Diabetes, Cognition and the Brain

描述（由申请人提供）：拟议工作的长期目标是增加我们对2型糖尿病（T2DM）和胰岛素抵抗（IR）中大脑受损机制的理解。在这个项目的前五年，我们发现T2DM患者（以及IR患者）有特定的记忆障碍和海马体积减少，这与年龄和整体脑萎缩无关，但与葡萄糖控制障碍的程度有关。最近的文献一致报道T2DM患者脑血管反应性降低。我们在当前资助期间的发现，加上脑血管反应性的这些缺陷，使我们开发了一个可测试的模型，将这两种现象联系起来。我们将测试脑血管反应性是否解释了记忆缺陷和海马体积减少。为了实现这一目标，我们将用标准的神经心理学测试来测量认知（包括记忆和额叶的表现），用经过验证和可靠的基于MRI的方法来测量海马体积，用基于MRI和经颅多普勒（TCD）的方法来测量脑血管反应性，以确定静止和呼吸二氧化碳增加条件下的脑血流量。我们将使用的基于MRI的血流方法最近得到了验证。我们假设我们对脑血管反应性的测量可以预测我们对记忆和海马体体积的测量。此外，我们还将测试额叶是否是T2DM影响的另一个部位，从而探索我们研究结果的解剖学特异性。我们还将确定炎症标志物（已知与T2DM、胰岛素抵抗和微血管疾病相关）如何改变海马完整性和脑血管反应性之间的假设关联。为了实现这些目标，我们将研究150名年龄在45-60岁之间的个体，其中50%为女性，根据年龄、性别、教育程度和种族分为三组，每组50人（T2DM、葡萄糖耐量正常的胰岛素抵抗组和胰岛素敏感组）。2型糖尿病患者没有广泛微血管疾病的证据，从未接受过胰岛素或胰岛素促分泌剂治疗。我们假设脑血管反应性与胰岛素敏感性直接相关。胰岛素敏感性将使用MINMOD方法计算，数据来自FSIVGTT。我们有基础设施和科学团队来成功地进行拟议的研究。我们将使用标准化和经过验证的技术进行数据采集。我们在进行这类研究方面有相当丰富的经验。通过展示T2DM患者大脑受影响的机制，本研究将为使用药理学靶点改善脑血流量和血管反应性以及减少炎症作为保护中年T2DM和IR患者大脑的一种方式创造基本原理。公共卫生相关性：由于肥胖的流行，2型糖尿病在美国也以惊人的速度增长。除了糖尿病对眼睛、肾脏和四肢的不良影响外，现在有证据表明，在疾病的早期，大脑也会受到影响。这项研究的目的是增加我们对大脑如何受到影响的理解，从而能够制定治疗策略，试图在糖尿病期间保护大脑。

DESCRIPTION (provided by applicant): The long-term goal of the proposed work is to increase our understanding of the mechanisms for how the brain is impaired in Type 2 Diabetes Mellitus (T2DM) and insulin resistance (IR). During the first five years of this project we found that individuals with T2DM (as well as those with IR) have specific memory impairments and hippocampal volume reductions that are independent of age and overall brain atrophy but that are related to the degree of impairment of glucose control. Recent literature has uniformly reported that there are reductions in cerebral vascular reactivity in T2DM. Our findings during the current funding period, coupled with these deficits in cerebral vascular reactivity, have led us to develop a testable model that links the two phenomena. We will test whether cerebral vascular reactivity explains the memory deficits and hippocampal volume reductions. Towards this goal we will measure cognition (including memory and frontal lobe measures of performance) with standard neuropsychological tests, hippocampal volumes with validated and reliable MRI- based methods, and cerebral vascular reactivity measured with MRI-based and trans-cranial Doppler (TCD) methods to determine cerebral blood flow at rest and under conditions of increased respiratory CO2. The MRI- based method of blood flow we will use has been recently validated. We hypothesize that our measures of cerebral vascular reactivity will predict our measures of memory and hippocampal volumes. In addition, we will also test whether frontal lobe is an alternative site of T2DM effects, and thus explore the anatomic specificity of our findings. We will also ascertain how inflammatory markers, which are known to be associated with T2DM, insulin resistance, and micro-vessel disease, modify the hypothesized associations between hippocampal integrity and cerebral vascular reactivity. To accomplish these objectives, we will study 150 individuals 45-60 years of age, 50% female, separated into three groups of 50 (T2DM, insulin resistant individuals with normal glucose tolerance, and insulin sensitive controls) matched on age, gender, education, and race. Participants with T2DM will have no evidence of extensive micro-vessel disease and will have never been treated with insulin or insulin secretagogues. We hypothesize that cerebral vascular reactivity will be directly associated with insulin sensitivity. Insulin sensitivity will be computed using the MINMOD approach with data derived from a FSIVGTT. We have the infrastructure and the scientific team in place to successfully carry out the proposed study. We will use standardized and validated techniques for our data acquisition. We have considerable experience in conducting these types of studies. By demonstrating a mechanism by which the brain is affected in T2DM, this study will create the rationale for the use of pharmacological targets to improve cerebral blood flow and vascular reactivity as well as decrease inflammation as a way of protecting the brain of mid-life individuals with T2DM and IR. PUBLIC HEALTH RELEVANCE: Due to the rampant obesity epidemic, type 2 diabetes is also increasing at an alarming rate in the USA. In addition to the ill effects of diabetes on the eyes, kidneys, and limbs, there is now evidence that the brain is also affected early in the disease. The goal of this research is to increase our understanding of how the brain is affected so as to be in a position to develop treatment strategies to try to protect the brain during diabetes.