Determinants of Insulin Mediated Glucose uptake in South Asians

南亚人胰岛素介导的葡萄糖摄取的决定因素

• 批准号: 8250465
• 负责人: THEMISTOCLES LEONARD ASSIMES
• 金额: $ 18.09万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250465
• 关键词: Abdomen; Accounting; Address; Adipocytes; Adipose tissue; Adult; Advisory Committees; Age; Asians; Atherosclerosis; Award; Biometry; Body fat; Cardiopulmonary; Cardiovascular system; Clinical Research; Collaborations; Complex; Development; Diabetes Mellitus; Dual-Energy X-Ray Absorptiometry; Epidemiology; Ethnic group; Europe; European; Exercise stress test; Fatty acid glycerol esters; Functional disorder; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genotype; Glucose; Gold; Grant; Heart; Heart Diseases; Hepatocyte; Hispanics; Hospitals; Human; Human Genetics; Inherited; Insulin; Insulin Resistance; International; Knowledge; Light; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Medicine; Mentors; Methods; Mexican; Molecular Biology; Monitor; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxygen; Pathway interactions; Physical Fitness; Physical activity; Physicians; Physiological; Plant Roots; Population; Population Sciences; Predisposition; Questionnaires; Race; Recruitment Activity; Regression Analysis; Research; Research Personnel; Research Proposals; Resources; Risk; Sampling; Scanning; Scientist; Secondary Prevention; South Asian; Stress Tests; Symptoms; Taiwan; Techniques; Testing; Tissues; United States National Institutes of Health; Universities; Visceral; Work; adverse outcome; base; cardiovascular disorder risk; career development; cohort; design; experience; genetic epidemiology; genome wide association study; genome-wide; glucose uptake; high risk; human subject; improved; innovation; insight; insulin sensitivity; insulin sensitizing drugs; interest; knowledge base; next generation; novel; professor; public health relevance; racial and ethnic; research study; sex; standard measure; subcutaneous; tool; trait; uptake

DESCRIPTION (provided by applicant): The purpose of this award is to provide Dr. Themistocles (Tim) Assimes, Assistant Professor of Medicine at Stanford University, the support necessary to transition him from a junior investigator to an independent physician scientist studying the genetic determinants of various human complex traits related to cardiovascular medicine. Dr. Assimes is an adult cardiologist with an advanced degree in epidemiology and biostatistics and significant experience conducting human genetic studies using existing sample sets. Career development activities focus on consolidating his expertise by 1) designing and implementing his first human subjects clinical research study involving handling of biospecimens, 2) increasing his involvement in several international genetic epidemiology collaborations, and 3) attending didactic courses to expand his knowledge base in contemporary genetics, molecular biology, advanced statistical genetics and the pathophysiology of insulin resistance (IR). An advisory committee, which includes his mentors, Drs. Thomas Quertermous and Gerald Reaven, will carefully monitor his progress towards independence. The research proposal builds on ongoing efforts in the candidate's division to identify the root causes of IR by studying South Asians, a racial/ethnic group known to be strongly predisposed to IR and its adverse consequences for unclear reasons. In this context, Specific Aim 1 proposes to quantify IR and its primary established determinants of adiposity and physical fitness in ~330 South Asians and ~100 white/Europeans using 'gold standard' measuring tools. These include an insulin suppression test to assess insulin mediated glucose uptake, DXA and abdominal MRI scans to determine total and regional body fat, pedometers to estimate current physical activity, and a symptom limited cardiopulmonary stress test to estimate maximum oxygen uptake (max VO2). A new research partnership between the non-profit South Asian Heart Center at El Camino Hospital, Mountain View, CA, and Division of Cardiovascular Medicine at Stanford University will facilitate recruitment. This aim will test the hypothesis that a predisposition to IR in South Asians is evident even after taking into account significant differences between the two racial/ethnic groups in adiposity and physical fitness not captured by more traditional methods of assessment of these variables (e.g., BMI and physical activity questionnaires). In Specific Aim 2, the candidate will perform genome wide genotyping in ~400 South Asians followed by gene/SNP set pathway analyses using innovative analytical techniques developed by collaborators at SAGE Bionetworks. The same analytical techniques will be applied to multiple other sample sets with GWAS and direct measures of IR representing 3 other race/ethnic groups including Europeans, East Asians, and Hispanics. This aim will compare and contrast pathways associated with IR across all groups and test the hypothesis that South Asians are more IR because they have inherited a relatively inefficient cellular mechanism of handling glucose compared to other racial/ethnic groups. PUBLIC HEALTH RELEVANCE: Insulin resistance is a physiologic state where fat, muscle and liver cells lose their ability to respond to insulin. The resulting high levels of insulin predispose to the development of diabetes, heart disease, and other serious conditions. Work proposed in this grant aims to identify the reasons some populations are particularly high risk of insulin resistance and its consequences.

描述（由申请人提供）：该奖项的目的是为斯坦福大学医学助理教授Themistocles（Tim）Assimes博士提供必要的支持，使他从初级研究员转变为独立的医生科学家，研究与心血管医学相关的各种人类复杂性状的遗传决定因素。Assimes博士是一名成人心脏病专家，拥有流行病学和生物统计学高级学位，并拥有使用现有样本集进行人类遗传研究的丰富经验。职业发展活动的重点是巩固他的专业知识，1）设计和实施他的第一个人类受试者临床研究，包括生物标本的处理，2）增加他在几个国际遗传流行病学合作的参与，和3）参加教学课程，以扩大他在当代遗传学，分子生物学，先进的统计遗传学和胰岛素抵抗（IR）的病理生理学的知识基础。一个咨询委员会，其中包括他的导师，托马斯Quertermous博士和杰拉尔德雷文，将仔细监测他走向独立的进展。该研究提案建立在候选人所在部门正在进行的努力的基础上，通过研究南亚人来确定IR的根本原因，南亚人是一个种族/族裔群体，已知其强烈倾向于IR及其不良后果，原因不明。在这种情况下，具体目标1建议使用“金标准”测量工具量化约330名南亚人和约100名白色/欧洲人的IR及其肥胖和体能的主要既定决定因素。这些包括胰岛素抑制试验，以评估胰岛素介导的葡萄糖摄取，DXA和腹部MRI扫描，以确定总的和局部的身体脂肪，计步器，以估计当前的身体活动，和症状限制心肺应激试验，以估计最大摄氧量（最大VO 2）。位于加利福尼亚州山景埃尔卡米诺医院的非营利南亚心脏中心和斯坦福大学心血管医学部之间的新研究伙伴关系将促进招聘。这一目的将检验这样的假设，即即使考虑到两个种族/民族群体在肥胖和身体健康方面的显著差异，南亚人的IR倾向也是明显的，而这些差异是更传统的评估这些变量的方法所不能捕捉到的（例如，BMI和体力活动问卷）。在具体目标2中，候选人将在约400名南亚人中进行全基因组基因分型，然后使用SAGE Bionetworks合作者开发的创新分析技术进行基因/SNP集途径分析。相同的分析技术将应用于具有GWAS的多个其他样本集，并直接测量代表其他3个人种/种族群体（包括欧洲人、东亚人和西班牙裔人）的IR。该目标将比较和对比所有组中与IR相关的途径，并检验南亚人更IR的假设，因为与其他种族/民族相比，他们继承了相对低效的处理葡萄糖的细胞机制。 胰岛素抵抗是一种生理状态，脂肪，肌肉和肝细胞失去了对胰岛素的反应能力。由此产生的高水平胰岛素易患糖尿病、心脏病和其他严重疾病。这项资助计划的目的是确定某些人群胰岛素抵抗风险特别高的原因及其后果。