Mechanisms of Prediabetic States in Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停的糖尿病前期状态机制
基本信息
- 批准号:10439458
- 负责人:
- 金额:$ 77.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipose tissueAffectAnimal ModelAnimalsBioenergeticsBiopsyBlood CirculationCeramidesClinicalClinical ResearchContinuous Positive Airway PressureCrossover DesignDiseaseEnergy-Generating ResourcesExtrahepaticFastingFatty AcidsFatty acid glycerol estersGlucoseGlucose IntoleranceGlycerolHepaticHypoxiaImpairmentIndirect CalorimetryInsulinInsulin ResistanceIsotopesLaboratoriesLipidsLipolysisMeasurementMetabolicMetabolic PathwayMetabolismMitochondriaMuscleNADHNonesterified Fatty AcidsNorepinephrineObstructive Sleep ApneaOxidation-ReductionOxygen ConsumptionPalmitatesPathway interactionsPatientsPharmacologyPlasmaPrediabetes syndromeProto-Oncogene Proteins c-aktPyruvateRandomizedReactive Oxygen SpeciesResearchResolutionRespirationSkeletal MuscleSupervisionTestingTissuesTracerWeightWorkacylcarnitineexperimental studyfatty acid oxidationfatty acid transportglucose disposalglucose metabolismglucose productionglucose toleranceglucose uptakehuman modelhuman studyimprovedinsightinsulin sensitivityinsulin signalinglipidomicsmitochondrial dysfunctionnoveloxidationpreventrisk predictionstable isotopetool
项目摘要
PROJECT SUMMARY/ABSTRACT
Substantial clinical and experimental evidence indicates that obstructive sleep apnea (OSA) is associated with
impaired glucose metabolism. Our laboratory has demonstrated that treatment of OSA by all-night continuous
positive airway pressure (CPAP) improves insulin sensitivity and glucose tolerance in prediabetes. To date,
the mechanisms by which OSA impairs glucose metabolism remain unclear. It is widely recognized that OSA
patients have increased sympathetic activity, which is a potent stimulator of adipose tissue lipolysis leading to
increased release of free fatty acids (FFA) into the systemic circulation. FFAs are a major source of energy for
the skeletal muscle, which is the tissue that accounts for the majority of insulin-stimulated glucose uptake.
Extensive research has demonstrated that ectopic lipid accumulation in the skeletal muscle is one of the key
determinants of insulin resistance. We therefore hypothesized is that increased adipose tissue lipolysis (i.e.
excess FFA delivery) induced by OSA impairs metabolism in the skeletal muscle, leading to insulin resistance
and glucose intolerance. We hypothesize that these impairments occur in part through mitochondrial
dysfunction, as mitochondria are important in glucose and fatty acid oxidation, and are highly abundant in the
skeletal muscle. Specifically, we will determine whether OSA leads to insulin resistance and glucose
intolerance through impairments of cellular metabolism resulting in incomplete substrate utilization and ectopic
lipid accumulation in the skeletal muscle (Aim 1) and determine to what extent the metabolic impairments in
OSA are explained by increased adipose tissue lipolysis and excess FFA release (Aim 2). To address these
aims, we propose to study OSA patients with prediabetes under three in-laboratory conditions in a randomized
cross-over design: untreated condition (OSA), treated condition (CPAP), untreated but pharmacologically
suppressed lipolysis condition (FFA-suppressed). We will perform whole body and cellular assessments under
each study condition. Glucose metabolism will be assessed during both fasting and postprandial states using
stable isotope tracers. In muscle tissue, we will assess mitochondrial oxygen consumption, reactive oxygen
species, glucose and fat oxidation, fatty acid transport to mitochondria, ectopic accumulation of lipid
metabolites, and insulin signaling. The proposed work will be the first to assess cellular bioenergetics (i.e.
mitochondrial function) in OSA patients and seeks to determine whether cellular metabolic impairments in the
skeletal muscle contribute to insulin resistance and glucose intolerance in OSA, and whether these
impairments are occurring in the presence of excess FFA delivery (i.e. by overwhelming mitochondrial capacity)
and/or are primary (occurring without excess FFA presence). The mechanistic insights that are expected to be
gained from the proposed work will help identify novel targets for risk prediction and/or treatment of metabolic
impairments in OSA beyond CPAP.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Esra Tasali其他文献
Esra Tasali的其他文献
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{{ truncateString('Esra Tasali', 18)}}的其他基金
Sleep Extension: A Novel Intervention for Weight Loss in Young Adults
延长睡眠:年轻人减肥的新干预措施
- 批准号:
10753226 - 财政年份:2023
- 资助金额:
$ 77.16万 - 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
- 批准号:
9762470 - 财政年份:2019
- 资助金额:
$ 77.16万 - 项目类别:
Mechanisms of Prediabetic States in Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停的糖尿病前期状态机制
- 批准号:
10222768 - 财政年份:2019
- 资助金额:
$ 77.16万 - 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
- 批准号:
10226277 - 财政年份:2019
- 资助金额:
$ 77.16万 - 项目类别:
Mechanisms of Prediabetic States in Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停的糖尿病前期状态机制
- 批准号:
9973169 - 财政年份:2019
- 资助金额:
$ 77.16万 - 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
- 批准号:
10677837 - 财政年份:2019
- 资助金额:
$ 77.16万 - 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
- 批准号:
10459449 - 财政年份:2019
- 资助金额:
$ 77.16万 - 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
- 批准号:
9980894 - 财政年份:2019
- 资助金额:
$ 77.16万 - 项目类别:
Technology-Supported Treatment of Sleep Apnea in Prediabetes
糖尿病前期睡眠呼吸暂停的技术支持治疗
- 批准号:
10886362 - 财政年份:2019
- 资助金额:
$ 77.16万 - 项目类别:
Mechanisms of Prediabetic States in Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停的糖尿病前期状态机制
- 批准号:
10674545 - 财政年份:2019
- 资助金额:
$ 77.16万 - 项目类别:
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