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 中枢神经系统在糖代谢调节中的主导和日益明显的作用 仍然是一个有吸引力的糖尿病治疗靶点。脑干和下丘脑的协调中心 多年来，摄食和葡萄糖动态平衡一直是很好的特征，但对变化的不确定性- OU的传入自主神经通路将信息从胃肠道传递到大脑。而动物种马- IES表明，传递血糖水平和其他营养物质变化信息的神经元传感器 位于肝门静脉内，对这些因素在人类中所知较少。事实上，受 缺乏非侵入性工具来询问人类的这些调节电路，临床翻译的大部分 在啮齿动物模型中，我们对摄食和血糖控制的理解最近的进展仍然是一个活跃的领域 调查的结果。为了克服这一关键限制，我们的团队最近发现了通过PE-1的神经调节。 外周聚焦超声(PFUS)作为一种有前景的无创、选择性改变自主神经的新工具 神经系统是大脑的传入神经。在几种糖尿病啮齿动物模型中进行了令人兴奋的初步研究 研究表明，超声脉冲瞬时作用于肝门神经丛可以产生持久的NOR-1。 下丘脑葡萄糖设定点的合并化，以胰岛素非依赖性的方式恢复正常血糖。这个 这项建议下的实验旨在以这项工作为基础来表征pFUS di的作用。 向人类新诊断的2型糖尿病患者的肝门神经丛倾斜。我们会 量化pFUS对胰岛素敏感性的影响，通过正常血糖钳夹、肝脏葡萄糖处理 碳13核磁共振合成糖原和长期CGM葡萄糖对这些反应的持久性 录音。这些研究将通过临床前糖尿病模型来加强，以确定额外的感觉 与血糖控制相关的领域。腹部肠系膜上段是一个很有希望的部位。 神经丛，我们发现当与肝门刺激相结合时，有能力增强耐受性- 降糖反应的稳定性，可能是通过与胰岛素轴接触来实现的。我们将进行额外的翻译- 在人类受试者中进行的常规研究，以确定这种鼓舞人心的双部位pFUS刺激反应 确实可以在2型糖尿病受试者身上复制。因此，pFUS代表的超声神经调节作用。 发送了一个范式转换的新工具来研究自主神经系统在体内平衡中的作用 如果我们的研究证实，受试者的血糖控制可能会导致全新的非 糖尿病患者的药物治疗选择。