Diabetes Research Center

糖尿病研究中心

• 批准号: 10285561
• 负责人: Steven Emanuel Kahn
• 金额: $ 34.64万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-10 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285561
• 关键词: Administrative Supplement; Affect; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Anxiety; Area; Astrocytes; Autopsy; Behavior; Blood; Blood - brain barrier anatomy; Blood Glucose; Brain; Breeding; Cell Communication; Cells; Cognition; Development; Diabetes Mellitus; Disease; Drug Kinetics; Eating; Feasibility Studies; Gatekeeping; Glial Fibrillary Acidic Protein; Glucose tolerance test; Goals; Hormones; Impaired cognition; Impairment; In Situ; Individual; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Insulin deficiency; Intervention; Investigation; Knockout Mice; Late Onset Alzheimer Disease; Learning; Link; Measures; Mediating; Memory; Metabolic syndrome; Metabolism; Molecular; Mus; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathologic; Patients; Perfusion; Peripheral; Pharmacologic Substance; Physiological; Pilot Projects; Principal Investigator; Process; Property; Proteins; Receptor Signaling; Regulation; Research; Rhea; Risk; Role; Running; SLC2A1 gene; Serum; Sex Differences; Signal Transduction; Structure; Suggestion; Surface; System; Tamoxifen; Therapeutic; Triglycerides; base; blood glucose regulation; brain endothelial cell; brain tissue; cell type; cerebrovascular pathology; cytokine; depressive symptoms; foot; glucose transport; improved; insulin regulation; insulin sensitivity; insulin signaling; interest; male; mild cognitive impairment; prevent; receptor sensitivity; regional difference; response

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.

项目摘要/摘要 这种行政补充是针对伊丽莎白·瑞亚（Elizabeth Rhea）作为校长的试点和可行性研究 研究者。 调节中枢神经系统（CNS）胰岛素的损害显然与 代谢综合征和糖尿病，但也因老年症患者（AD），与年龄相关的认知能力下降， 和轻度认知障碍（MCI）。通常与II型糖尿病相关的外周胰岛素抵抗 （T2D）将开发AD的风险增加了56％。存在均降低大脑胰岛素水平和 脑胰岛素信号传导受损（即胰岛素抵抗）是这种胰岛素作用降低的原因。尽管 外周胰岛素抵抗和中央胰岛素抵抗是两个不同的条件，后果是 相同：损失或减少对胰岛素的反应。胰岛素疗法可以改善两个健康受试者的认知 以及那些患有认知障碍的人，这表明随着中枢神经系统水平的提高，CNS胰岛素 阻力可以部分克服。尽管该领域的大部分重点都放在克服CNS上 在分子水平上的胰岛素耐药性，我们认为损伤可能位于血脑屏障（BBB）上。 T2D对BBB具有多种不利影响，T2D和晚期AD之间的联系部分是由于 脑血管病理。中枢神经系统胰岛素是从血液中得出的，并以饱和运输方式越过BBB 系统。因此，在这些疾病中的中枢神经系统中观察到的胰岛素抵抗可能是 胰岛素缺乏和胰岛素BBB运输不足。胰岛素传输的外围调节剂（血清 胰岛素/甘油三酸酯水平和炎症）已被广泛研究，CNS的直接作用经常 被忽略。星形胶质细胞是围绕脑内皮细胞的主要细胞类型。因此，目标的目标 研究是为了研究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的作用。 SA1会 确定星形细胞胰岛素受体的丧失是否会改变胰岛素BBB的转运。 SA2将调查是否 星形细胞胰岛素受体的丧失对BBB具有直接影响。基于CNS的治疗益处 AD中的胰岛素，我们认为BBB是一种可以针对药物干预措施的调节结构 关于T2D引起的CNS胰岛素抵抗的发展。