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.

项目概要 中枢神经系统在葡萄糖代谢调节中的主导作用和日益明显的作用 仍然是糖尿病有吸引力的治疗靶点。脑干和下丘脑协调中心 多年来，喂养和葡萄糖稳态已得到很好的表征，但各种变化的不确定性 将信息从胃肠道传递到大脑的自主传入神经通路仍然存在。虽然动物种马- 这些表明神经元传感器传递有关葡萄糖水平和其他营养素变化的信息 位于肝门静脉内，人们对人类的这些因素知之甚少。事实上，受制于 缺乏非侵入性工具来询问人类的这些调节回路，大部分的临床转化 我们对啮齿动物模型喂养和葡萄糖控制的理解的最新进展仍然是一个活跃的领域 的调查。为了克服这一关键限制，我们的小组最近发现了通过pe- 周围聚焦超声（pFUS）作为一种有前途的新工具，可以非侵入性地、选择性地改变自主神经 神经系统传入大脑。在几种糖尿病啮齿动物模型中进行的令人兴奋的初步研究 研究表明，对肝门丛短暂施加超声波脉冲可以产生持久的正常作用 下丘脑葡萄糖设定值的正常化以不依赖于胰岛素的方式恢复血糖正常。这 本提案下的实验旨在以这项工作为基础来表征 pFUS di- 针对新诊断的 2 型糖尿病患者的肝门神经元丛。我们将 量化 pFUS 对胰岛素敏感性的影响，通过正常血糖钳、肝葡萄糖处理来测量 碳 13 NMR 的糖原合成以及长期 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得到加强，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前景广阔的部位 我们发现，当与肝门刺激相结合时，神经丛能够增强耐久性 降糖反应的有效性，可能是通过肠促胰素轴参与。我们将进行额外的翻译 在人类受试者中进行的多项研究，以确定这是否会鼓励双位点 pFUS 刺激反应 确实可以在 2 型糖尿病受试者中复制。因此，pFUS 的超声神经调节代表 发送了一种范式转变的新工具来研究自主神经系统在稳态中的作用 人类受试者的血糖控制如果被我们的研究证实可能会导致全新的非 糖尿病患者的药物治疗选择。