可能导致衰老过程中的认知能力下降，这在患有 2 型糖尿病和高血压的老年人中已有记录。在更极端的病理情况下，脑胰岛素抵抗可能与神经退行性疾病如阿尔茨海默病有关，以及阿尔茨海默病之前的疾病，即遗忘型轻度认知障碍。在接下来的综述中，我们讨论了胰岛素抵抗可能引发或加剧病理性脑衰老的机制，从而创造出促进神经退行性变和相关认知能力下降的神经生物学环境。考虑到与胰岛素抵抗相关的疾病，如糖尿病和肥胖症，已经达到了流行的程度，这个话题非常及时。这种慢性疾病的流行，加上人口的迅速老龄化，可能会导致阿尔茨海默病和其他认知障碍的患病率相应增加。幸运的是，与胰岛素抵抗相关的疾病可以通过药物和生活方式干预来治疗，这可能会减轻胰岛素抵抗对衰老大脑的有害影响。
