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
• 负责人: BARBARA A GOWER
• 金额: $ 51.84万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2016-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892171
• 关键词: Admixture; Adult; African; African American; American; Bioenergetics; Blood Pressure; Blood Vessels; Body mass index; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Chronic; Coupled; Coupling; Data; Development; Diabetes Mellitus; Dyslipidemias; Electron Transport; Endothelial Cells; Ethnic Origin; Etiology; Euglycemic Clamping; European; Fatty acid glycerol esters; Functional disorder; Genetic; Genotype; Glucose; Glucose Clamp; Health; Hepatic; Hydrogen Peroxide; Impairment; In Vitro; Individual; Insulin; Insulin Resistance; Label; Leptin; Lipids; Literature; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolic Diseases; Methods; Muscle Fibers; Muscle Mitochondria; National Institute of Diabetes and Digestive and Kidney Diseases; Natural History; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overweight; Oxidative Phosphorylation; Oxidative Stress; Participant; Patient Self-Report; Patients; Physiological; Play; Prevention; Production; Race; Reactive Oxygen Species; Reference Standards; Relative (related person); Research; Research Priority; Risk; Role; Secondary to; Serum amyloid A protein; Skeletal Muscle; Specific qualifier value; Strategic Planning; TNF gene; Testing; Tracer; Visceral; Woman; adipokines; adiponectin; base; blood glucose regulation; cytokine; endothelial dysfunction; ethnic difference; fasting glucose; glucose disposal; glucose production; individualized medicine; insulin sensitivity; insulin sensitivity/resistance; lean body mass; named group; personalized medicine; racial and ethnic disparities; treatment strategy

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（申请人提供）：项目摘要。胰岛素抵抗在慢性代谢疾病的病因中起主要作用，其中许多疾病与种族/种族不同。先前使用间接方法的研究表明，非裔美国人（AA）与欧洲裔美国人（EA）中的胰岛素敏感性较低。但是，结果是差异的，与参与者的方法和肥胖状态不同。我们使用参考标准葡萄糖夹的初步数据表明，在精益个体中，胰岛素敏感性I在AA中降低，而在肥胖个体中，AA之间的胰岛素敏感性较高。我们假设该种族/体重指数（BMI）的相互作用可以部分地通过AA的内脏/肝肥胖大大降低，从而导致肥胖AA个体中胰岛素敏感性的损害较小。相反，我们假设固有的更大的氧化应激会损害AA中的胰岛素敏感性，从而解释了瘦的AA中胰岛素较低的敏感性 与EA。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中的胰岛素刺激的葡萄糖处置显着相关，而不是EA，并且在AA中，AA与EA中的活性氧（ROS）的产生更大。我们建议使用高胰岛素血糖葡萄糖夹在健康的瘦肉，超重和肥胖的AA和EA中前瞻性地比较骨骼肌和肝胰岛素敏感性，以检验这些假设。祖先遗传混合物的分析将允许同时评估祖先对主要结果的贡献。以我们的第一个目的，我们将检验以下假设：与EA相比，与EA相比，在低BMI AA中，将检测到N骨骼肌和肝胰岛素敏感性的N骨骼肌和肝胰岛素敏感性较小，但在高BMI中，AA更敏感。第二个目标将检验以下假设：在高BMI，AA由于肝脂肪和内脏脂肪降低而具有更大的肝肌胰岛素敏感性。第三个目的将检验以下假设：骨骼肌线粒体内的生物能效率和ROS产生的较高与较低的骨骼肌胰岛素敏感性有关。次要目标将测试 假设EA中的骨骼肌和肝胰岛素敏感性比AA中的脂肪因子，细胞因子，脂质，血压和血管功能更好。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有所不同，这可能指导发展个性化治疗策略，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。