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

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性疾病的病因学中起主要作用,其中许多因种族/民族而异。以前的研究主要采用间接方法,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,结果是不一致的,与所使用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夹的初步数据表明,在瘦个体中,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。我们推测,这种种族/体重指数(BMI)的相互作用可能部分解释为AA中内脏/肝脏肥胖的显着降低,导致肥胖AA个体的胰岛素敏感性受损较少。相反,我们假设AA中固有的更大的氧化应激损害胰岛素敏感性,解释了瘦AA中胰岛素敏感性较低的原因 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志物与AA中胰岛素刺激的葡萄糖处置显著相关,但与EA无关,并且体外活性氧(ROS)的产生在AA中比EA更大。我们建议测试这些假设,前瞻性地比较骨骼肌和肝脏的胰岛素敏感性,在健康的瘦,超重,肥胖AA和EA使用高胰岛素异糖基化葡萄糖钳夹示踪剂标记的葡萄糖。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。对于我们的第一个目标,我们将检验以下假设:与EA相比,在骨骼肌和肝脏胰岛素敏感性中将检测到显著的种族-BMI相互作用,使得在低BMI时AA的胰岛素敏感性较低,但在高BMI时AA的胰岛素敏感性更高。第二个目的是检验假设,即在高BMI时,AA由于肝脏和内脏脂肪较低而具有更高的肝脏和骨骼肌胰岛素敏感性。第三个目标将测试这一假设,即骨骼肌线粒体内更大的生物能量效率和ROS产生将与瘦AA中骨骼肌胰岛素敏感性降低相关。第二个目标将测试 假设骨骼肌和肝脏胰岛素敏感性与EA中的脂肪因子、细胞因子、脂质、血压和血管功能比AA中更好地相关。本案无关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与遗传背景不同,这可能会指导个性化治疗策略的开发,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)。

项目成果

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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

UAB Precision Nutrition Clinical Center
UAB精准营养临床中心
  • 批准号:
    10540242
  • 财政年份:
    2021
  • 资助金额:
    $ 56.68万
  • 项目类别:
UAB Precision Nutrition Clinical Center
UAB精准营养临床中心
  • 批准号:
    10384253
  • 财政年份:
    2021
  • 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:
    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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