Measurement of glucose homeostasis in human brain by NMR

低血糖意识受损（IAH），即感知低血糖发作的能力下降 (HG)并且通常与对HG的反调节激素反应（CRR）的减少共存， 1型糖尿病（T1 D）患者发生潜在致死性重度低血糖的风险。我们长久以来- 长期目标仍然是确定复发性HG如何导致T1 D IAH的临床综合征。这里我们将 研究T1 D暴露后实验性复发性HG后IAH的脑机制 并检验T1 D患者反复出现的HG导致脑葡萄糖转运上调的假设 以及多巴胺能和γ-氨基丁酸能紧张度的改变。我们将使用MRS方法， 在同一个会话中评估大脑皮层和下丘脑，以同时评估大脑 意识受损和CRR受损的相关者/介导者。高MR数据质量和再现性将 通过使用高场磁共振扫描仪和我们在上一个赠款周期取得的技术进步， （自动体素放置、实时体素跟踪、动态频率和垫片更新）。连续 血糖监测和体动记录将用于记录血糖变异性和活动/运动/睡眠 在每次实验前的几周内，评估这些变量对IAH的影响。我们的具体目标 为： 目的1：测量T1 D患者（N=50）治疗前后对低血糖的神经化学反应 诱导IAH。神经化学特征包括谷氨酸、GABA和葡萄糖将在 额叶皮层，在先前的神经成像工作中与IAH相关的区域，以及下丘脑，其调节 CRR，在基线和复发性HG方案（强烈诱导 T1 D和NAH患者的IAH。 目的2：测定T1 D（N=50）在诱导IAH前后的脑葡萄糖转运。动力学 将使用高血糖仪测量额叶皮层和下丘脑中葡萄糖转运的参数。 在基线和复发性HG后以3特斯拉夹紧。 这些实验将确定是否复发性HG改变大脑葡萄糖的可用性和谷氨酸和GABA T1 D中的张力，以及这些大脑适应是否与CRR钝化的发展相关， T1 D患者的症状减轻。此外，我们还将了解血糖波动和 活动/睡眠影响IAH的诱导。这些观察结果有望导致新的方法来预防和 治疗这种危及生命的T1 D疾病。

Impaired awareness of hypoglycemia (IAH), which is a diminished ability to perceive the onset of hypoglycemia (HG) and typically co-exists with a reduction in the counterregulatory hormone responses (CRR) to HG, triples the risk of experiencing potentially fatal severe hypoglycemia for patients with type 1 diabetes (T1D). Our long- term goal remains to identify how recurrent HG leads to the clinical syndrome of IAH in T1D. Here we will study the cerebral mechanisms of IAH in the setting of T1D following exposure to experimental recurrent HG and test the hypothesis that recurrent HG in T1D leads to an upregulation in brain glucose transport and alterations in glutamatergic and GABAergic tone. We will use MRS methodology that permits evaluation of cerebral cortex and hypothalamus in the same session to simultaneously evaluate the cerebral correlates/mediators of impaired awareness and impaired CRR. High MR data quality and reproducibility will be ensured by using high field MR scanners and technical advances we made during the last grant cycle (automated voxel placement, real-time voxel tracking, dynamic frequency and shim updates). Continuous glucose monitoring and actigraphy will be used to chronicle glucose variability and activity/exercise/sleep during the weeks before each experiment to assess the impact of these variables on IAH. Our specific aims are: Aim 1: To measure the neurochemical response to hypoglycemia in T1D (N=50) before and after induction of IAH. Neurochemical profiles including glutamate, GABA and glucose will be measured in the frontal cortex, a region associated with IAH in prior neuroimaging work, and in hypothalamus, which regulates CRR, during euglycemia and HG at 7 tesla, at baseline and after a recurrent HG protocol that robustly induces IAH in patients with T1D and NAH. Aim 2: To measure cerebral glucose transport in T1D (N=50) before and after induction of IAH. Kinetic parameters for glucose transport will be measured in the frontal cortex and hypothalamus using hyperglycemic clamps at 3 tesla at baseline and after recurrent HG. These experiments will establish if recurrent HG alters cerebral glucose availability and glutamate and GABA tone in T1D and if these cerebral adaptations are associated with the development of blunted CRR and diminished symptoms in patients with T1D. In addition, we will learn how glycemic excursions and activity/sleep impact the induction of IAH. These observations are expected to lead to new ways to prevent and treat this life-threatening condition in T1D.