Adaptations of Brain Energy Metabolism to Hypoglycemia

描述(由申请人提供)：糖尿病并发症可以通过强化胰岛素治疗使血糖水平正常化来减少。这种治疗虽然有效，但有增加复发性低血糖发生率的风险。它削弱了中枢对低血糖的反调节反应(反调节失败)，从而放大了严重低血糖和脑损伤的风险。这项建议的总体目标是了解这些现象背后的大脑新陈代谢变化，并确定可能的治疗方法以预防它们。我们将确定中链脂肪酸强化饮食对低血糖无意识严格控制的T1 DM受试者大脑代谢的影响，并建立其动物模型。我们将进一步检验这一假设，即长期摄入中链脂肪酸可以改善受试者在低血糖下的认知表现。从我们的动物研究中收集的数据显示，在暴露于先前的复发性低血糖后，低血糖下神经元能量代谢的特定变化，使神经元更难利用葡萄糖或乳酸等燃料。我们还发现，在反复低血糖后，乳酸被促进进入大脑，但由于随后线粒体不能像在控制条件下那样有效地利用乳酸，乳酸可能不是理想的燃料。这让我们可以寻找不同的替代底物，这些底物遵循与乳酸相同的吸收途径，但通过不同的途径进入新陈代谢。符合这些标准的一组燃料是酮体和中链脂肪酸。将最先进的技术，如体内核磁共振波谱，应用到我们的反复低血糖的动物模型中，将使我们能够解决这样的假设，即它们更适合支持新陈代谢。我们将使用这个动物模型来确定糖尿病如何混淆仅由反复低血糖引起的适应，然后继续将我们的发现转化为对强化治疗的T1糖尿病患者的认知和代谢的临床研究。我们的工作是将候选分子开发成新的疗法的第一步，这种疗法将保护大脑免受低血糖引起的脑损伤。这里提出的项目是建立在我在NRSA奖学金培训期间和此后进行的初步研究的基础上的。他们将给我一个理想的机会，继续我的核磁共振波谱及其在神经科学和糖尿病相关并发症方面的应用方面的培训。到目前为止，我接受的大部分培训都是在使用基础科学方法和动物模型。然而，想要成为一名训练有素的内科科学家，我意识到我仍然需要更多的人类调查方面的培训。为此，我参加了一个健康科学硕士项目，以接受进一步的翻译方法培训。这项职业奖励的资助将使我能够继续这些活动，并让我有时间从临床职责中解脱出来，实现我的职业目标--建立一名独立资助的内科科学家，最终与我自己的实验室和工作组一起工作。 公共卫生相关性：了解强化治疗的1型糖尿病患者大脑能量底物运输和代谢的变化，将为确定能够保护大脑免受低血糖损伤的新的治疗方法提供基础。这反过来可以在低血糖下维持正常的大脑新陈代谢，还可以更严格地控制血糖，更好地保护自己免受长期糖尿病相关并发症的影响。

DESCRIPTION (provided by applicant): Diabetic complications can be reduced by normalization of blood glucose levels via intensive insulin therapy. This treatment, while effective, bears the risk of an increased incidence of recurrent hypoglycemia. It blunts the central counterregulatory response to low blood glucose (counterregulatory failure) and thereby magnifies the risk of severe hypoglycemia and brain injury. The overall goal of this proposal is to understand the changes in brain metabolism that underlie these phenomena and identify possible therapies in order to prevent them. We will determine the impact of a medium chain fatty acid enriched diet on brain metabolism in tightly controlled T1DM subjects with hypoglycemia unawareness and an animal model thereof. We will further test the hypothesis that chronic provision of medium chain fatty acids can improve cognitive performance under hypoglycemia in human subjects. Data gathered from our animal studies revealed a specific change of neuronal energy metabolism under hypoglycemia following exposure to antecedent recurrent hypoglycemia that make is more difficult for neurons to utilize fuels like glucose or lactate. We also found that after recurrent hypoglycemia, lactate uptake into the brain was facilitated, but because it could subsequently not be utilized by mitochondria as effectively as under control conditions, it may not be an ideal fuel. This let us to look for different alternate substrates that follow the same route of uptake as lactate, but enter metabolism via a different pathway. One group of fuels that fulfill these criteria are ketone bodies and medium chain fatty acids. Applying state of the art technologies like in vivo NMR spectroscopy to our animal model of recurrent hypoglycemia will allows us address the hypothesis that they are better suited to support metabolism. We will use this animal model to determine how diabetes confounds the adaptations induced by recurrent hypoglycemia alone and then go on to translate our findings to a clinical study of cognition and metabolism in intensively treated T1DM patients. Our work is the first step towards developing candidate molecules into novel therapies that would protect the brain from hypoglycemia induced brain injury. The projects proposed here are building on preliminary studies that I have performed during my NRSA fellowship training and since then. They will give me the ideal opportunity to continue my training in NMR spectroscopy and its application to neuroscience and diabetes related complications. Most of my training thus far has been in the use of basic science methods and animal models. Wanting to become a well trained physician scientist however I realized that I still needed more training in human investigation. To that end I enrolled in a Master of Health Sciences program to receive further training in translational methods. Funding under this career award will allow me to continue these activities and give me the protected time from clinical duties that I will need to accomplish my career goal of establishing myself as an independently funded physician-scientist, eventually with my own laboratory and workgroup. PUBLIC HEALTH RELEVANCE: Understanding the changes of brain energy substrate transport and metabolism in intensively treated type 1 diabetic patients will provide the basis for the identification of novel therapeutic approaches that could protect the brain from hypoglycemia induced injury. This in turn could then sustain normal brain metabolism under hypoglycemia and would also allow for tighter glucose control with better protection from long-term diabetic related complications.