University of South Carolina School of Medicine, Department of Pharmacology, Physiology, & Neuroscience, Columbia, SC, USA; WJB Dorn VA Medical Center, Columbia, SC 29209, USA.
University of South Carolina School of Medicine, Department of Pharmacology, Physiology, & Neuroscience, Columbia, SC, USA; WJB Dorn VA Medical Center, Columbia, SC 29209, USA.
Exp Neurol. 2019 Aug;318:71-77. doi: 10.1016/j.expneurol.2019.04.012. Epub 2019 Apr 24.
In the periphery insulin plays a critical role in the regulation of metabolic homeostasis by stimulating glucose uptake into peripheral organs. In the central nervous system (CNS), insulin plays a critical role in the formation of neural circuits and synaptic connections from the earliest stages of development and facilitates and promotes neuroplasticity in the adult brain. Beyond these physiological roles of insulin, a shared feature between the periphery and CNS is that decreases in insulin receptor activity and signaling (i.e. insulin resistance) contributes to the pathological consequences of type 2 diabetes (T2DM) and obesity. Indeed, clinical and preclinical studies illustrate that CNS insulin resistance elicits neuroplasticity deficits that lead to decreases in cognitive function and increased risk of neuropsychiatric disorders. The goals of this review are to provide an overview of the literature that have identified the neuroplasticity deficits observed in T2DM and obesity, as well as to discuss the potential causes and consequences of insulin resistance in the CNS, with a particular focus on how insulin resistance impacts hippocampal neuroplasticity. Interestingly, studies that have examined the effects of hippocampal-specific insulin resistance illustrate that brain insulin resistance may impair neuroplasticity independent of peripheral insulin resistance, thereby supporting the concept that restoration of brain insulin activity is an attractive therapeutic strategy to ameliorate or reverse cognitive decline observed in patients with CNS insulin resistance such as T2DM and Alzheimer's Disease.
在周围组织中，胰岛素通过刺激外周器官摄取葡萄糖，在调节代谢稳态方面发挥着关键作用。在中枢神经系统 (CNS) 中，胰岛素在神经回路的形成和突触连接中发挥着关键作用，从发育的最早阶段就开始，并促进成年大脑的神经可塑性。除了胰岛素的这些生理作用外，外周组织和中枢神经系统之间的一个共同特征是，胰岛素受体活性和信号的降低（即胰岛素抵抗）导致 2 型糖尿病 (T2DM) 和肥胖的病理后果。事实上，临床和临床前研究表明，中枢神经系统胰岛素抵抗会引发神经可塑性缺陷，导致认知功能下降和神经精神疾病风险增加。本综述的目的是概述已确定的 T2DM 和肥胖症中观察到的神经可塑性缺陷的文献，并讨论中枢神经系统中胰岛素抵抗的潜在原因和后果，特别关注胰岛素抵抗如何影响海马神经可塑性。有趣的是，研究检查了海马特异性胰岛素抵抗的影响，表明大脑胰岛素抵抗可能独立于外周胰岛素抵抗损害神经可塑性，从而支持这样一种观点，即恢复大脑胰岛素活性是一种有吸引力的治疗策略，可以改善或逆转中枢神经系统胰岛素抵抗患者（如 2 型糖尿病和阿尔茨海默病）观察到的认知能力下降。
