Enhancement of cerebral vasoreactivity and cognition by intranasal insulin in typ

描述（由申请人提供）：2型糖尿病（T2DM）是血管性痴呆的主要危险因素。糖尿病改变胰岛素在血脑屏障中的转运，影响灌注和神经元功能。鼻内给药能够有效地将胰岛素输送到大脑。临床研究表明，健康和认知受损人群的认知功能和记忆得到改善。我们的目的是确定鼻内胰岛素对老年糖尿病患者局部灌注和认知的急性影响。我们提出了一项试点研究，采用双盲、安慰剂对照、交叉设计，研究单剂量鼻内胰岛素对30名2型糖尿病患者和30名50岁健康对照者的局部血管反应性和认知功能的影响。目的1：我们将确定单次40 iu剂量鼻内胰岛素与安慰剂对对照组和糖尿病组的局部灌注和血管反应性的急性影响，通过3特斯拉的3- d连续动脉自旋标记（CASL） MRI测量。我们将使用经颅多普勒来确定鼻内胰岛素和安慰剂对基于心跳间压力-血流速度关系测量的动态自动调节的影响。目的2：我们将确定与安慰剂和对照组相比，鼻内胰岛素是否能改善老年糖尿病患者的认知功能，包括注意力、记忆和执行功能。这项转化研究将解决鼻内胰岛素对老年糖尿病患者脑血流调节和认知的影响这一尚未研究的重要领域。鼻内注射胰岛素可能为预防和治疗T2DM微血管疾病和脑血管并发症提供新的治疗靶点。如果成功，这种方法可能会对大量老年T2DM患者的临床管理产生重大影响。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM) is a major risk factor for vascular dementia. DM alters insulin transport across blood-brain barrier affecting perfusion and neuronal function. Intranasal administration enables to effectively deliver insulin to the brain. Clinical studies demonstrated improvement of cognitive function and memory in healthy and cognitively impaired people. Our goal is to determine the acute effects of intranasal insulin on regional perfusion and cognition in older diabetic adults. We propose a pilot study to examine the effects of a single dose of intranasal insulin on regional vasoreactivity and cognitive functions in 30 subjects with T2DM and 30 healthy controls >50 years old using a double blinded, placebo-controlled, cross-over design. Aim 1: We will determine the acute effects of a single 40-IU dose of intranasal insulin vs. placebo on regional perfusion and vasoreactivity to CO2 challenge measured by 3-D continuous arterial spin labeling (CASL) MRI at 3 Tesla in the control and diabetic groups. We will use transcranial Doppler to determine effects on intranasal insulin vs. placebo on dynamic autoregulation based on measurements of beat-to-beat pressure-flow velocity relationship. Aim 2: We will determine whether intranasal insulin improves cognitive functioning including attention, memory and executive function in older diabetic patients as compared with placebo and the control group. This translational study will address an important area about the effects of intranasal insulin on cerebral blood flow regulation and cognition in older diabetic people that has not been studied. Intranasal insulin administration may provide a novel therapeutic target for prevention and treatment of microvascular disease and cerebrovascular complications of T2DM. If successful, this approach may have significant impact on clinical management of large population of older adults with T2DM. PUBLIC HEALTH RELEVANCE: Diabetes mellitus is a major risk factor for both large and small vessel atherosclerosis, strokes, and vascular dementia. This pilot study aims to determine the efficacy of intranasal insulin to improve cerebral vasoreactivity and to explore the effects on cognitive function in older diabetic adults. If proven effective, intranasal insulin may become a new preventive and therapeutic target for treatment of cerebromicrovascular disease in older diabetic patients.