In vivo studies of brain glycogen in hypoglycemia

描述（由申请人提供）： 低血糖无意识是胰岛素强化治疗的并发症，常发生在医源性低血糖发作后。据报道，健康人在单次低血糖发作后会出现相关的反调节减弱。大脑检测低血糖浓度的机制尚不确定。大脑中含有大约3 mM的糖原，可在中度低血糖期间充当燃料。在大多数组织中，糖原代谢是胰岛素和葡萄糖敏感的。因此，脑糖原提供了脑碳水化合物代谢的一个方面，其对葡萄糖稳态的改变敏感，例如在糖尿病患者中所见的那些。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，以及糖原代谢在介导低血糖无意识中的潜在参与。此外，我们将评估低血糖时葡萄糖转运和脑血流之间的关系。本课题的假设是：（a）脑糖原浓度和代谢受体内血糖和/或胰岛素浓度的调节。(b)这种脑糖原可以作为葡萄糖等价物的储存库，在体内低血糖期间，当葡萄糖转运成为代谢的速率限制并且脑血流量增加时，葡萄糖等价物被用于延长的时间段。(c)在低血糖发作后，大脑储存更多的脑糖原，使得需要更长和更深的后续低血糖来消耗脑糖原，这可能提供导致低血糖无意识的机制，具有以下特定目的：（1）将急性升高的脑葡萄糖浓度与升高的血浆胰岛素浓度对体内脑糖原代谢的影响分开。(2)确定分级低血糖后脑糖原的超代偿程度，并确定脑糖原在低血糖期间作为葡萄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，脑糖原的消耗以及CBF的急性增加被触发。这些目标将在大鼠大脑中实现使用本地化的1H和13 C NMR光谱和基于灌注的功能磁共振成像。

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.