Hippocampal insulin signaling deficits in diabetic rats

描述(申请人提供)：这项建议将研究糖尿病引起的胰岛素受体(IR)信号转导机制的损害，包括胰岛素刺激的蛋白磷酸化和葡萄糖转运体(GLUT)运输，与糖尿病受试者认知障碍的发展之间的关系。海马体是哺乳动物中枢神经系统(CMS)学习和记忆的重要整合中心，对胰岛素浓度的变化特别敏感和敏感。胰岛素治疗可以改善包括糖尿病在内的各种生理和病理生理环境下的认知能力。相反，IR表达和/或信号的减少可能有助于糖尿病脑病的发展，包括在1型受试者中观察到的认知障碍。与外周IR系统不同，关于IRS在CMS中的功能作用以及糖尿病表型中神经元IR系统的活性如何受损，人们知之甚少。鉴于胰岛素与认知之间的关系以及海马区在认知中的重要性，本研究的目的是：1)建立大鼠海马区IR系统各组成部分的功能关系，包括磷脂酰肌醇3-激酶(PI3-K)、丝裂原活化蛋白激酶(MARK)信号和胰岛素敏感谷氨酸；2)确定糖尿病的神经后果是否包括IR表达和/或信号的损害；3)确定IR在大鼠海马区的表达下调是否导致IR/PI3-K/MAPK信号转导和过量运输的损伤，从而为1型糖尿病实验模型中观察到的行为表现下降提供机制基础。这些研究的成功完成将：1)确定大脑中IR系统的信号转导机制；2)深入了解胰岛素在生理环境中增强认知功能的机制；3)在IR表达和/或信号障碍与与1型糖尿病相关的形态、电生理和认知缺陷之间提供一座基本的机制桥梁。

DESCRIPTION (provided by applicant): This proposal will examine the relationship between diabetes-mediated impairments in insulin receptor (IR) signal transduction mechanisms, including insulin-stimulated protein phosphorylation and glucose transporter (GLUT) trafficking, and the development of cognitive deficits in diabetic subjects. The hippocampus is an important integration center for learning and memory in the mammalian central nervous system (CMS) and is particularly sensitive and responsive to changes in insulin concentrations. Insulin administration improves cognitive performance in a variety of physiological and pathophysiological settings, including diabetes. Conversely, decreases in IR expression and/or signaling may contribute to the development of diabetic encephalopathy, including cognitive deficits observed in type 1 subjects. Unlike the peripheral IR system, little is known about the functional role of IRs in the CMS and how the activity of the neuronal IR system may be impaired in diabetes phenotypes. In view of the emerging relationship between insulin and cognition and the importance of the hippocampus in cognition, the aims of this proposal are: 1) to establish the functional relationships of components of the IR system in the rat hippocampus, including phosphatidylinositol 3-kinase (PI3-K), mitogen-activated protein kinase (MARK) signaling and the insulin-sensitive GLUTs; 2) to determine whether the neurological consequences of diabetes include impairments in IR expression and/or signaling; 3) to determine whether downregulation of IR expression in the rat hippocampus produces impairments in IR/PI3-K/MAPK signaling and GLUT trafficking, thereby providing a mechanistic basis for decreases in behavioral performance observed in experimental models of type 1 diabetes. Successful completion of these studies will: 1) determine the signal transduction mechanisms of the IR system in the brain; 2) provide insight into the mechanisms through which insulin enhances cognitive function in physiological settings; 3) provide a fundamental mechanistic bridge between impairments in IR expression and/or signaling and the morphological, electrophysiological and cognitive deficits associated with type 1 diabetes.