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
• 负责人: BARBARA A GOWER
• 金额: $ 52.03万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115157
• 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; 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; circulating biomarkers; 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)：项目总结。胰岛素抵抗在慢性代谢性疾病的病因中起着重要作用，其中许多疾病因种族/民族而异。以前主要使用间接方法的研究表明，非裔美国人(AA)的胰岛素敏感性低于欧洲裔美国人(EA)。然而，结果是不同的，不同的方法和参与者的肥胖状况不同。我们使用参考标准葡萄糖钳的初步数据显示，在瘦的个体中，再生障碍性贫血的胰岛素敏感性I较低，而在肥胖个体中，再生障碍性贫血的胰岛素敏感性较高。我们假设，这种种族/体重指数(BMI)的相互作用可能部分是由于AA患者的内脏/肝脏肥胖率显著降低，从而导致肥胖AA患者的胰岛素敏感性损伤较少。相反，我们假设内在较高的氧化应激损害再生障碍性贫血患者的胰岛素敏感性，从而解释了瘦性再生障碍性贫血患者较低的胰岛素敏感性。 VS EA。这是基于我们的初步数据，表明累积氧化应激的循环标记物在AA中与胰岛素刺激的葡萄糖处置显著相关，而在EA中没有，而且AA与EA在体外产生的活性氧物种(ROS)比EA更多。我们建议通过前瞻性地比较健康瘦身、超重和肥胖的AA和EA患者的骨骼肌和肝脏胰岛素敏感性来检验这些假设，方法是使用带有示踪剂标记葡萄糖的高胰岛素等血糖钳夹。对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。在我们的第一个目标中，我们将检验这样一个假设，即骨骼肌和肝脏对胰岛素敏感性将检测到显著的逐个BMI相互作用，即与EA相比，在低BMI时AA对胰岛素不敏感，而在高BMI时AA对胰岛素更敏感。第二个目标将检验这一假设，即在高BMI时，由于肝脏和内脏脂肪较低，AA将具有更高的肝脏和骨骼肌胰岛素敏感性。第三个目标将检验这一假设，即更高的生物能量效率和骨骼肌线粒体内ROS的产生将与瘦肉型再障患者骨骼肌较低的胰岛素敏感性相关。次要目标将考验 假设骨骼肌和肝脏的胰岛素敏感性与脂肪因子、细胞因子、血脂、血压和血管功能的相关性在电针组比在再障组更好。关联性。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不同，可能会指导个性化治疗策略的发展，并对几种慢性代谢性疾病(例如，2型糖尿病、心血管疾病和癌症)产生影响。