Mechanism of ultrasound neuromodulation effects on glucose homeostasis and diabetes

超声神经调节对葡萄糖稳态和糖尿病的影响机制

• 批准号: 10586211
• 负责人: Raimund Ingo Herzog
• 金额: $ 78.49万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586211
• 关键词: Abdomen; Acute; Address; Affect; Afferent Neurons; Animal Model; Animals; Area; Autonomic Pathways; Autonomic nervous system; Brain; Brain Stem; Carbon; Cell Nucleus; Cells; Central Nervous System; Circulation; Clinical; Clinical Data; Clinical Research; Closure by clamp; Data; Denervation; Development; Diabetes Mellitus; Diagnosis; Distal; Focused Ultrasound; Focused Ultrasound Therapy; Gastrointestinal tract structure; Genetic; Glucagon; Glucose; Glucose Clamp; Glycogen; Hepatic; Hepatology; Homeostasis; Hormones; Human; Hyperglycemia; Hyperinsulinism; Hypothalamic structure; Individual; Ingestion; Insulin; Insulin Resistance; Investigation; Ion Channel; Link; Liver Glycogen; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mediator; Mesentery; Metabolic; Methods; Microelectrodes; Modality; Modeling; Molecular; Mus; NMR Spectroscopy; Nerve; Nerve Fibers; Nerve Plexus; Nervous System; Neuroendocrinology; Neurons; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; OGTT; Patients; Peripheral; Physiologic pulse; Pilot Projects; Play; Portal vein structure; Pre-Clinical Model; Reflex action; Reflex control; Regulation; Resistance; Rodent Model; Role; Scientist; Sensory; Signal Transduction; Site; Testing; Therapeutic Effect; Time; Tracer; Transgenic Organisms; Type 2 diabetic; Uncertainty; Validation; Work; alternative treatment; blood glucose regulation; cell type; clinical translation; design; diabetic; diabetic patient; euglycemia; experimental study; feeding; gastrointestinal; ghrelin; glucagon-like peptide 1; glucose disposal; glucose metabolism; glucose sensor; glucose tolerance; glycemic control; human subject; imaging modality; innovation; insulin sensitivity; neural circuit; neuroregulation; novel; optogenetics; pre-clinical; preclinical study; response; sensor; skills; stable isotope; synergism; therapeutic target; tool; translational study; treatment site; ultrasound

Project Summary The dominant and increasingly evident role of the central nervous system in glucose metabolism regulation remains an attractive therapeutic target for diabetes. Brain stem and hypothalamic coordinating centers of feeding and glucose homeostasis have been well characterized over the years, yet uncertainty over the vari- ous afferent autonomic pathways relaying information from the GI tract to the brain remains. While animal stud- ies indicate that neuronal sensors relaying information about changes in glucose levels and other nutrients are situated within the hepatic portal vein, less is known about these factors in humans. In fact, constrained by a lack of non-invasive tools to interrogate these regulatory circuits in humans, clinical translation of much of the recent advances in our understanding of feeding and glucose control in rodent models remains an active area of investigation. To overcome this critical limitation our group has recently identified neuromodulation via pe- ripheral focused ultrasound (pFUS) as a promising new tool to non-invasively and selectively alter autonomic nervous system afferents to the brain. Exciting preliminary studies in several rodent models of diabetes have revealed that transient application of ultrasound pulses to the hepatoportal plexus can enact long-lasting nor- malization of the hypothalamic glucose setpoint to restore euglycemia in an insulin-independent manner. The experiments under this proposal are designed to build upon this work to characterize the effect of pFUS di- rected towards the hepatoportal neuronal plexus in humans with newly diagnosed type 2 diabetics. We will quantify pFUS's impact on insulin sensitivity, as measured by euglycemic clamps, hepatic glucose disposal and glycogen synthesis by carbon13 NMR and the durability of these responses by long-term CGM glucose recordings. These studies will be augmented with preclinical diabetes models to identify additional sensory fields relevant to glycemic control. One site that holds great promise is the abdominal superior mesenteric plexus, which we found when combined with hepatoportal stimulation has the capacity to enhance the durabil- ity of the glucose-lowering response, likely by engaging the incretin axis. We will conduct additional transla- tional studies in human subjects to determine whether this encouraging dual site pFUS stimulation response indeed can be reproduced in type 2 diabetic subjects. As such ultrasound neuromodulation by pFUS repre- sents a paradigm shifting new tool to investigate the role of the autonomous nervous system in homeostatic glucose control in human subjects which if confirmed by our studies might lead to entirely new non- pharmaceutical treatment options for patients with diabetes.

项目摘要 中枢神经系统在葡萄糖代谢调节中的主要和越来越明显的作用 仍然是糖尿病的有吸引力的治疗靶标。脑干和下丘脑协调中心 多年来，喂养和葡萄糖稳态的特征已经很好，但对变量的不确定性 OUS传入的自主途径将信息从胃肠道传达到大脑。而动物螺栓 - IE表明神经元传感器会中继有关葡萄糖水平和其他营养变化的信息 位于肝门静脉内，对人类的这些因素知之甚少。实际上，受到一个约束 缺乏无创的工具来询问人类的这些监管电路，大部分的临床翻译 我们对啮齿动物模型中对喂养和葡萄糖控制的理解的最新进展仍然是一个活跃的区域 调查。为了克服这一关键限制，我们的小组最近通过PE-确定了神经调节 与配对的超声（PFU）是一种有希望的新工具，可无创，有选择地改变自主神经 神经系统传播到大脑。几种啮齿动物模型的令人兴奋的初步研究具有 揭示了超声脉冲在肝脏丛中的瞬时应用可以实现长期持久的 下丘脑葡萄糖设定点的恶性以胰岛素独立的方式恢复尤利克血糖。这 该提案下的实验旨在建立在这项工作的基础上，以表征Pfus di的影响 在新诊断的2型糖尿病患者的人类中，朝着肝脏神经元丛进行了反应。我们将 量化PFU对胰岛素敏感性的影响，如葡萄糖夹具测量 碳13 NMR的糖原合成以及这些反应的耐用性，长期CGM葡萄糖 录音。这些研究将通过临床前糖尿病模型增强，以鉴定其他感觉 与血糖控制有关的场。一个拥有巨大诺言的地点是腹部上肠系膜 我们发现与肝脏刺激结合时发现的丛 降葡萄糖反应的影响，可能是通过接合肠降直直染蛋白轴。我们将进行其他翻译 在人类受试者中的研究研究，以确定这种鼓励双位点PFUS刺激反应是否 确实可以在2型糖尿病患者中再现。因此，PFUS repre-这样的超声神经调节 构成了一种范式移动新工具，以调查自主神经系统在体内平衡中的作用 人类受试者中的葡萄糖控制，如果我们的研究确认，可能会导致全新的非 - 糖尿病患者的药物治疗选择。