Memory Advancement by Intranasal Insulin in Type 2 Diabetes (MemAID)

 描述(申请人提供)：2型糖尿病(DM)加速大脑老化，增加患痴呆症和阿尔茨海默病(AD)的风险。目前，尚无治疗糖尿病相关认知功能减退的方法。近年来，鼻腔胰岛素(INI)治疗已经成为一种潜在的新的解决方案，它可以安全地将胰岛素输送到大脑，并治疗糖尿病相关的认知障碍。我们的初步研究表明，单次40IU的INI剂量改善了成年2型糖尿病患者和健康对照组的特定认知领域和功能连接。此前的研究表明，短期INI治疗是安全的，可能会改善患有认知障碍和AD的非糖尿病患者的记忆力。这些研究为INI的潜在有效性和安全性提供了概念验证；并为确定在糖尿病人群中长期使用INI治疗的长期效果和安全性奠定了基础。我们提出了以下目标：目标1：我们提出了一项随机、双盲、安慰剂对照研究，对象为200名患有2型糖尿病的老年患者和200名非糖尿病对照组，研究在24周的时间里，每天注射40IU INI是否会改善以下方面：a.视觉空间注意力和记忆、语言学习(主要结果)的特定领域；b.双重任务中的步态速度(作为总体健康的预测指标)、日常生活功能和抑郁，与接受无菌生理盐水的糖尿病组和非糖尿病组相比。非糖尿病组将为正常衰老时出现的认知功能减退和胰岛素抵抗的临床表型提供INI效应的参考。目的2：我们将确定预测INI治疗临床相关阳性反应的表型，并确定DM组与安慰剂组和非DM组INI对学习和记忆影响的长期轨迹。临床上相关的预测因素将基于认知功能和步态与人口统计学、血糖控制、胰岛素抵抗、内皮功能和遗传指标(ApoE4)之间的关联来确定。在治疗24周和治疗后6个月评估认知、步态双重任务和功能表现的轨迹。核磁共振亚研究将探索对血流灌注和静息状态功能连接的长期影响，以及它们与认知结果的关系。目的3：比较鼻用胰岛素与安慰剂在血糖控制(空腹血糖、糖化血红蛋白、低血糖发作)、生命体征和体重方面的长期安全性。这项研究将帮助我们确定延长INI治疗的安全性；最佳结果领域；以及将在未来的大规模疗效研究中使用的最佳患者特征。预测INI治疗最佳反应的临床表型和时间进程将使INI治疗有可能针对INI治疗，以最大限度地保护老年糖尿病患者的认知功能。

 DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (DM) accelerates brain aging and increases the risk for dementia and Alzheimer's disease (AD). Currently, there is no treatment for DM-related cognitive decline. Recently, intranasal insulin (INI) therapy has emerged as a potential new solution to deliver insulin safely to the brain and treat DM- related cognitive impairment. Our pilot study showed that a single INI dose of 40IU improved specific cognitive domains and functional connectivity in type 2 DM adults and healthy controls. Previous studies showed that short-term INI treatment is safe and may improve memory in non-diabetic people with cognitive impairment and AD. These studies provided proof-of-concept supporting the potential usefulness and safety of INI; and lay the ground work to determine the long-term effects and safety of prolonged treatment with INI in diabetic population. We propose the following Aims: Aim 1: We propose a randomized, double-blind, placebo-controlled study in 200 older adults with type 2 DM and 200 non-diabetic controls examining whether 40 IU INI once daily over a 24 week period improves: a. specific domains of visuospatial attention and memory, verbal learning (primary outcomes); b. gait speed during a dual task ( as a predictor of overall health), daily living functioning and depression as compared to the DM group receiving sterile saline and the non-diabetic groups. The non-DM groups will provide reference of INI effects in a clinical phenotype of cognitive decline and insulin resistance that occurs with normal aging. Aim 2: We will determine a phenotype predicting a clinically relevant positive response to INI therapy and identify long-term trajectories of INI effects on learning and memory in the DM group vs. the placebo and the non-DM groups. Clinically relevant predictors will be determined based on associations between cognitive function and gait and demographic, glycemic control, insulin resistance, endothelial function and genetic (ApoE4) measures. The trajectory of cognitive, gait dual task and functional performances will be assessed during the 24 weeks of therapy and at 6 months post-treatment. MRI substudy will explore long-term effects on perfusion and resting state functional connectivity and their relationships to cognitive outcomes. Aim 3: To determine the long-term safety of intranasal insulin vs. placebo with regard to glycemic control (fasting glucose, Hb1Ac, hypoglycemic episodes) and vital signs and body mass. This study will help us to determine the safety of prolonged INI treatment; the best outcome domains; and the best patient characteristics to be used in future large-scale efficacy studies. The clinical phenotype and time course predicting optimal response to INI therapy would make it possible to target INI treatment for maximal benefits for preserving cognitive function in older diabetic adults.