Diabetes, Cognition and the Brain

描述(申请人提供)：这项拟议工作的长期目标是增加我们对2型糖尿病(T2 DM)和胰岛素抵抗(IR)大脑受损机制的了解。在这个项目的前五年，我们发现T2 DM患者(以及IR患者)有特定的记忆障碍和海马体体积缩小，这些损害与年龄和整体脑萎缩无关，但与血糖控制受损的程度有关。最近的文献一致报道，T2 DM患者的脑血管反应性降低。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可以解释记忆缺陷和海马体体积减少。为了实现这一目标，我们将使用标准的神经心理测试来测量认知能力(包括记忆力和额叶表现)，使用经过验证和可靠的基于MRI的方法来测量海马体体积，并使用基于MRI和经颅多普勒(TCD)的方法来测量脑血管的反应性，以确定静止和呼吸二氧化碳增加的条件下的脑血流量。我们将使用的基于MRI的血流测量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将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T2 DM影响的替代部位，从而探索我们发现的解剖学特异性。我们还将确定已知与T2 DM、胰岛素抵抗和微血管疾病相关的炎性标志物如何改变海马体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岁之间的人，其中50%为女性，分为三组，每组50人(T2 DM、正常糖耐量的胰岛素抵抗患者和胰岛素敏感对照组)，这些患者在年龄、性别、教育程度和种族上匹配。患有T2 DM的患者没有广泛的微血管疾病的证据，也从未接受过胰岛素或胰岛素促分泌剂的治疗。我们假设脑血管反应性将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，可以成功地开展拟议的研究。我们将使用标准化和经过验证的技术来获取数据。我们在进行这类研究方面有相当的经验。通过证明T2 DM患者大脑受到影响的机制，这项研究将为使用药物靶点改善脑血流和血管反应性以及减少炎症作为保护T2 DM和IR中年个体大脑的一种方式创造理论基础。与公共卫生相关：由于肥胖症的猖獗流行，2型糖尿病在美国也在以惊人的速度增加。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，大脑在疾病的早期也会受到影响。这项研究的目的是增加我们对大脑如何受到影响的了解，以便能够制定治疗策略，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.