Diabetes Research Center

项目总结/摘要 这是行政补充试验和可行性研究与伊丽莎白瑞亚作为校长 调查员 中枢神经系统（CNS）胰岛素调节的损伤不仅与 代谢综合征和糖尿病，但也与阿尔茨海默病（AD），年龄相关的认知能力下降， 轻度认知障碍（MCI）。外周胰岛素抵抗通常与II型糖尿病相关 (T2D)患AD的风险增加了56%。有证据表明脑胰岛素水平降低， 受损的脑胰岛素信号传导（即，胰岛素抵抗）作为这种胰岛素作用降低的原因。而 外周胰岛素抵抗和中枢胰岛素抵抗是两种不同的情况，其后果是 同样的：对胰岛素的反应丧失或降低。胰岛素治疗可以改善两个健康受试者的认知能力 以及那些患有认知障碍的人，这表明随着CNS水平的增加，CNS胰岛素 可以部分克服阻力。虽然该领域的大部分重点放在克服CNS 胰岛素抵抗在分子水平，我们认为损害可能在于血脑屏障（BBB）。 T2 D对BBB具有多种不利影响，T2 D和迟发性AD之间的联系部分归因于 脑血管病CNS胰岛素来源于血液，以可饱和转运方式穿过BBB 系统因此，在这些疾病的CNS中观察到的胰岛素抵抗可能是以下因素的结果： 胰岛素缺乏和胰岛素BBB转运不足。胰岛素转运的外周调节剂（血清 胰岛素/甘油三酯水平和炎症）已经被广泛研究，CNS的直接作用通常 忽视星形胶质细胞是围绕脑内皮细胞的主要细胞类型。因此，这一目标 本研究旨在探讨星形胶质细胞胰岛素受体在调节中枢神经系统胰岛素水平中的作用。SA 1将 确定星形胶质细胞胰岛素受体的缺失是否改变胰岛素BBB转运。SA 2将调查是否 星形胶质细胞胰岛素受体的丧失对BBB有直接影响。基于CNS的治疗获益 我们认为，血脑屏障是一种调节结构，可以作为药物干预的靶点 2型糖尿病引起的中枢神经系统胰岛素抵抗的发展。

Project Summary/Abstract This administrative supplement is for a pilot and feasibility study with Elizabeth Rhea as the Principal Investigator. Impairments in the regulation of central nervous system (CNS) insulin are clearly associated not only with metabolic syndrome and diabetes mellitus but also with Alzheimer's disease (AD), age-related cognitive decline, and mild cognitive impairment (MCI). Peripheral insulin resistance commonly associated with type II diabetes (T2D) increases the risk for developing AD by 56%. Evidence exists for both decreased brain insulin levels and impaired brain insulin signaling (i.e., insulin resistance) as causes for this decreased insulin action. While peripheral insulin resistance and central insulin resistance are two different conditions, the consequences are the same: loss of or reduced response to insulin. Insulin therapy can improve cognition in both healthy subjects as well as those suffering from cognitive impairments, suggesting that with increased CNS levels, CNS insulin resistance can be partially overcome. While much of the focus in this area has been placed on overcoming CNS insulin resistance at the molecular level, we believe the impairment could lie at the blood-brain barrier (BBB). T2D has multiple detrimental effects on the BBB and the link between T2D and late-onset AD is partly due to cerebrovascular pathologies. CNS insulin is derived from the blood and crosses the BBB in a saturable transport system. Therefore, the insulin resistance observed in the CNS in these diseases could be a consequence of insulin deficiency and inadequate insulin BBB transport. Peripheral modulators of insulin transport (serum insulin/triglyceride levels and inflammation) have been extensively studied, with the direct role of the CNS often ignored. Astrocytes are the primary cell type that surround brain endothelial cells. Therefore, the goal of this study is to investigate the role the astrocyte insulin receptor has in regulating CNS insulin levels. SA1 will determine whether loss of the astrocytic insulin receptor alters insulin BBB transport. SA2 will investigate whether the loss of the astrocytic insulin receptor has a direct effect on the BBB. Based on the therapeutic benefit of CNS insulin in AD, we believe the BBB is a regulatory structure that could be targeted for pharmaceutical interventions on the development of CNS insulin resistance due to T2D.