Mechanisms linking insulin resistance to brain structure, pathology, and function

描述（由申请人提供）：代谢紊乱，特别是2型糖尿病（T2D），是常见的，并且随着当代生活方式的增加发病率。然而，大脑中胰岛素抵抗的原因和影响是复杂的，因为它与其他激素信号系统相互作用，特别是强烈影响胰岛素敏感性的脂肪因子（如脂联素和瘦素）。表征胰岛素抵抗患者患AD风险增加的分子机制现在具有很大的科学意义（PAS-11-029），它们的阐明可能导致新的治疗策略。胰岛素抵抗是T2D的核心特征，可能导致脑部病理增加。T2D与脑血管疾病有一定的相关性，但可能更令人感兴趣的是，最近的数据显示脑胰岛素信号异常与AD病理，特别是淀粉样蛋白- β和tau相关病理相关。此外，在AD中也发现了脂肪因子受体表达异常。该跨学科合作项目的总体目标是建立人类大脑中连接胰岛素、过猪素和瘦素信号的分子机制，并确定该网络中的失调如何与大脑结构、病理和功能（包括AD和认知障碍）相关。该研究将量化胰岛素、脂联素和瘦素信号、神经元和突触的标志物，并使用现有的病理和临床数据，这些数据来自200名社区居住的女性和男性，有或没有T2D，并在认知功能范围内，这些患者在临床表现良好，死亡并作为宗教团体研究（P30AG010161; R01AG015819）的参与者进行尸检。首先，我们将描述脑胰岛素、脂联素和瘦素途径成分在有和没有T2D受试者中的表达水平（目的1）。然后，在人类死后组织中使用一种新的离体刺激范式，我们将实验测试大脑组织中胰岛素和脂肪因子信号的刺激反应和相互作用（目的2）。最后，在本研究的临床病理转化部分，我们将测试胰岛素、脂联素和lepti信号与大脑结构（突触标记）、病理（淀粉样蛋白- β和tau）和功能（认知）的关系。由于胰岛素抵抗是一种常见的疾病，已有治疗方法，因此本研究将在人类大脑中胰岛素和脂肪因子机制的研究方面开辟新的领域，并显示胰岛素抵抗和脂肪因子功能障碍在多个层面上与人类大脑的变化相关，从而提供具有改善公众健康潜力的重要数据。

DESCRIPTION (provided by applicant): Metabolic disturbances in particular type 2 diabetes mellitus (T2D), are common and increasing in incidence with contemporary lifestyles. T2D is associated with adverse health consequences, including impaired brain Yet, the causes and effects of insulin resistance in the brain are complex, as there are reciprocal interactions with other hormone signaling systems, in particular the adipokines (e.g., adiponectin and leptin) which strongly affect insulin sensitivity. Characterizing the molecular mechanisms that increase risk of AD for persons with insulin resistance is now of great scientific interest (PAS-11-029) and their elucidation may lead to novel therapeutic strategies. Insulin resistance, a core feature of T2D, may lead to increased brain pathology. T2D is modestly associated with cerebrovascular disease, but perhaps of even greater interest, recent data show brain insulin signaling abnormalities associated with AD pathology, specifically amyloid-ß and tau-related pathology as well. Furthermore, adipokine receptor expression abnormalities have also been found in AD. The overall goal of the proposed interdisciplinary collaborative project is to establish molecular mechanisms linking insulin, adopinectin, and leptin signaling in human brain, and determine how dysregulation in this network is associated with brain structure, pathology, and function, including AD and cognitive impairment. The proposed study will quantify markers of insulin, adiponectin, and leptin signaling, neurons and synapses, and use existing pathologic and clinical data from 200 community-dwelling women and men, with and without T2D and across a spectrum of cognitive function, who were well-characterized clinically and died and came to autopsy as participants in the Religious Orders Study (P30AG010161; R01AG015819). First, we will describe expression levels of brain insulin, adiponectin, and leptin pathway components in subjects with and without T2D (Aim 1). Then, using a novel ex-vivo stimulation paradigm in human postmortem tissue, we will experimentally test the stimulated responses and interactions of insulin and adipokine signaling in brain tissue (Aim 2). Finally, in the clinicopathologic translational component of the study, we will test the relations of insulin, adiponectin, and lepti signaling to brain structure (synaptic markers), pathology (amyloid-ß and tau), and function (cognition). Because insulin resistance is a common condition for which therapies are available, this study will break new ground in research of insulin and adipokine mechanisms in human brain, and show insulin resistance and adipokine dysfunction are associated with changes in the human brain at multiple levels, thus providing important data with potential to improve public health.