CNS Mechanisms Governing Diabetic Hyperglycemia

 描述(由申请者提供)：这个项目是基于大脑在血糖控制中发挥重要作用的证据。最重要的假设是，无论是对缺乏可用燃料(葡萄糖)还是对储存的能量(脂肪质量)，大脑都会激活神经回路，以驱动摄食和血糖的增加，以确保向大脑提供足够的营养。因此，通过类似于对低血糖的反向调节反应(CRR)，大脑以一种循序渐进的方式招募并激活多个多余的机制，因为随着胰岛素缺乏的发生，体内脂肪储备的耗尽进展，这些反应在糖尿病高血糖的发病机制中起着关键作用。在特定的目标1中，我们建议描绘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)它们的逆转在多大程度上解释瘦素介导的血糖下降。在具体目标2中，我们建议识别神经回路，a)通过激活神经内分泌效应促进高血糖，b)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，利用光遗传学方法确定了一种新的神经回路，通过该回路，投射到终纹床核(ABNST)的下丘脑腹内侧(VMN)神经元的光激活可以在其他非糖尿病小鼠中诱导高血糖。为了实现这些目标，我们将使用光遗传学和DREADDS技术，结合外科手术、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。总体而言，这项工作有可能从根本上促进我们对调节葡萄糖代谢的中枢神经系统机制的理解，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.