CNS Mechanisms Governing Diabetic Hyperglycemia

 描述（由申请人提供）：该项目基于大脑在血糖控制中起重要作用的证据。总体假设是，为了应对可用燃料（葡萄糖）或储存能量（脂肪量）不足，大脑激活神经回路以驱动进食和血糖增加，以确保向大脑提供足够的营养。因此，通过类比对低血糖的反调节反应（CRR），大脑以逐步的方式招募和激活多种冗余机制，因为在胰岛素缺乏症发作后进行体脂肪储存的消耗，并且这些反应在糖尿病高血糖症的发病机制中起关键作用。在具体目标1中，我们建议描述a）驱动糖尿病高血糖的神经内分泌反应，B）这些反应被招募的时间过程，以及c）它们的逆转解释瘦素介导的血糖降低的程度。在具体目标2中，我们提出鉴定以下神经回路：a）通过激活神经内分泌效应促进高血糖，和B）是瘦素介导的降糖uDM的基础。为了支持这一点，我们的初步数据，使用光遗传学方法确定了一种新的神经回路，其中投射到终纹床核（aBNST）的腹内侧下丘脑（VMN）神经元的光激活在其他非糖尿病小鼠中诱导高血糖症。为了实现这些目标，我们将采用光遗传学和DREADDs技术结合手术、免疫组织化学和最先进的方法来测量已建立的Cre驱动的小鼠模型中的葡萄糖代谢。总的来说，这项工作有可能从根本上推进我们对调节葡萄糖代谢的CNS机制的理解，并有可能促进糖尿病治疗新方法的开发。

 DESCRIPTION (provided by applicant): This project is based on evidence that the brain plays an important role in glycemic control. The overarching hypothesis is that in response to either deficient available fuel (glucose) or stored energy (adipose mass), the brain activates neurocircuits to drive increases of feeding and blood glucose to ensure adequate nutrient delivery to the brain. Thus, by analogy to the counter-regulatory response (CRR) to hypoglycemia, the brain recruits and activates multiple, redundant mechanisms in a stepwise manner as depletion of body fat stores progresses following the onset of insulin deficiency and these responses play a key role in the pathogenesis of diabetic hyperglycemia. In Specific Aim 1, we propose to delineate the a) neuroendocrine responses driving diabetic hyperglycemia, b) time-course over which these responses are recruited, and c) extent to which their reversal explains leptin-mediated glucose lowering. In Specific Aim 2 we propose to identify neurocircuits that a) promote hyperglycemia by activating neuroendocrine effects and b) underlie leptin-mediated glucose lowering uDM. In support of this, our Preliminary Data, using an optogenetics approach identifies a novel neurocircuit whereby photo-activation of ventromedial hypothalamic (VMN) neurons that project to the bed nucleus of the stria terminalis (aBNST), induces hyperglycemia in otherwise non-diabetic mice. To accomplish these objectives, we will employ optogenetics and DREADDs technologies in combination with surgical, immunohistochemical and state-of-the-art methods for measuring glucose metabolism in established Cre- driven mouse models. Overall, this work has the potential to fundamentally advance our understanding of CNS mechanisms that regulate glucose metabolism and has the potential to facilitate the development of new approaches to diabetes treatment.