Hippocampal insulin signaling deficits in diabetic rats

描述（由申请人提供）：该提案将研究糖尿病介导的胰岛素受体（IR）信号转导机制损伤，包括胰岛素刺激的蛋白质磷酸化和葡萄糖转运蛋白（GLUT）运输，与糖尿病受试者认知缺陷的发展之间的关系。海马是哺乳动物中枢神经系统（CMS）重要的学习和记忆整合中心，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多种生理和病理生理环境下的认知表现。相反，IR表达和/或信号的减少可能导致糖尿病性脑病的发展，包括在1型受试者中观察到的认知缺陷。与外周IR系统不同，人们对IR在CMS中的功能作用知之甚少，也不知道神经元IR系统的活性如何在糖尿病表型中受损。鉴于胰岛素与认知之间的关系以及海马在认知中的重要性，本研究的目的是：1)建立大鼠海马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）信号和胰岛素敏感的GLUTs；2)确定糖尿病的神经系统后果是否包括IR表达和/或信号的损害；3)确定大鼠海马IR表达下调是否会导致IR/PI3-K/MAPK信号通路和GLUT转运受损，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依据。这些研究的成功完成将：1)确定IR系统在大脑中的信号转导机制；2)深入了解胰岛素在生理环境下增强认知功能的机制；3)在IR表达和/或信号的损伤与1型糖尿病相关的形态学、电生理和认知缺陷之间提供了一个基本的机制桥梁。

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.