In vivo studies of brain glycogen in hypoglycemia

低血糖中脑糖原的体内研究

• 批准号: 6685206
• 负责人: ROLF GRUETTER
• 金额: $ 27.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6685206
• 关键词: vivo; studies; brain; glycogen; hypoglycemia

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.

描述（由申请人提供）：低血糖不认识是经过多种胰岛素疗法的强化胰岛素治疗的并发症，经常在多种糖类发作后遇到。据报道，相关的反调节的钝性发生在健康人类中发生在健康的人类中。大脑检测到低血糖浓度的机制尚不确定。大脑含有大约3 mM糖原，在中度低血糖期间可以用作燃料。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，该方面对葡萄糖稳态的改变（例如糖尿病患者中看到的）敏感。该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不认识中的潜在参与。此外，我们将评估低血糖期间葡萄糖转运与脑血流之间的关系。该项目的假设是（a）脑糖原浓度和代谢是由体内血浆葡萄糖和/或胰岛素浓度调节的。 （b）脑糖原可以用作葡萄糖等效物的储层，当葡萄糖转运成为代谢和大脑血流的速率限制时，这些葡萄糖等效物用于延长的时间段。 （c）在低血糖发作之后，大脑存储更多的脑糖原，因此需要更长，更深的随后的低血糖来消耗大脑糖原，这可能会提供一种机制，从而导致低血糖的机制不认识，具有以下特定目的：（1）与脑glluce浓缩的浓度升高的影响：（1）代谢。 （2）确定分级低血糖后脑糖原的超级补偿程度，并确定脑糖原在低血糖期间是葡萄糖基单元的重要储备。 （3）确定脑葡萄糖浓度接近己糖激酶的低km时，会触发脑糖原的消耗以及CBF的急性增加。使用局部的1H和13C NMR光谱和基于灌注的fMRI，将在大鼠脑中实现这些目标。