CNS Mechanisms Governing Diabetic Hyperglycemia

中枢神经系统控制糖尿病高血糖的机制

• 批准号: 9221324
• 负责人: GREGORY J MORTON
• 金额: $ 43.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221324
• 关键词: Adipose tissue; Anterior; Area; Automobile Driving; Behavioral; Blood Glucose; Body fat; Brain; Corticosterone; Data; Defect; Development; Diabetes Mellitus; Disease; Dose; Electrical Stimulation of the Brain; Ensure; Enterobacteria phage P1 Cre recombinase; Epidemic; Glucagon; Glucose; Goals; Hour; Hyperglycemia; Hypoglycemia; Hypothalamic structure; Insulin; Leptin; Leptin deficiency; Lifting; Measures; Mediating; Medical; Methods; Microinjections; Modeling; Mus; Nature; Neurons; Neurosciences; Neurosecretory Systems; Nutrient; Operative Surgical Procedures; Paper; Pathogenesis; Peripheral; Plasma; Play; Prevention; Publications; Publishing; Rattus; Recruitment Activity; Reporting; Research; Role; SF1; Societies; Streptozocin; Streptozocin Diabetes; Structure of terminal stria nuclei of preoptic region; System; Technology; Time; Tissues; Work; base; blood glucose regulation; cost; designer receptors exclusively activated by designer drugs; diabetic; feeding; glucose metabolism; glycemic control; insulin secretion; lateral ventricle; mouse model; non-diabetic; novel; novel strategies; optogenetics; photoactivation; physiologic model; prevent; promoter; public health relevance; response; ventromedial hypothalamic nucleus

 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.

 描述（由适用提供）：该项目基于证据表明大脑在血糖控制中起重要作用。总体假设是，为了响应不足的可用燃料（葡萄糖）或储存的能量（脂肪质量），大脑会激活神经信号以驱动喂养和血糖的增加，以确保足够的养分向大脑递送。通过类似于对低血糖症的反调节反应（CRR），大脑以逐步的方式招募并激活多种冗余机制，因为胰岛素缺乏症的开始后，体内脂肪储存的耗竭会发展，这些反应在糖尿病高难度的致病性中起着关键作用。在特定的目标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）招募这些反应的时间顺序，c）c）其反转解释瘦素介导的葡萄糖降低的程度。在特定目标2中，我们建议鉴定神经循环剂a）通过激活神经内分泌作用和b）瘦素介导的降低UDM来促进高血糖。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型的神经循环剂，从而将腹膜下丘脑（VMN）神经元进行光激活，该神经元将其投射到Striaia末端（ABNST）的核usus（ABNST）中，诱导非糖尿病的高血糖症。为了实现这些目标，我们将采用光遗传学和Dreadds技术与外科，免疫组织化学和最先进的方法结合使用，以测量已建立的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，并有可能支持开发新的糖尿病治疗方法。