Adaptations of CNS Metabolism to Hypoglycemia in Diabetes

中枢神经系统代谢对糖尿病低血糖的适应

基本信息

批准号：
7222950
负责人：
Raimund Ingo Herzog
金额：
$ 5.8万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2008-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Long term complications of diabetes can be reversed by intensive insulin therapy; however a major obstacle is the development of hypoglycemia. The adverse effects of hypoglycemia predominantly involve brain function, particularly cognition. Our goal is to better understand the consequences of CNS hypoglycemia and how it affects normal brain metabolism in diabetes and under intensive insulin treatment. The experiments described in this proposal are going to address the fundamental mechanisms underlying brain energy substrate utilization during hypoglycemia. Preliminary data our group has generated from type 1 diabetic patients suggests that during hypoglycemia uptake and metabolism of fuels other than glucose are increased. Based on this we want to assess the ability of short and medium chain fatty acids to support brain metabolism under hypoglycemia. We are interested in the effect of antecedent recurrent hypoglycemic episodes in diabetic and normal animals on rates of metabolism and blood brain barrier uptake of the alternate fuels lactate, acetate and octanoate. The respective contribution of these substrates to brain oxidative capacity in rodent models of diabetes and hypoglycemia has not yet been fully characterized. We are going to address this question in our first aim via MR spectroscopy in vivo, where we will look at the influence of recurrent hypoglycemia on metabolic flux rates of acetate and octanoid and associated glutamate/ glutamine cycling in the neuronal and astrocytic compartments. We will investigate in our second aim whether recurrent hypoglycemia in normal and diabetic rats induces an increase in blood brain barrier uptake of the alternate substrates lactate, acetate and octanoid. A potential underlying molecular mechanism to increased monocarboxylic acid transport could be the upregulation of transporter proteins. By measuring the mRNA and protein levels of monocarboxylic acid transporters 1, 2 and 4 by in situ hybridization and western blot we will be able to answer this question. Whether alternate fuels, changes in substrate utilization and increased metabolism are indeed able to sustain normal brain activity under hypoglycemia will be tested in aim three in a functional assay using EEC as well as by MR spectroscopy looking for high-energy phosphates. The long term goal of this proposal is to better understand the changes to transport and metabolism of alternate fuels that occur within the brain during hypoglycemia and how diabetes and intensive insulin treatment affect this process. This will provide the basis for the development of novel therapeutic approaches that could be used in clinical practice to protect the brain from hypoglycemia-induced injury.

描述（由申请人提供）：糖尿病的长期并发症可以通过强化胰岛素治疗来逆转；但是，主要障碍是低血糖的发展。低血糖的不利影响主要涉及大脑功能，尤其是认知。我们的目标是更好地了解CNS低血糖的后果及其如何影响糖尿病和强化胰岛素治疗下的正常脑代谢。该提案中描述的实验将解决低血糖期间脑能量底物利用的基本机制。我们小组从1型糖尿病患者产生的初步数据表明，在低血糖摄取和葡萄糖以外的其他燃料的代谢期间增加了。基于此，我们希望评估短链脂肪酸在低血糖下支持脑代谢的能力。我们对糖尿病和正常动物的先行复发性降血糖发作对代谢率和血脑屏障摄入率的影响感兴趣。这些底物对糖尿病和低血糖啮齿动物模型中脑氧化能力的各自贡献尚未充分表征。我们将通过体内MR光谱法在我们的第一个目标中解决这个问题，在那里我们将研究反复糖类对神经元和星形胶质细胞隔室中乙酸盐和octanoid的代谢通量速率的影响。我们将在第二个目标中研究正常和糖尿病大鼠的复发性低血糖症是否会诱导乳酸，乙酸乳酸和肠tonainoi的替代底物的血液屏障摄取增加。单羧酸转运增加的潜在潜在分子机制可能是转运蛋白的上调。通过测量原位杂交和蛋白质印迹的单羧酸转运蛋白1、2和4的mRNA和蛋白质水平，我们将能够回答这个问题。替代燃料，底物利用率的变化和代谢增加是否确实能够在低血糖下维持正常的大脑活动，将在使用EEC的功能测定中测试AIM三，以及通过EEC以及MR光谱法寻找高能磷酸盐。该提案的长期目标是更好地了解低血糖期间大脑内发生的交替燃料的运输和代谢的变化，以及糖尿病和强化胰岛素治疗如何影响这一过程。这将为开发新型治疗方法的发展提供基础，这些方法可在临床实践中使用，以保护大脑免受低血糖引起的损伤。