BRAIN ENERGY METABOLISM AND HYPOGLYCEMIA

脑能量代谢与低血糖

• 批准号: 6187737
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6187737
• 关键词: bioenergetics; brain metabolism; carbon; clinical research; cortisol; glucose clamp technique; glucose metabolism; glutamates; hormone regulation /control mechanism; human subject; hypercortisolism; hyperinsulinism; hypoglycemia; insulin; insulin dependent diabetes mellitus; ketones; lactates; mass spectrometry; radiotracer; stable isotope; statistics /biometry

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.

大脑是一种强制性的葡萄糖消费者，无法合成或存储超过几分钟的葡萄糖，以便在低血糖期间使用。 经历复发性低血糖的正常受试者在随后的低血糖期间增加了脑葡萄糖摄取率，因此无需发出反调节激素反应的信号以增加全身性葡萄糖的产生。 这种改变会导致低正常葡萄糖浓度的症状不认识。在1型糖尿病的患者中，这种适应导致严重低血糖症的风险增加（癫痫发作，昏迷和需要其他人以康复的帮助）。这种适应发生的确切机制以及可以引起的适应时间过程尚未阐明。与全身性葡萄糖浓度低的一致，在低血糖期间皮质醇浓度升高，并可能参与诱导脑葡萄糖摄取量增加。与低血糖相关的过度胰岛素化也可能在脑葡萄糖摄取增加和低血糖不认识的发展中发挥作用。 在本提案的最初几年计划的实验中，正常人将解决上述问题的每个问题。 过去在新墨西哥大学的实验表明，尽管全脑葡萄糖摄取大量降低，但在低血糖期间，脑氧利用率的速率仍未降低。两种可能的机制似乎是可替代的：1）葡萄糖代谢的厌氧量减少和/或2）乳酸，酮或谷氨酸等替代燃料被氧化而不是葡萄糖。利用均匀标记的13C-葡萄糖动力学的实验，并确定皮质静脉流出物质中均匀标记的13C乳酸的外观速率将评估低血糖期间厌氧性糖酵解率是否降低。同样，由于在低血糖期间大脑可能具有消耗乳酸或酮的能力，因此使用这些潜在燃料的稳定同位素的动力学建模将完成，以评估其用作替代燃料的用途。这些研究将有助于定义与100万多名1型糖尿病患者相关的基本脑代谢。 因此，更好的代谢控制是预防糖尿病长期并发症的关键，因此将变得更加可实现。