Measurement of glucose homeostasis in human brain by NMR

对低血糖(IAH)的认识受损，这是一种感知低血糖发生的能力减弱 (HG)，通常与对HG的反调节激素反应(CRR)减少共存，是HG的三倍 1型糖尿病(T1D)患者发生可能致命的严重低血糖的风险。我们的长- 长期目标仍然是确定复发的HG如何导致T1D的IAH的临床综合征。在这里，我们将 实验性复发性汞暴露后T1D时IAH的脑机制研究 并验证T1D中复发的HG导致大脑葡萄糖转运上调的假设 谷氨酸和γ-氨基丁酸能张力的改变。我们将使用MRS方法，允许 同时对大脑皮质和下丘脑进行评估以同时评估大脑 意识受损和CRR受损的相关性/中介物。高质量的磁共振数据和可重复性将 通过使用高场磁共振扫描仪和我们在上一个赠款周期中取得的技术进步来确保 (自动体素放置、实时体素跟踪、动态频率和填隙更新)。连续式 血糖监测和活动记录仪将用于记录血糖变异性和活动/锻炼/睡眠 在每次实验前几周评估这些变量对IAH的影响。我们的具体目标 包括： 目的1：检测T1D患者(N=50)低血糖前后的神经化学反应 IAH的诱导。包括谷氨酸、GABA和葡萄糖在内的神经化学特征将在 额叶皮质，在先前的神经成像工作中与IAH相关的区域，以及下丘脑，它调节 CRR，在正常血糖和7特斯拉时的HG期间，基线和反复HG方案后，强有力地诱导 T1D和NAH患者的IAH。 目的：检测IAH诱导前后T1D(N=50)大鼠脑葡萄糖转运情况。动能 将使用高血糖测量额叶皮质和下丘脑的葡萄糖转运参数 在基线和复发HG后以3特斯拉的速度夹住。 这些实验将确定复发的HG是否会改变大脑的葡萄糖供应以及谷氨酸和GABA T1D的音调以及这些大脑适应是否与钝性CRR和 T1D患者症状减轻。此外，我们还将学习血糖短途旅行和 活动/睡眠影响IAH的诱发。这些观察结果有望导致新的方法来预防和 在T1D治疗这种危及生命的疾病。

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.