New twist on neuronal insulin receptor signaling in health, disease, and therapeutics.
New twist on neuronal insulin receptor signaling in health, disease, and therapeutics.
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DOI：
10.1254/jphs.crj05006x
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发表时间：
2005-10
影响因子：
3.5
通讯作者：
A. Wada;H. Yokoo;T. Yanagita;Hideyuki Kobayashi
中科院分区：
文献类型：
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作者：
A. Wada;H. Yokoo;T. Yanagita;Hideyuki Kobayashi
早在开创性的研究记录了胰岛素（1967年）和胰岛素受体（1978年）在大脑中的存在之后，在过去的十年中，人们对胰岛素受体信号在健康和疾病中的大脑区域特异性多重作用的理解取得了非凡的进展。在下丘脑，胰岛素调节食物摄入、体重、外周脂肪沉积、肝脏糖异生、生殖内分泌轴和对低血糖的反调节激素的代偿分泌。在海马体中，胰岛素促进学习和记忆，独立于胰岛素的血糖调节作用。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）患者的痴呆相关；在血糖正常的情况下，全身注射胰岛素可以逆转认知障碍。鼻内注射胰岛素可增强健康人的记忆力和情绪，减轻体重，而不会引起低血糖。在下丘脑，胰岛素诱导的磷酸肌肽3激酶途径的激活，随后是atp敏感的K+通道的打开，这与胰岛素的多重作用有关。然而，胰岛素的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。
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.