Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease.
Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease.
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DOI：
10.3389/fendo.2014.00161
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发表时间：
2014
影响因子：
5.2
通讯作者：
Ruiz-Albusac JM
中科院分区：
文献类型：
--
作者：
Blázquez E;Velázquez E;Hurtado-Carneiro V;Ruiz-Albusac JM
虽然大脑一直被认为是胰岛素不敏感的器官，但最近关于胰岛素及其受体在大脑中的位置的报道已经引入了考虑这种激素负责几种功能的新方法。胰岛素在大脑中的来源已被解释为外周或中枢来源，或两者兼而有之。无论胰岛素是外周来源还是在大脑中产生，这种激素都可以通过大脑中存在的自身受体发挥作用。胰岛素在大脑中起作用的分子事件与在外周中起作用的分子事件相同。然而，某些胰岛素作用在中枢神经系统中是不同的，例如由于低胰岛素敏感性GLUT-4活性以及由于GLUT-1和GLUT-3的主要存在而引起的胰岛素诱导的葡萄糖摄取。此外，脑中的胰岛素有助于控制营养稳态、生殖、认知和记忆，以及神经营养、神经调节和神经保护作用。这些功能活动的改变可能导致几种临床实体的表现，如中枢胰岛素抵抗、2型糖尿病（T2 DM）和阿尔茨海默病（AD）。据报道，T2 DM和AD之间存在密切关联，在某种程度上，AD在糖尿病患者中的发生率是正常人的两倍，一些作者提出将这种关联命名为“3型糖尿病”。AD和T2 DM之间通过线粒体改变和氧化应激、能量和葡萄糖代谢改变、胆固醇修饰、功能障碍性蛋白O-GlcNAc化、淀粉样斑块形成、Aβ代谢改变和tau蛋白过度磷酸化存在联系。临床前AD和T2 DM知识的进步可能是开发预防这些疾病致病事件的治疗的主要刺激因素，主要是那些专注于降低脑胰岛素抵抗的治疗，这似乎是两种病理实体的共同点。
Although the brain has been considered an insulin-insensitive organ, recent reports on the location of insulin and its receptors in the brain have introduced new ways of considering this hormone responsible for several functions. The origin of insulin in the brain has been explained from peripheral or central sources, or both. Regardless of whether insulin is of peripheral origin or produced in the brain, this hormone may act through its own receptors present in the brain. The molecular events through which insulin functions in the brain are the same as those operating in the periphery. However, certain insulin actions are different in the central nervous system, such as hormone-induced glucose uptake due to a low insulin-sensitive GLUT-4 activity, and because of the predominant presence of GLUT-1 and GLUT-3. In addition, insulin in the brain contributes to the control of nutrient homeostasis, reproduction, cognition, and memory, as well as to neurotrophic, neuromodulatory, and neuroprotective effects. Alterations of these functional activities may contribute to the manifestation of several clinical entities, such as central insulin resistance, type 2 diabetes mellitus (T2DM), and Alzheimer’s disease (AD). A close association between T2DM and AD has been reported, to the extent that AD is twice more frequent in diabetic patients, and some authors have proposed the name “type 3 diabetes” for this association. There are links between AD and T2DM through mitochondrial alterations and oxidative stress, altered energy and glucose metabolism, cholesterol modifications, dysfunctional protein O-GlcNAcylation, formation of amyloid plaques, altered Aβ metabolism, and tau hyperphosphorylation. Advances in the knowledge of preclinical AD and T2DM may be a major stimulus for the development of treatment for preventing the pathogenic events of these disorders, mainly those focused on reducing brain insulin resistance, which is seems to be a common ground for both pathological entities.
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