Race - adiposity interactions regulate mechanisms determining insulin sensitivity
种族-肥胖相互作用调节决定胰岛素敏感性的机制
基本信息
- 批准号:8504840
- 负责人:
- 金额:$ 56.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-19 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdmixtureAdultAfricanAfrican AmericanAmericanBioenergeticsBlood PressureBlood VesselsBody mass indexCardiovascular DiseasesCardiovascular PhysiologyCardiovascular systemChronicCoupledCouplingDataDevelopmentDiabetes MellitusDyslipidemiasElectron TransportEndothelial CellsEthnic OriginEtiologyEuglycemic ClampingEuropeanFatty acid glycerol estersFunctional disorderGeneticGenotypeGlucoseGlucose ClampHepaticHydrogen PeroxideImpairmentIn VitroIndividualInsulinInsulin ResistanceLabelLeptinLipidsLiteratureMagnetic Resonance ImagingMalignant NeoplasmsMeasuresMediatingMetabolicMetabolic DiseasesMethodsMuscle FibersMuscle MitochondriaNational Institute of Diabetes and Digestive and Kidney DiseasesNatural HistoryNon-Insulin-Dependent Diabetes MellitusObesityOutcomeOverweightOxidative PhosphorylationOxidative StressParticipantPatient Self-ReportPatientsPhysiologicalPlayPreventionProductionRaceReactive Oxygen SpeciesReference StandardsRelative (related person)ResearchResearch PriorityRiskRoleSecondary toSerum amyloid A proteinSkeletal MuscleSpecific qualifier valueStrategic PlanningTNF geneTestingTracerVisceralWomanadipokinesadiponectinbaseblood glucose regulationcytokineethnic differencefasting glucoseglucose disposalglucose productioninsulin sensitivityinsulin sensitivity/resistancenamed grouppublic health relevanceracial and ethnic disparitiestreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Project summary. Insulin resistance plays a major role in the etiology of chronic metabolic diseases, many of which differ with race/ethnicity. Previous studies using mainly indirect methods suggest that insulin sensitivity is lower in African-Americans (AA) vs. European-Americans (EA). However, results are discrepant, differing with the method used and the obesity status of the participants. Our preliminary data using the reference standard glucose clamp indicate that in lean individuals, insulin sensitivity i lower among AA, while in obese individuals, insulin sensitivity is higher among AA. We hypothesize that this race/body mass index (BMI) interaction may be explained in part by significantly lower visceral/hepatic adiposity in AA that results in less impairment of insulin sensitivity among obese AA individuals. Conversely, we hypothesize that inherently greater oxidative stress impairs insulin sensitivity in AA, explaining lower insulin sensitivity in lean AA
vs. EA. This is based on our preliminary data indicating that a circulating marker of cumulative oxidative stress was significantly associated with insulin-stimulated glucose disposal in AA but not EA, and that production of reactive oxygen species (ROS) in vitro was greater in AA vs. EA. We propose to test these hypotheses by prospectively comparing skeletal muscle and hepatic insulin sensitivity in healthy lean, overweight, and obese AA and EA using the hyperinsulinemic isoglycemic glucose clamp with tracer-labeled glucose. Analysis of ancestral genetic admixture will permit simultaneous assessment of the contribution of ancestry to main outcomes. With our first aim, we will test the hypothesis that a significant race-by-BMI interaction will be detected n skeletal muscle and hepatic insulin sensitivity, such that at low BMI AA are less insulin sensitive but at high BMI AA are more insulin sensitive, when compared with EA. The second aim will test the hypothesis that at high BMI, AA will have greater hepatic and skeletal muscle insulin sensitivity due to lower hepatic and visceral fat. The third aim will test the hypothesis that greater bioenergetic efficiency and ROS production within skeletal muscle mitochondria will be associated with lower skeletal muscle insulin sensitivity in lean AA. A secondary aim will test the
hypothesis that skeletal muscle and hepatic insulin sensitivity are better associated with adipokines, cytokines, lipids, blood pressure, and vascular function in EA than in AA. Relevance. Results from this study elucidating why the underlying pathophysiology of insulin resistance differs with genetic background may guide development of personalized treatment strategies with implications for several chronic metabolic diseases (e.g., type 2 diabetes, cardiovascular disease, and cancer).
描述(由申请人提供):项目摘要。胰岛素抵抗在慢性代谢疾病的病因学中起着重要作用,其中许多疾病因种族/民族而异。先前主要使用间接方法的研究表明,非洲裔美国人 (AA) 的胰岛素敏感性低于欧洲裔美国人 (EA)。然而,由于所使用的方法和参与者的肥胖状况不同,结果存在差异。我们使用参考标准葡萄糖钳夹的初步数据表明,在瘦人中,AA 中的胰岛素敏感性较低,而在肥胖个体中,AA 中的胰岛素敏感性较高。我们假设,这种种族/体重指数 (BMI) 相互作用的部分原因可能是 AA 中内脏/肝脏脂肪含量显着降低,从而导致肥胖 AA 个体的胰岛素敏感性损害较小。相反,我们假设本质上更大的氧化应激会损害 AA 中的胰岛素敏感性,这解释了瘦 AA 中胰岛素敏感性较低的原因
与 EA 相比。这是基于我们的初步数据,表明累积氧化应激的循环标志物与 AA 中胰岛素刺激的葡萄糖处理显着相关,但与 EA 中无关,并且 AA 中体外活性氧 (ROS) 的产生量高于 EA。我们建议通过使用高胰岛素等血糖葡萄糖钳和示踪剂标记的葡萄糖前瞻性比较健康瘦、超重和肥胖 AA 和 EA 中的骨骼肌和肝脏胰岛素敏感性来检验这些假设。对祖先遗传混合的分析将允许同时评估祖先对主要结果的贡献。出于我们的第一个目标,我们将测试以下假设:在骨骼肌和肝脏胰岛素敏感性中将检测到显着的种族与 BMI 相互作用,使得与 EA 相比,低 BMI AA 的胰岛素敏感性较低,但高 BMI 的 AA 胰岛素敏感性更高。第二个目标将检验以下假设:在高 BMI 情况下,由于肝脏和内脏脂肪较低,AA 的肝脏和骨骼肌胰岛素敏感性会更高。第三个目标将检验以下假设:骨骼肌线粒体内较高的生物能效率和 ROS 产生与瘦 AA 中较低的骨骼肌胰岛素敏感性相关。次要目标将测试
假设 EA 中的骨骼肌和肝脏胰岛素敏感性比 AA 中的脂肪因子、细胞因子、血脂、血压和血管功能更好地相关。关联。这项研究的结果阐明了为什么胰岛素抵抗的潜在病理生理学因遗传背景而异,可能会指导个性化治疗策略的制定,并对几种慢性代谢疾病(例如 2 型糖尿病、心血管疾病和癌症)产生影响。
项目成果
期刊论文数量(0)
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BARBARA A GOWER其他文献
BARBARA A GOWER的其他文献
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{{ truncateString('BARBARA A GOWER', 18)}}的其他基金
Obesity risk in African American women is determined by a diet-by-phenotype interaction
非裔美国女性的肥胖风险是由饮食与表型的相互作用决定的
- 批准号:
9769722 - 财政年份:2018
- 资助金额:
$ 56.68万 - 项目类别:
Obesity risk in African American women is determined by a diet-by-phenotype interaction
非裔美国女性的肥胖风险是由饮食与表型的相互作用决定的
- 批准号:
9914264 - 财政年份:2018
- 资助金额:
$ 56.68万 - 项目类别:
Obesity risk in African American women is determined by a diet-by-phenotype interaction
非裔美国女性的肥胖风险是由饮食与表型的相互作用决定的
- 批准号:
10397052 - 财政年份:2018
- 资助金额:
$ 56.68万 - 项目类别:
Race - adiposity interactions regulate mechanisms determining insulin sensitivity
种族-肥胖相互作用调节决定胰岛素敏感性的机制
- 批准号:
8737888 - 财政年份:2013
- 资助金额:
$ 56.68万 - 项目类别:
Race - adiposity interactions regulate mechanisms determining insulin sensitivity
种族-肥胖相互作用调节决定胰岛素敏感性的机制
- 批准号:
8892171 - 财政年份:2013
- 资助金额:
$ 56.68万 - 项目类别:
Race - adiposity interactions regulate mechanisms determining insulin sensitivity
种族-肥胖相互作用调节决定胰岛素敏感性的机制
- 批准号:
9115157 - 财政年份:2013
- 资助金额:
$ 56.68万 - 项目类别:
UAB Pre-Doctoral Training Program in Obesity-Related Research
UAB 肥胖相关研究博士前培训项目
- 批准号:
10469322 - 财政年份:2010
- 资助金额:
$ 56.68万 - 项目类别:
UAB Pre-Doctoral Training Program in Obesity-Related Research
UAB 肥胖相关研究博士前培训项目
- 批准号:
10206227 - 财政年份:2010
- 资助金额:
$ 56.68万 - 项目类别:
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