Wada Akihiko, Yokoo Hiroki, Yanagita Toshihiko, Kobayashi Hideyuki
Department of Pharmacology, Miyazaki Medical College, University of Miyazaki, Miyazaki 889-1692, Japan.
J Pharmacol Sci. 2005 Oct;99(2):128-43. doi: 10.1254/jphs.crj05006x. Epub 2005 Oct 6.
Long after the pioneering studies documenting the existence of insulin (year 1967) and insulin receptor (year 1978) in brain, the last decade has witnessed extraordinary progress in the understanding of brain region-specific multiple roles of insulin receptor signalings in health and disease. In the hypothalamus, insulin regulates food intake, body weight, peripheral fat deposition, hepatic gluconeogenesis, reproductive endocrine axis, and compensatory secretion of counter-regulatory hormones to hypoglycemia. In the hippocampus, insulin promotes learning and memory, independent of the glucoregulatory effect of insulin. Defective insulin receptor signalings are associated with the dementia in normal aging and patients with age-related neurodegenerative diseases (e.g., Alzheimer's disease); the cognitive impairment can be reversed with systemic administration of insulin in the euglycemic condition. Intranasal administration of insulin enhances memory and mood and decreases body weight in healthy humans, without causing hypoglycemia. In the hypothalamus, insulin-induced activation of the phosphoinositide 3-kinase pathway followed by opening of ATP-sensitive K+ channel has been shown to be related to multiple effects of insulin. However, the precise molecular mechanisms of insulin's pleiotropic effects still remain obscure. More importantly, much remains unknown about the quality control mechanisms ensuring correct conformational maturation of the insulin receptor, and the cellular mechanisms regulating density of cell surface functional insulin receptors.
在记录大脑中胰岛素（1967年）和胰岛素受体（1978年）存在的开创性研究之后很久，过去十年见证了在理解胰岛素受体信号在健康和疾病中的脑区特异性多种作用方面取得的非凡进展。在下丘脑中，胰岛素调节食物摄入、体重、外周脂肪沉积、肝糖异生、生殖内分泌轴以及对低血糖的反调节激素的代偿性分泌。在海马体中，胰岛素促进学习和记忆，这与胰岛素的血糖调节作用无关。胰岛素受体信号缺陷与正常衰老和年龄相关神经退行性疾病（如阿尔茨海默病）患者的痴呆有关；在血糖正常的情况下全身给予胰岛素可逆转认知障碍。鼻内给予胰岛素可增强健康人的记忆力和情绪，并降低体重，而不会引起低血糖。在下丘脑中，胰岛素诱导的磷酸肌醇3激酶途径激活，随后ATP敏感性钾通道开放，已被证明与胰岛素的多种作用有关。然而，胰岛素多效性作用的确切分子机制仍然不清楚。更重要的是，关于确保胰岛素受体正确构象成熟的质量控制机制以及调节细胞表面功能性胰岛素受体密度的细胞机制，仍有许多未知之处。
