Diabetes, glucose metabolism, and neuroplasticity in the vagal complex

项目摘要 糖尿病是一个主要的健康问题，在美国有3000多万人受到影响。严重的 糖尿病引起的并发症包括心脏病、中风、高血压、失明、紧张 系统受损和自主神经功能障碍。发展成功的糖尿病的主要障碍 治疗(相对于治疗症状)是关于多面性和冗余性的相对知识差距 受代谢稳态影响并有助于控制代谢稳态的系统。这份提案调查了 控制自主神经功能的中枢神经回路与疾病相关的可塑性。实验利用小鼠 1型和2型糖尿病模型。孤束核内的二级内脏感觉神经元 (NTS)是葡萄糖感受器，通过以下方式对葡萄糖稳态的自主调节做出重大贡献 向直接调节全身血糖水平的大脑区域发出整合的内脏和体液信号， 包括迷走神经背侧运动核(DMV)，它含有迷走神经运动神经元。迷路的 糖尿病患者运动功能改变，导致自主神经失调，包括肝脏葡萄糖过多。 生产和胃动力功能障碍。我们已经发现，GABA神经元活性的变化或改变 NTS中的葡萄糖途径影响全身[葡萄糖]。谷氨酸和GABA受体重组，并且 迷走神经复合体中NTS-GABA神经元的突触兴奋持续增强 1型糖尿病模型中的高血糖。NTS中的大多数GABA神经元对 血糖升高，兴奋或抑制，但糖尿病患者的葡萄糖兴奋反应迟钝 老鼠。垂直袖状胃切除术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；收敛的数据表明，脑干背侧迷走神经复合体(DVC)是 这样的回应。脑片NTS神经元的电生理记录--化学发生和药理学 操纵NTS神经元的活动，并直接测量对照组NTS的谷氨酸和葡萄糖 糖尿病小鼠将被用来获得与糖尿病相关的功能细胞和分子数据 NTS对链脲佐菌素处理小鼠和BKS-db小鼠葡萄糖代谢的影响 分别为2型糖尿病。这一提议的广泛假设是迷走神经功能的改变 复合体反映了糖尿病病理的神经源性成分。本方案中的实验旨在：1) 确定与糖尿病相关的DVC尾端葡萄糖反应性的细胞结果；2)； 确定DVC手法对全身糖代谢的影响；3)确定减肥治疗的效果 迷走神经复合体中糖尿病相关神经可塑性的外科治疗。结果将指导未来的发展 新的疾病修正疗法，基于调节迷走神经系统中的特定神经功能 解决糖尿病患者的血糖调节失调问题。

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.