MRS Studies of Brain Metabolic Adaptations in Diabetes

描述(由申请人提供)： 在接受强化治疗的T1 DM患者中，在低血糖期间，在严重认知功能障碍之前，通常会同时丧失反调节反应和轻微的认知症状。这两种适应都被认为是低血糖意识丧失的重要原因，这增加了严重低血糖的风险。利用一种结合~(13)C-MRS和[2-13C]醋酸酯输注的新方法，我们发现强化治疗的T1 DM患者的皮质单羧酸转运(MCT)和代谢上调了2倍。在目标1中，我们将评估增加乳酸的使用量，乳酸是低血糖时血液中浓度最高的一元羧酸(MCA)，在强化治疗的T1 DM受试者中是否起到保护神经元能量代谢的重要作用。在目标2中，我们将评估MCT上调是否是由最近长期低血糖暴露引起的。这些研究提供了对皮质代谢适应低血糖的详细了解，这将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的低血糖意识。在目标3中，我们将使用一种新的1H MRS方法来测量大脑葡萄糖转运，以评估强化治疗的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，即反复低血糖导致的醋酸盐转运和代谢增加是由于血脑屏障MCT活性上调所致。最后，在目标5中，我们将在动物模型中进一步评估MCT活性上调是否有可能预防低血糖能量衰竭。如果MCAS或中链脂肪酸可以预防低血糖能量衰竭，它们可能被用作夜间低血糖发作的保护性治疗。

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.