Adaptations of CNS Metabolism to Hypoglycemia in Diabetes

糖尿病的长期并发症可以通过强化胰岛素治疗来逆转，但这是一个主要障碍。 是低血糖的发展。低血糖的不良反应主要累及大脑 功能，尤其是认知。我们的目标是更好地了解中枢神经系统低血糖的后果 以及它如何影响糖尿病和强化胰岛素治疗下的正常大脑代谢。这个 这项提案中描述的实验将解决大脑潜在的基本机制 低血糖时能量底物的利用。我们小组从类型1生成的Preliminray数据 糖尿病患者提示，在低血糖期间，葡萄糖以外的其他燃料的摄取和代谢 增加了。基于此，我们想要评估短链和中链脂肪酸支持 低血糖状态下的脑代谢：我们对先期复发性低血糖的影响感兴趣 糖尿病动物和正常动物的代谢率和血脑屏障摄取 替代燃料乳酸盐、醋酸盐和辛酸盐。这些底物对脑的各自贡献 糖尿病和低血糖啮齿动物模型的氧化能力尚未完全确定。 在我们的第一个目标中，我们将通过体内的磁共振光谱学来解决这个问题，我们将在那里查看 反复低血糖对醋酸酯、辛烷及其相关代谢通量的影响 谷氨酸/谷氨酰胺在神经元和星形胶质细胞中的循环。我们将在第二次调查中 目的正常大鼠和糖尿病大鼠反复低血糖是否导致血脑屏障增加 对交替底物乳酸、乙酸酯和辛烷的吸收。潜在的潜在分子机制 单羧酸转运的增加可能是转运蛋白的上调。通过测量 原位杂交和原位杂交检测单羧酸转运蛋白1、2和4的mRNA和蛋白水平 西方的污点我们将能够回答这个问题。 替代燃料、底物利用率的变化和新陈代谢的增加是否真的能够 在目标三中，将使用EEC进行功能测试，以在低血糖状态下维持正常的大脑活动 以及寻找高能磷酸盐的磁共振光谱学。 这项建议的长期目标是更好地了解营养物质的运输和代谢的变化 低血糖时大脑中的替代燃料以及糖尿病和强化胰岛素是如何 治疗会影响这一过程。这将为开发新的治疗方法提供基础 可用于临床实践以保护大脑免受低血糖所致损伤的方法。

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. Preliminray 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 have 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 lacate, 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 hybridisation and western blot we will be able to answer this question. Whether alternate fuels, changes in substrate utilisation 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.