Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?
Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?
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DOI：
10.1007/s00125-009-1501-x
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发表时间：
2009-11-01
期刊：
影响因子：
8.2
通讯作者：
Schultes, B.
中科院分区：
文献类型：
--
作者：
Hallschmid, M.;Schultes, B.
胰岛素的功能和信号通路的研究传统上集中在外周组织，如肌肉，脂肪和肝脏，而大脑通常被认为对胰腺β细胞分泌的这种激素的作用不敏感。然而，自从大约30年前发现胰岛素受体普遍存在于中枢神经系统中以来，不断增长的研究工作最终表明，循环胰岛素进入大脑，其本身不合成胰岛素，并在中枢神经网络中发挥关键作用。作为反映体脂量的肥胖信号，胰岛素向控制全身能量和葡萄糖稳态的下丘脑核团提供直接负反馈。此外，胰岛素影响不同的认知过程，例如。G.通过触发心理记忆内容的形成。因此，代谢和认知障碍如肥胖症、2型糖尿病和阿尔茨海默病与中枢神经结构对胰岛素作用的抗性有关，这可能源自遗传多态性以及由于外周胰岛素抗性而长期暴露于过量的循环胰岛素。因此，克服中枢神经胰岛素抵抗，G.通过药物干预，似乎是治疗和预防这些疾病的一个有吸引力的策略。在基础研究方法中，通过鼻内胰岛素、胰岛素类似物和胰岛素增敏剂给药来增强中枢神经胰岛素信号传导，已经产生了令人鼓舞的结果，这预示着将这些作用成功转化为未来的临床实践。
Research on functions and signalling pathways of insulin has traditionally focused on peripheral tissues such as muscle, fat and liver, while the brain was commonly believed to be insensitive to the effects of this hormone secreted by pancreatic beta cells. However, since the discovery some 30 years ago that insulin receptors are ubiquitously found in the central nervous system, an ever-growing research effort has conclusively shown that circulating insulin accesses the brain, which itself does not synthesise insulin, and exerts pivotal functions in central nervous networks. As an adiposity signal reflecting the amount of body fat, insulin provides direct negative feedback to hypothalamic nuclei that control whole-body energy and glucose homeostasis. Moreover, insulin affects distinct cognitive processes, e. g. by triggering the formation of psychological memory contents. Accordingly, metabolic and cognitive disorders such as obesity, type 2 diabetes mellitus and Alzheimer's disease are associated with resistance of central nervous structures to the effects of insulin, which may derive from genetic polymorphisms as well as from long-term exposure to excess amounts of circulating insulin due to peripheral insulin resistance. Thus, overcoming central nervous insulin resistance, e. g. by pharmacological interventions, appears to be an attractive strategy in the treatment and prevention of these disorders. Enhancement of central nervous insulin signalling by administration of intranasal insulin, insulin analogues and insulin sensitisers in basic research approaches has yielded encouraging results that bode well for the successful translation of these effects into future clinical practice.