Enhancing cerebral vasoreativity & cognition by intranasal insulin in T2DM

描述（由申请人提供）：2型糖尿病（T2 DM）是血管性痴呆的主要风险因素。DM改变胰岛素通过血脑屏障的转运，影响灌注和神经功能。鼻内给药能够有效地将胰岛素递送至大脑。临床研究表明，改善健康和认知受损的人的认知功能和记忆。我们的目标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。我们提出了一项初步研究，采用双盲、安慰剂对照、交叉设计，在30例年龄>50岁的T2 DM受试者和30例健康对照者中检查单剂量鼻内胰岛素对局部血管反应性和认知功能的影响。目标1：我们将在对照组和糖尿病组中通过3-D连续动脉自旋标记（CASL）MRI在3 T下测量40 IU单剂量鼻内胰岛素与安慰剂对CO2激发的局部灌注和血管反应性的急性影响。我们将使用经颅多普勒来确定鼻内胰岛素与安慰剂对基于心跳间压力-流速关系测量的动态自动调节的影响。目标二：我们将确定与安慰剂组和对照组相比，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、记忆力和执行功能。这项转化研究将解决一个重要领域的影响鼻内胰岛素对脑血流调节和认知老年糖尿病患者尚未研究。鼻内胰岛素给药可能为防治2型糖尿病微血管病变和脑血管并发症提供新的治疗靶点。如果成功，这种方法可能对大量老年T2 DM患者的临床管理产生重大影响。 公共卫生相关性： 糖尿病是大血管和小血管动脉粥样硬化、中风和血管性痴呆的主要危险因素。本初步研究旨在确定鼻内胰岛素改善老年糖尿病患者脑血管反应性的疗效，并探讨其对认知功能的影响。如果证实有效，鼻内胰岛素可能成为治疗老年糖尿病患者微血管疾病的新的预防和治疗靶点。

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.