Adaptations of Brain Energy Metabolism to Hypoglycemia

描述（由申请人提供）：糖尿病并发症可通过强化胰岛素治疗使血糖水平正常化而减少。这种治疗虽然有效，但有增加复发性低血糖发生率的风险。它削弱了对低血糖的中枢反调节反应（反调节失败），从而增加了严重低血糖和脑损伤的风险。这项提议的总体目标是了解这些现象背后的脑代谢变化，并确定可能的治疗方法来预防它们。我们将确定中链脂肪酸富集饮食对严格控制的T1DM伴低血糖无意识患者脑代谢的影响，并建立动物模型。我们将进一步验证长期提供中链脂肪酸可以改善人类受试者在低血糖情况下的认知表现的假设。我们从动物实验中收集的数据显示，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以利用葡萄糖或乳酸盐等燃料。我们还发现，反复低血糖后，乳酸被大脑吸收，但由于它随后不能被线粒体有效地利用，因为在控制条件下，它可能不是一种理想的燃料。这让我们寻找不同的替代底物，它们遵循与乳酸盐相同的摄取途径，但通过不同的途径进入代谢。满足这些标准的一类燃料是酮体和中链脂肪酸。将体内核磁共振波谱等最先进的技术应用于我们的复发性低血糖动物模型，将使我们能够解决它们更适合支持新陈代谢的假设。我们将使用该动物模型来确定糖尿病如何混淆复发性低血糖引起的适应性，然后继续将我们的发现转化为强化治疗的T1DM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疗法的第一步，这些新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奖学金培训期间和之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，继续我在核磁共振波谱及其在神经科学和糖尿病相关并发症中的应用方面的培训。到目前为止，我的大部分训练都是在使用基础科学方法和动物模型。然而，我想成为一名训练有素的内科科学家，我意识到我还需要更多的人体研究方面的训练。为此，我报名参加了一个健康科学硕士课程，接受进一步的翻译方法培训。这项职业奖的资助将使我能够继续这些活动，并为我提供免受临床职责的保护时间，我将需要完成我的职业目标，使我成为一名独立资助的医师科学家，最终拥有自己的实验室和工作组。

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.