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
基本信息
- 批准号:10586211
- 负责人:
- 金额:$ 78.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AbdomenAcuteAddressAffectAfferent NeuronsAnimal ModelAnimalsAreaAutonomic PathwaysAutonomic nervous systemBrainBrain StemCarbonCell NucleusCellsCentral Nervous SystemCirculationClinicalClinical DataClinical ResearchClosure by clampDataDenervationDevelopmentDiabetes MellitusDiagnosisDistalFocused UltrasoundFocused Ultrasound TherapyGastrointestinal tract structureGeneticGlucagonGlucoseGlucose ClampGlycogenHepaticHepatologyHomeostasisHormonesHumanHyperglycemiaHyperinsulinismHypothalamic structureIndividualIngestionInsulinInsulin ResistanceInvestigationIon ChannelLinkLiver GlycogenMagnetic Resonance ImagingMeasurementMeasuresMediatingMediatorMesenteryMetabolicMethodsMicroelectrodesModalityModelingMolecularMusNMR SpectroscopyNerveNerve FibersNerve PlexusNervous SystemNeuroendocrinologyNeuronsNewly DiagnosedNon-Insulin-Dependent Diabetes MellitusNutrientOGTTPatientsPeripheralPhysiologic pulsePilot ProjectsPlayPortal vein structurePre-Clinical ModelReflex actionReflex controlRegulationResistanceRodent ModelRoleScientistSensorySignal TransductionSiteTestingTherapeutic EffectTimeTracerTransgenic OrganismsType 2 diabeticUncertaintyValidationWorkalternative treatmentblood glucose regulationcell typeclinical translationdesigndiabeticdiabetic patienteuglycemiaexperimental studyfeedinggastrointestinalghrelinglucagon-like peptide 1glucose disposalglucose metabolismglucose sensorglucose toleranceglycemic controlhuman subjectimaging modalityinnovationinsulin sensitivityneural circuitneuroregulationnoveloptogeneticspre-clinicalpreclinical studyresponsesensorskillsstable isotopesynergismtherapeutic targettooltranslational studytreatment siteultrasound
项目摘要
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作用日益明显
仍然是糖尿病的有吸引力的治疗靶点。脑干和下丘脑协调中心
多年来,进食和葡萄糖体内平衡已经得到了很好的表征,但对瓦里
将信息从胃肠道传递到大脑的自主神经传入通路仍然存在。当动物研究-
研究表明,神经元传感器传递有关葡萄糖水平和其他营养物质变化的信息,
位于肝门静脉内,对人类中的这些因子知之甚少。事实上,受一个
由于缺乏非侵入性工具来询问人类的这些调节回路,
在啮齿动物模型中,我们对进食和血糖控制的理解的最新进展仍然是一个活跃的领域
调查。为了克服这个关键的限制,我们的团队最近发现了通过pe的神经调节,
外周聚焦超声(pFUS)作为一种有前途的新工具,非侵入性和选择性地改变自主神经,
神经系统对大脑的传入。在几种啮齿动物糖尿病模型中进行的令人兴奋的初步研究,
显示,瞬时应用超声脉冲到肝门静脉丛可以产生长期的非-
使下丘脑葡萄糖设定点正常化,以胰岛素非依赖性方式恢复正常。的
在此建议下的实验旨在建立在这项工作的基础上,以表征pFUS二,
针对新诊断的2型糖尿病患者的肝门静脉神经丛。我们将
量化pFUS对胰岛素敏感性的影响,如通过正葡萄糖钳夹、肝葡萄糖处置
通过碳13 NMR和糖原合成以及长期CGM葡萄糖对这些反应的持久性
录音.这些研究将增加临床前糖尿病模型,以确定额外的感觉
与血糖控制相关的字段。腹部上级肠系膜是一个很有希望的部位
我们发现,当与肝门静脉刺激相结合时,
降低血糖反应的稳定性,可能是通过参与肠促胰岛素轴。我们将进行更多的翻译-
在人类受试者中进行的常规研究,以确定这是否鼓励双部位pFUS刺激反应
确实可以在2型糖尿病受试者中重现。因此,pFUS的超声神经调节代表-
发送了一个范式转移的新工具,以调查自主神经系统在稳态中的作用,
在人类受试者中的葡萄糖控制,如果我们的研究证实,
糖尿病患者的药物治疗选择。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Raimund Ingo Herzog其他文献
Ein Polymorphismus im Intron 3 des p53-Gens und erhöhtes Risiko für Ovarialkarzinom
- DOI:
10.18725/oparu-108 - 发表时间:
2000-05 - 期刊:
- 影响因子:0
- 作者:
Raimund Ingo Herzog - 通讯作者:
Raimund Ingo Herzog
Raimund Ingo Herzog的其他文献
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{{ truncateString('Raimund Ingo Herzog', 18)}}的其他基金
Reversing brain metabolic adaptations to recurrent hypoglycemia in older adults with type 1 diabetes using a Predictive Low Glucose Management (PLGM) system
使用预测性低血糖管理 (PLGM) 系统逆转患有 1 型糖尿病的老年人的大脑代谢适应,以应对复发性低血糖
- 批准号:
9236876 - 财政年份:2016
- 资助金额:
$ 78.49万 - 项目类别:
Human Brain Ketone Metabolism in Type 1 Diabetes and Hypoglycemia.
1 型糖尿病和低血糖中的人脑酮代谢。
- 批准号:
8622673 - 财政年份:2014
- 资助金额:
$ 78.49万 - 项目类别:
Regulation of Brain Glucose Metabolism in Type 1 Diabetes
1 型糖尿病脑葡萄糖代谢的调节
- 批准号:
10379262 - 财政年份:2014
- 资助金额:
$ 78.49万 - 项目类别:
Regulation of Brain Glucose Metabolism by Alternate Fuels in Type 1 Diabetes
1 型糖尿病中替代燃料对脑葡萄糖代谢的调节
- 批准号:
8818284 - 财政年份:2014
- 资助金额:
$ 78.49万 - 项目类别:
Human Brain Ketone Metabolism in Type 1 Diabetes and Hypoglycemia.
1 型糖尿病和低血糖中的人脑酮代谢。
- 批准号:
8779720 - 财政年份:2014
- 资助金额:
$ 78.49万 - 项目类别:
Regulation of Brain Glucose Metabolism by Alternate Fuels in Type 1 Diabetes
1 型糖尿病中替代燃料对脑葡萄糖代谢的调节
- 批准号:
9097688 - 财政年份:2014
- 资助金额:
$ 78.49万 - 项目类别:
Regulation of Brain Glucose Metabolism by Alternate Fuels in Type 1 Diabetes
1 型糖尿病中替代燃料对脑葡萄糖代谢的调节
- 批准号:
9280934 - 财政年份:2014
- 资助金额:
$ 78.49万 - 项目类别:
Regulation of Brain Glucose Metabolism in Type 1 Diabetes
1 型糖尿病脑葡萄糖代谢的调节
- 批准号:
9897264 - 财政年份:2014
- 资助金额:
$ 78.49万 - 项目类别:
Regulation of Brain Glucose Metabolism in Type 1 Diabetes
1 型糖尿病脑葡萄糖代谢的调节
- 批准号:
10619549 - 财政年份:2014
- 资助金额:
$ 78.49万 - 项目类别:
Adaptations of Brain Energy Metabolism to Hypoglycemia
脑能量代谢对低血糖的适应
- 批准号:
8535731 - 财政年份:2010
- 资助金额:
$ 78.49万 - 项目类别:
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