PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction
PDE5 抑制治疗肥胖相关的心脏代谢功能障碍
基本信息
- 批准号:9113813
- 负责人:
- 金额:$ 77.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-01 至 2020-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAddressAdultAdverse effectsAerobicAreaBeta CellBiochemicalBiogenesisBiological MarkersBlindedBody CompositionBody Weight decreasedBranched-Chain Amino AcidsCardiopulmonaryCardiovascular DiseasesCardiovascular systemCell physiologyChronicClinicalClinical TrialsCyclic GMPDataDiabetes MellitusDual-Energy X-Ray AbsorptiometryEffectivenessEnergy MetabolismEnzyme InhibitionEvaluationExerciseExercise stress testExhibitsExperimental ModelsFastingFatty acid glycerol estersFunctional disorderHealthHomeostasisHumanIndividualInsulinInsulin ResistanceInterventionInvestigationKnowledgeMeasurementMeasuresMediator of activation proteinMetabolicMetabolismMitochondriaMusNatriuretic PeptidesNitric OxideObesityOrganOutcomeOxygen ConsumptionParticipantPathway interactionsPharmaceutical PreparationsPhysiologicalPilot ProjectsPlacebosPlasmaPopulationProductionPublic HealthQuality of lifeQuality-of-Life AssessmentRandomizedResearch DesignResearch PersonnelResistanceRestRiskSF-36SamplingSecond Messenger SystemsSignal PathwaySignal TransductionSkeletal MuscleTechniquesTestingTransgenic AnimalsWeightWeight Gainanimal datacardiometabolic riskcardiovascular risk factorcirculating biomarkersclinically relevantdiabetes riskeffective therapyfitnessglucose metabolismguanylateheart disease riskhigh riskhuman dataimprovedindexinginhibitor/antagonistinsightinsulin secretioninsulin sensitivityintravenous glucose tolerance testlean body massmetabolic ratemetabolomicsnovelphosphoric diester hydrolasepreventpublic health relevancerandomized placebo controlled trialrecidivismresponsesecond messengertadalafiltraittreatment group
项目摘要
DESCRIPTION (provided by applicant): The metabolic and cardiovascular sequelae of obesity constitute a major financial and public health burden. Increased cardiovascular risk in obesity is directly related to metabolic dysregulation, key features of which include abnormalities
in energy homeostasis and insulin resistance. The effectiveness of weight loss efforts to reduce cardiometabolic risk in obesity is limited due to high weight gain recidivism. Therefore, interventions that directly target metabolic fitness in obesity represent an important area of investigation. Evidence in experimental models and our preliminary data in humans suggest that the cyclic guanylate monophosphate pathway (cGMP) is a critical mediator of insulin resistance and energy homeostasis. Increased cGMP signaling raises resting energy expenditure and provides resistance to obesity and diabetes. Cyclic GMP also stimulates mitochondrial biogenesis and oxidative capacity in skeletal muscle. Phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil prevent the degradation of cGMP. These medications are well-tolerated and improve glucose metabolism, but have not been comprehensively tested as a target for obesity-related cardiometabolic dysfunction in humans. We propose a randomized, placebo-controlled study to examine the cardiometabolic effects of PDE5 inhibition in obese prediabetic individuals. Participants will receive tadalafil 20 mg per day or placebo for 12 weeks.
Aim 1 will examine the effect of chronic PDE5 inhibition on resting and exercise energy expenditure using a metabolic chamber. In Aim 2, we will test the effect of PDE5 inhibition on insulin sensitivity and secretion. We will also assess body composition, quality of life, and sexua function. A Secondary Aim will examine the effect of PDE5 inhibition on cGMP sensitivity and circulating mediators of diabetes risk. The proposed study will be the first large comprehensive evaluation of PDE5 inhibition in a population at high risk of cardiovascular disease. Our endpoints were selected to provide highly relevant clinical outcomes and mechanistic insight into the cardiometabolic effects of cGMP action. Therapy that improves metabolic fitness independent of weight loss would represent an important advance in the effort to reduce cardiovascular risk in obesity.
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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Evan L Brittain其他文献
Aortic insufficiency following transcatheter aortic valve replacement is underestimated by echocardiography compared with cardiac MRI
- DOI:
10.1186/1532-429x-16-s1-o101 - 发表时间:
2014-01-16 - 期刊:
- 影响因子:
- 作者:
Wissam M Abdallah;Chris A Semder;Evan L Brittain;Michael T Baker;Lisa A Mendes;Marshall H Crenshaw;Joseph L Fredi;Mark A Robbins;Sonia L Scalf;William S Bradham;Sean G Hughes;Mark A Lawson;David X Zhao - 通讯作者:
David X Zhao
Evan L Brittain的其他文献
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{{ truncateString('Evan L Brittain', 18)}}的其他基金
Impact of Physical Activity, Sleep, and Genetic Background on Cardiovascular Risk in the All of Us Program
“我们所有人”计划中体力活动、睡眠和遗传背景对心血管风险的影响
- 批准号:
10795533 - 财政年份:2023
- 资助金额:
$ 77.78万 - 项目类别:
The MObile Health InterVEntion in Pulmonary Arterial Hypertension (MOVE PAH) Study
肺动脉高压的移动健康干预 (MOVE PAH) 研究
- 批准号:
10525960 - 财政年份:2022
- 资助金额:
$ 77.78万 - 项目类别:
The MObile Health InterVEntion in Pulmonary Arterial Hypertension (MOVE PAH) Study
肺动脉高压的移动健康干预 (MOVE PAH) 研究
- 批准号:
10723261 - 财政年份:2022
- 资助金额:
$ 77.78万 - 项目类别:
Network Medicine and Systems Pharmacology to Advance Precision Medicine in Combined Pulmonary Hypertension
网络医学和系统药理学推进联合肺动脉高压的精准医学
- 批准号:
10625481 - 财政年份:2022
- 资助金额:
$ 77.78万 - 项目类别:
Network Medicine and Systems Pharmacology to Advance Precision Medicine in Combined Pulmonary Hypertension
网络医学和系统药理学推进联合肺动脉高压的精准医学
- 批准号:
10467751 - 财政年份:2022
- 资助金额:
$ 77.78万 - 项目类别:
Effect of PDE5 Inhibition on Adipose Metabolism in Humans
PDE5 抑制对人体脂肪代谢的影响
- 批准号:
10557112 - 财政年份:2021
- 资助金额:
$ 77.78万 - 项目类别:
Effect of PDE5 Inhibition on Adipose Metabolism in Humans
PDE5 抑制对人体脂肪代谢的影响
- 批准号:
10333359 - 财政年份:2021
- 资助金额:
$ 77.78万 - 项目类别:
Clinical, Genetic, and Proteomic Risk Factors for Pulmonary Hypertension in Heart Failure
心力衰竭肺动脉高压的临床、遗传和蛋白质组学危险因素
- 批准号:
10163899 - 财政年份:2019
- 资助金额:
$ 77.78万 - 项目类别:
Clinical, Genetic, and Proteomic Risk Factors for Pulmonary Hypertension in Heart Failure
心力衰竭肺动脉高压的临床、遗传和蛋白质组学危险因素
- 批准号:
9913572 - 财政年份:2019
- 资助金额:
$ 77.78万 - 项目类别:
Clinical, Genetic, and Proteomic Risk Factors for Pulmonary Hypertension in Heart Failure
心力衰竭肺动脉高压的临床、遗传和蛋白质组学危险因素
- 批准号:
10394320 - 财政年份:2019
- 资助金额:
$ 77.78万 - 项目类别:
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