BRAIN ENERGY METABOLISM AND HYPOGLYCEMIA

脑能量代谢与低血糖

基本信息

批准号：
6639322
负责人：
PATRICK J. BOYLE
金额：
$ 9.44万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-06 至 2004-03-31
项目状态：
已结题

项目摘要

The brain is an obligate glucose consumer and is unable to synthesize or store more than a few minutes of glucose for use during hypoglycemia. Normal subjects who experience recurrent hypoglycemia have increased rates of brain glucose uptake during subsequent hypoglycemia and therefore have no need to signal for counterregulatory hormone responses to increase systemic glucose production. This alteration leads to symptomatic unawareness of subnormal glucose concentrations. In patients with type 1 diabetes this adaptation contributes to an increased risk of serious hypoglycemia (seizures, comas, and episodes requiring the assistance of others in order to recover). The precise mechanism by which this adaptation occurs and the time course over which it can be induced have not been elucidated. In concert with low systemic glucose concentrations, cortisol concentrations rise during hypoglycemia and may be involved in inducing an increased brain glucose uptake. Over-insulinization associated with hypoglycemia may also play a role in the development of increased brain glucose uptake and the development of hypoglycemia unawareness. Each of the afore-mentioned issues will be addressed in normal man in experiments planned for the initial years of this proposal. Past experiments at the University of New Mexico have demonstrated that rates of brain oxygen utilization fail to decrease during hypoglycemia despite significant reductions in whole brain glucose uptake. Two possible mechanisms seem tenable: 1) that the amount of glucose metabolized anaerobically decreases and/or 2) alternate fuels like lactate, ketones or glutamate are oxidized instead of glucose. Experiments utilizing uniformly labeled 13C-glucose kinetics and determining the rate of appearance of uniformly labeled 13C-lactate in cortical venous effluent will assess whether or not rates of anaerobic glycolysis decrease during hypoglycemia. Also, since the brain may have the capacity to consume lactate or ketones during hypoglycemia, kinetic modeling utilizing stable isotopes of these potential fuels will be completed to assess their use as alternate fuels. These studies will help define basic brain metabolism pertinent to over 1 million patients with type 1 diabetes. Better metabolic control, the key to the prevention of long-term complications of diabetes, will thus become more achievable.

大脑是一个专性葡萄糖消耗者，无法合成或储存超过几分钟的葡萄糖以供低血糖期间使用。经历反复低血糖的正常受试者在随后的低血糖期间脑葡萄糖摄取率增加，因此不需要发出反调节激素反应的信号来增加全身葡萄糖的产生。这种改变导致对血糖浓度低于正常的症状无意识。在 1 型糖尿病患者中，这种适应会导致严重低血糖的风险增加（癫痫发作、昏迷以及需要他人帮助才能恢复的发作）。这种适应发生的精确机制以及诱导它的时间过程尚未阐明。与低全身葡萄糖浓度相一致，皮质醇浓度在低血糖期间升高，并可能参与诱导大脑葡萄糖摄取增加。与低血糖相关的过度胰岛素也可能在大脑葡萄糖摄取增加和低血糖意识的发展中发挥作用。上述每个问题都将在本提案最初几年计划的实验中在正常人身上得到解决。新墨西哥大学过去的实验表明，尽管全脑葡萄糖摄取量显着减少，但低血糖期间脑氧利用率并未降低。两种可能的机制似乎是成立的：1）无氧代谢的葡萄糖量减少和/或2）替代燃料如乳酸、酮或谷氨酸被氧化而不是葡萄糖。利用统一标记的 13C-葡萄糖动力学并确定皮质静脉流出物中统一标记的 13C-乳酸的出现率的实验将评估低血糖期间无氧糖酵解率是否降低。此外，由于大脑在低血糖期间可能有能力消耗乳酸或酮，因此将完成利用这些潜在燃料的稳定同位素的动力学模型，以评估它们作为替代燃料的用途。这些研究将有助于定义与超过 100 万 1 型糖尿病患者相关的基本大脑代谢。更好的代谢控制是预防糖尿病长期并发症的关键，因此将变得更容易实现。