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

• 批准号: 9917092
• 负责人: Bret N Smith
• 金额: $ 48.3万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917092
• 关键词: Address; Affect; Animal Model; Area; Autonomic Dysfunction; Blindness; 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; Glucose; Glutamate Receptor; Glutamates; Glycemic Index; Goals; Health; Heart Diseases; Hepatic; Homeostasis; Human; Hyperglycemia; Hypertension; Ingestion; Insulin-Dependent Diabetes Mellitus; Knowledge; Lead; 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; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Outcome; Output; Palliative Care; Pancreas; Pathology; Pathway interactions; Patients; Peripheral; Pharmacology; 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; base; blood glucose regulation; cell motility; curative treatments; diabetes mellitus therapy; diabetic; dorsal motor nucleus; experimental study; gamma-Aminobutyric Acid; gastrointestinal; glucose metabolism; glucose production; improved; in vivo; inhibitory neuron; mouse model; nerve supply; neural circuit; neurochemistry; novel; relating to nervous system; response; symptom treatment; synaptic function; trafficking

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.

项目概要 糖尿病是一个主要的健康问题，影响着美国超过 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、神经病 系统损伤、植物神经功能紊乱。成功发展糖尿病的主要障碍 治疗（相对于治疗症状）是关于多方面和冗余的相对知识差距 受代谢稳态影响并有助于控制代谢稳态的系统。本提案调查 控制自主功能的中枢神经回路的疾病相关可塑性。实验利用小鼠 1型和2型糖尿病模型。孤束核中的二级内脏感觉神经元 (NTS) 是葡萄糖传感器，通过以下方式对葡萄糖稳态的自主调节做出显着贡献： 将内脏和体液信号整合到直接调节全身血糖水平的大脑区域， 包括迷走神经背运动核（DMV），其中含有迷走运动神经元。迷走神经 糖尿病患者的运动功能发生改变，导致自主神经失调，包括肝葡萄糖过多 生产和胃动力功能障碍。我们发现 GABA 神经元活性的变化或改变 NTS 中的葡萄糖通路影响全身[葡萄糖]。谷氨酸和 GABA 受体被重组，并且 几天后迷走神经复合体中 NTS GABA 神经元的突触兴奋持续增加 1 型糖尿病模型中的高血糖。 NTS 中的大多数 GABA 神经元对 [葡萄糖]升高，要么被兴奋，要么被抑制，但糖尿病患者的葡萄糖兴奋反应减弱 老鼠。垂直袖状胃切除术可迅速改善糖尿病患者和动物模型的血糖指数， 与体重减轻无关；收敛数据表明脑干背侧迷走神经复合体（DVC）是 这个回应。 NTS 神经元切片、化学遗传学和药理学的电生理记录 操纵 NTS 神经元活动，并从对照 NTS 直接测量谷氨酸和葡萄糖 糖尿病小鼠将用于获得与糖尿病的贡献相关的功能性细胞和分子数据。 NTS 对链脲佐菌素处理的小鼠和 BKS-db 小鼠（1 型和 1 型模型）中葡萄糖代谢的影响 分别为2型糖尿病。该提议的广泛假设是改变了迷走神经的神经功能 复合体反映了糖尿病病理学的神经源性成分。本提案中的实验旨在：1） 确定与糖尿病相关的尾部 DVC 中葡萄糖反应性的细胞结果； 2）； 确定 DVC 操作对全身葡萄糖代谢的影响； 3) 确定减肥的效果 迷走神经复合体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 新颖的疾病缓解疗法，基于调节迷走神经系统中的特定神经功能 解决患者与糖尿病相关的血糖失调问题。