Cerebral responses to insulin-induced hypoglycemia

描述(由申请人提供)：本项目的总体目标是确定大脑对胰岛素诱导的低血糖的反应。在糖尿病患者中，低血糖限制了我们达到正常血糖的能力，从而减少了疾病的长期并发症。反复发作的低血糖还会导致临床症状的低血糖意识不清，患者失去了检测低血糖的能力，直到发生神经性低血糖。大脑如何适应反复出现的低血糖尚不确定，但对这一过程的更深入了解将为我们如何更好地治疗糖尿病患者提供见解。在这项研究中，我们将使用高场磁共振成像和13C磁共振波谱直接检测人脑对体内低血糖的反应。我们将利用脑血流和神经元激活之间的关系来确定是否可以在人类中识别葡萄糖敏感区，并确定糖尿病患者的前驱血糖是否改变了大脑对低血糖的反应。我们还将确定胰岛素是否对大脑有独立于血糖的影响。我们打算检验的假设和为解决每一种假设而计划的研究目标如下。 假设1：低血糖时，大脑下丘脑、杏仁核和脑干等对葡萄糖敏感神经元丰富的区域在葡萄糖浓度较高的情况下会增加血流量。目的#1：确定低血糖时局部脑血流量增加的血糖和脑葡萄糖浓度。 假设2：在控制不佳的糖尿病患者、1型糖尿病和低血糖患者以及健康志愿者中，在相同脑葡萄糖但不同血糖浓度的低血糖期间，脑血流量将增加。目的#2A：测定控制不佳的糖尿病患者在低血糖期间局部脑血流量增加的血液和脑葡萄糖浓度，并将这些值与健康志愿者的测量值进行比较。目的#2B：确定1型糖尿病和低血糖意识不清的患者在低血糖期间局部脑血流量增加的血液和脑葡萄糖浓度，并将这些值与健康志愿者的测量值进行比较。 假设3：胰岛素对脑血流量的影响不依赖于葡萄糖。目的3：确定血清胰岛素浓度的变化是否改变脑血流量。 目的#4：通过测量事件相关电位来确定胰岛素是否改变了神经元的激活。

DESCRIPTION (provided by applicant): The overall goal of this project is to define the cerebral response to insulin-induced hypoglycemia. In diabetes, hypoglycemia limits our ability to achieve normoglycemia and thereby reduce the long-term complications of the disease. Recurrent episodes of hypoglycemia also lead to the clinical syndrome of hypoglycemia unawareness in which patients lose their ability to detect hypoglycemia until neuroglycopenia occurs. How the brain adapts to recurrent hypoglycemia is uncertain, but greater understanding of this process will provide insights into how we can better treat patients with diabetes. In this investigation, we will directly examine how the human brain responds to hypoglycemia in vivo using high field magnetic resonance imaging and 13C magnet resonance spectroscopy. We will take advantage of the relationship between cerebral blood flow and neuronal activation to determine if glucose sensing regions can be identified in humans and to determine if the response of the brain to hypoglycemia is altered by antecedent glycemia in diabetes. We will also determine if insulin has effects on the brain that are independent of glycemia. The hypotheses we intend to examine and the aims of the studies planned to address each hypothesis are below. Hypothesis #1: During hypoglycemia, regions of the brain with an abundance of glucose sensing neurons such as the hypothalamus, amygdala, and brainstem will increase blood flow at a higher glucose concentration than will other brain regions. Aim #1: To determine blood and brain glucose concentrations at which regional cerebral blood flow is increased during hypoglycemia. Hypothesis #2: Cerebral blood flow will increase during hypoglycemia at the same brain glucose but at different blood glucose concentration in patients with poorly controlled diabetes, patients with type 1 diabetes and hypoglycemia and in healthy volunteers.Aim #2A: To determine the blood and brain glucose concentrations at which regional cerebral blood flow increases during hypoglycemia in patients with poorly controlled diabetes and compare these values to those measured in healthy volunteers.Aim #2B: To determine the blood and brain glucose concentrations at which regional cerebral blood flow increases during hypoglycemia in patients with type 1 diabetes and hypoglycemia unawareness and compare these values to those measured in healthy volunteers. Hypothesis #3: Insulin has effects independent of glucose on cerebral blood flow.Aim #3: To determine if cerebral blood flow is altered by changes in serum insulin concentrations. Aim #4: To determine if insulin alters neuronal activation as measured event-related potentials.