In vivo studies of brain glycogen in hypoglycemia

描述(申请人提供)：低血糖意识不清是强化胰岛素治疗的并发症，通常在医源性低血糖发作后遇到。据报道，在健康的人中，在发生一次低血糖后，与之相关的反调节钝化。大脑检测低血糖浓度的机制尚不确定。大脑含有大约3毫米糖原，在中度低血糖时可以作为燃料。在大多数组织中，糖原代谢是胰岛素和葡萄糖敏感的。因此，脑糖原提供了大脑碳水化合物代谢的一个方面，对葡萄糖稳态的变化很敏感，例如在糖尿病患者中看到的变化。本项目的目的是确定低血糖对脑糖原和葡萄糖代谢的影响，以及糖原代谢在调节低血糖意识中的潜在参与。此外，我们还将评估低血糖时葡萄糖转运与脑血流的关系。该项目的假设是：(A)脑内糖原浓度和代谢受体内血糖和/或胰岛素浓度的调节。(B)脑糖原可以作为葡萄糖当量的储存库，在体内低血糖期间，当葡萄糖转运成为新陈代谢的限速和脑血流量增加时，可延长使用时间。(C)在低血糖发作后，大脑储存了更多的脑糖原，从而需要更长时间和更深的后续低血糖来耗尽脑糖原，这可能提供了一种导致低血糖意识的机制，其具体目的如下：(1)分离急性脑葡萄糖浓度升高和血浆胰岛素浓度升高对体内脑糖原代谢的影响。(2)确定分级低血糖后脑糖原的超代偿程度，并确定在低血糖时脑糖原是糖基单位的重要储存库。(3)确定当脑葡萄糖浓度接近己糖激酶的低KM时，脑糖原耗竭以及脑血流量的急剧增加被触发。这些目标将在大鼠大脑中使用定位的1H和13C核磁共振波谱和基于灌注的功能磁共振成像来实现。

DESCRIPTION (provided by applicant): Hypoglycemia unawareness is a complication of intensive insulin therapy often encountered after episodes of iatrogenic hypoglycemia. The associated blunting of counterregulation has been reported to occur in healthy humans after a single episode ofhypoglycemia. The mechanisms by which the brain detects low blood sugar concentrations are uncertain. The brain contains approximately 3 mM glycogen that may serve as a fuel during moderate hypoglycemia. In most tissues, glycogen metabolism is insulin- and glucose-sensitive. Brain glycogen thus provides an aspect of cerebral carbohydrate metabolism that is sensitive to alterations in glucose homeostasis such as those seen in diabetic patients. The purpose of this project is to determine the effect of hypoglycemia on brain glycogen and glucose metabolism and a potential involvement of glycogen metabolism in mediating hypoglycemia unawareness. In addition, we will assess the relationship between glucose transport and cerebral blood flow during hypoglycemia. The hypotheses of this project are (a) That brain glycogen concentration and metabolism are modulated by plasma glucose and/or insulin concentrations in vivo. (b) That brain glycogen can serve as a reservoir of glucose equivalents that are used for extended time periods during hypoglycemia in vivo when glucose transport becomes rate limiting for metabolism and cerebral blood flow is increased. (c) That following a hypoglycemic episode, the brain stores more brain glycogen such that longer and deeper subsequent hypoglycemia is necessary to deplete brain glycogen, which may provide a mechanism leading to hypoglycemia unawareness with the following specific aims: (1) To separate the effect of acutely elevated brain glucose concentrations from elevated plasma insulin concentrations on in vivo brain glycogen metabolism. (2) To determine the degree of supercompensation of brain glycogen following graded hypoglycemia and to establish that brain glycogen serves as a significant reservoir of glucosyl units during hypoglycemia. (3) To determine that depletion of brain glycogen as well as the acute increase in CBF is triggered when brain glucose concentrations approach the low Km of hexokinase. These aims will be achieved in rat brain using localized 1H and 13C NMR spectroscopy and perfusion-based fMRI.