MRS Studies of Brain Metabolic Adaptations in Diabetes

描述（由申请人提供）： 在低血糖期间接受强化治疗的T1 DM受试者中，在重度认知功能障碍之前，通常会出现反调节反应和轻度认知症状丧失。这两种适应被认为是显著有助于低血糖无意识，这增加了严重低血糖的风险。使用一种结合13 C MRS和[2- 13 C]醋酸盐输注的新方法，我们发现在强化治疗的T1 DM患者中，皮质单羧酸转运（MCT）和代谢上调2倍。在目标1中，我们将评估增加乳酸盐（低血糖期间血液中浓度最高的一元羧酸（MCA））的使用是否在强化治疗的T1 DM受试者中保护神经元能量代谢方面发挥重要作用。在目标2中，我们将评估MCT上调是否是由近期暴露于长期低血糖所致。这些研究提供的皮质代谢对低血糖的适应性的详细了解，应有助于制定对抗低血糖的策略，这可能有助于恢复此类患者对低血糖的认识。在目标3中，我们将使用一种新的1H MRS方法来测量脑葡萄糖转运，以评估强化治疗TIDM中葡萄糖转运的上调。在目标4中，我们将使用动物模型来验证我们的解释，即由于反复低血糖导致的乙酸盐转运和代谢增加是由于血脑屏障MCT活性上调。最后，在目标5中，我们将在动物模型中进一步评估MCT活性的上调是否可以潜在地防止低血糖能量衰竭。如果MCAs或中链脂肪酸可以预防低血糖能量衰竭，则它们可能作为夜间低血糖发作的保护性治疗给药。

DESCRIPTION (provided by applicant): In intensively treated subjects with T1DM during hypoglycemia there is often a loss of both the counterregulatory response and the mild cognitive symptoms prior to severe cognitive dysfunction. Both of these adaptations are believed to contribute significantly to hypoglycemic unawareness, which increases the risk of severe hypoglycemia. Using a novel method combining 13C MRS and [2-13C] acetate infusion we found that cortical monocarboxylic acid transport (MCT) and metabolism is up regulated 2-fold in patients with intensively treated T1DM. In Aim 1 we will assess whether increased usage of lactate, the monocarboxylic acid (MCA) with the highest concentration in blood during hypoglycemia, plays a significant role in preserving neuronal energy metabolism in subjects with intensively treated T1DM. In Aim 2 we will assess whether MCT upregulation is specifically caused by recent exposure to extended hypoglycemia. The detailed understanding provided by these studies of cortical metabolic adaptations to hypoglycemia should aid in the development of strategies for counteracting them, which may help restore awareness of hypoglycemia in such patients. In Aim 3 we will use a novel 1H MRS method for measuring brain glucose transport to assess upregulation of glucose transport in intensively treated TIDM. In Aim 4 we will use an animal model to validate our interpretation that the increase in acetate transport and metabolism due to repeated hypoglycemia is due to upregulation of blood brain barrier MCT activity. Finally in Aim 5 we will further assess in the animal model whether the upregulation of MCT activity can potentially protect against hypoglycemic energy failure. If MCAs or alternatively medium chain fatty acids can protect against hypoglycemic energy failure they may potentially be administered as a protective therapy for nocturnal hypoglycemic episodes.