Diabetes, glucose metabolism, and neuroplasticity in the vagal complex

糖尿病、葡萄糖代谢和迷走神经复合体的神经可塑性

基本信息

批准号：
10685540
负责人：
Bret N Smith
金额：
$ 47.72万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685540
关键词：
Address Affect Animal Model Area Autonomic Dysfunction Blindness Blood Blood Glucose Body Weight decreased Brain Brain Stem Brain region Cell Nucleus Chronic Complex Data Development Diabetes Mellitus Diabetic mouse Disease Dorsal Electrophysiology (science)Functional disorder Future GABA Receptor Gastrectomy Gastrointestinal tract structure Genetic Glucose Glutamate Receptor Glutamates Glycemic Index Goals Health Heart Diseases Hepatic Homeostasis Human Hyperglycemia Hypertension Ingestion Insulin-Dependent Diabetes Mellitus Knowledge Liver Measurement Mediating Metabolic Control Modeling Modification Molecular Monitor Motor Motor Neurons Mus N-Methyl-D-Aspartate Receptors Nervous System Trauma Neuronal Plasticity Neurons Neurophysiology - biologic function Nutrient Outcome Output Palliative Care Pancreas Pathology Pathway interactions Patients Peripheral Persons Phenotype Physiological Play Public Health Regulation Role Signal Transduction Slice Stomach Streptozocin Stroke Symptoms Synapses System United States Vagus nerve structure Viscera Visceral bariatric surgery blood glucose regulation cell motility curative treatments diabetes control diabetes mellitus therapy diabetic dorsal motor nucleus experimental study gamma-Aminobutyric Acid gastrointestinal glucose metabolism glucose production improved in vivo inhibitory neuron mouse model neural neural circuit neurochemistry novel pharmacologic response symptom treatment synaptic function trafficking type I and type II diabetes

项目摘要

Project Summary Diabetes mellitus is a major health concern, affecting over 30 million people in the United States. Serious complications resulting from diabetes including include heart disease, stroke, hypertension, blindness, nervous system damage, and autonomic dysfunction. A major impediment to developing successful diabetes treatments (versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant systems that are affected by and contribute to control of metabolic homeostasis. This proposal investigates disease-related plasticity of central neural circuitry controlling autonomic function. Experiments utilize murine models of type 1 and type 2 diabetes. Second-order viscerosensory neurons in the nucleus tractus solitarius (NTS) are glucosensors and contribute significantly to autonomic regulation of glucose homeostasis by signaling integrated visceral and humoral signals to brain areas that directly regulate systemic glucose levels, including the dorsal motor nucleus of the vagus nerve (DMV), which contains vagal motor neurons. Vagal motor function is altered in diabetes, leading to autonomic dysregulation, including excess hepatic glucose production and gastric motility dysfunction. We have found that changes in activity of GABA neurons or altering glucose pathways in the NTS affect systemic [glucose]. Glutamate and GABA receptors are reorganized, and synaptic excitation of NTS GABA neurons is persistently increased in the vagal complex after a few days of hyperglycemia in a model of type 1 diabetes. The majority of GABA neurons in the NTS is responsive to elevated [glucose], being either excited or inhibited, but glucose-excitatory responses are blunted in diabetic mice. Vertical sleeve gastrectomy rapidly improves glycemic index in patients and animal models of diabetes, independent of weight loss; convergent data suggest the brainstem dorsal vagal complex (DVC) is integral to this response. Electrophysiological recordings from NTS neurons in slices, chemogenetic and pharmacological manipulation of NTS neuron activity, and direct glutamate and glucose measurements from the NTS of control and diabetic mice will be used to obtain functional cellular and molecular data relevant to the contribution of the NTS to glucose metabolism in the streptozotocin-treated mouse and the BKS-db mouse, models of type 1 and type 2 diabetes, respectively. The broad hypothesis of this proposal is that altered neural function in the vagal complex reflects a neurogenic component of diabetic pathology. The experiments in this proposal aim to: 1) Identify cellular outcomes of glucose responsiveness in the caudal DVC associated with diabetes; 2); Determine effects of DVC manipulation on systemic glucose metabolism; and 3) Determine effects of bariatric surgery on diabetes-related neuroplasticity in the vagal complex. Results will guide future development of novel disease-modifying therapies, based on modulating specific neural functions in the vagal system to address diabetes-related glycemic dysregulation in patients.

项目摘要糖尿病是主要的健康问题，影响了美国超过3000万人。严肃的糖尿病引起的并发症包括心脏病，中风，高血压，失明，神经系统损害和自主神经功能障碍。发展成功糖尿病的主要障碍治疗（与治疗症状相对于治疗症状）是关于多方面和多余的相对知识差距受代谢稳态控制和控制的系统。该提案调查了控制自主功能的中央神经回路的疾病相关可塑性。实验利用鼠 1型和2型糖尿病的模型。细胞核solitarius中的二阶内脏神经元（NTS）是葡萄糖传感器，并通过信号传导对直接调节全身葡萄糖水平的大脑区域进行集成的内脏和体液信号，包括迷走神经的背运动核（DMV），其中包含迷走运动神经元。迷走神经糖尿病的运动功能会改变，导致自主性失调，包括过量的肝葡萄糖生产和胃运动功能障碍。我们发现GABA神经元活动的变化或改变 NTS中的葡萄糖途径会影响全身性[葡萄糖]。谷氨酸和GABA受体进行了重组，并且几天后，在迷走神经复合物中，NTS GABA神经元的突触激发持续增加 1型糖尿病模型中的高血糖。 NTS中的大多数GABA神经元对升高的[葡萄糖]被激发或抑制，但糖尿病中的葡萄糖兴奋剂反应钝化老鼠。垂直袖胃切除术迅速改善糖尿病患者和动物模型的血糖指数，独立于减肥；收敛数据表明脑干背迷走神经复合物（DVC）是不可或缺的这个回应。 NTS神经元的电生理记录，切片，化学和药理操纵NTS神经元活性，以及对照NTS的直接谷氨酸和葡萄糖测量糖尿病小鼠将用于获得与与该功能的细胞和分子数据有关链霉菌素处理的小鼠和BKS-DB小鼠的NTS到葡萄糖代谢，类型1的模型和 2型糖尿病。该提议的广泛假设是迷走神经的神经功能改变复合体反映了糖尿病病理学的神经源成分。该提案中的实验旨在：1）鉴定与糖尿病相关的尾状DVC中葡萄糖反应性的细胞结局； 2）; 确定DVC操纵对全身葡萄糖代谢的影响； 3）确定减肥迷走神经复合物中与糖尿病相关的神经可塑性的手术。结果将指导未来的发展基于对迷走神经系统中的特定神经功能调节的新型疾病改良疗法解决患者与糖尿病相关的血糖失调。