Proteomic determinants of direct measures of insulin sensitivity

直接测量胰岛素敏感性的蛋白质组决定因素

• 批准号: 9899979
• 负责人: THEMISTOCLES LEONARD ASSIMES
• 金额: $ 69.56万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899979
• 关键词: Adipocytes; Adult; Atherosclerosis; Biological Assay; Biological Markers; Blood; Body Weight decreased; Brain; Cardiovascular Diseases; Cell Line; Complex; Congestive Heart Failure; Consumption; Coronary artery; Data; Developed Countries; Developing Countries; Development; Diagnostic tests; Dyslipidemias; Epidemic; Epidemiology; Etiology; European; Fatty Liver; Female; Foundations; Gene Expression; Genes; Genomics; Glucose Clamp; Glycogen; Gold; Hepatocyte; Heterogeneity; Human; Human Cell Line; Human body; Hypertension; Individual; Insulin; Insulin Resistance; Insulin Resistance Pathway; Ischemic Stroke; Knock-out; Life; Lipolysis; Liver diseases; Longitudinal Studies; Malignant Neoplasms; Measures; Mediating; Metabolic; Molecular; Muscle Fibers; Myocardial Infarction; NAT2 gene; Nature; Neck; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Organ; Participant; Peripheral arterial disease; Pharmacological Treatment; Pharmacology; Physiological; Plasma; Polycystic Ovary Syndrome; Population; Prevalence; Process; Property; Proteins; Proteome; Proteomics; Public Health; Randomized; Research; Research Personnel; Resources; Risk; Sensitivity and Specificity; Signal Transduction; Statistical Methods; Statistical Models; Stroke; Susceptibility Gene; Techniques; Technology; Testing; Thiazolidinediones; Time; Tissues; Translational Research; Universities; Validation; Visit; base; biomarker discovery; causal variant; clinical predictors; cohort; experience; follow-up; genome editing; genome wide association study; genomic data; glucose uptake; high risk; improved; insight; insulin sensitivity; knock-down; lipid biosynthesis; male; men; new technology; new therapeutic target; novel; novel marker; predictive modeling; protein biomarkers; screening; sedentary; trait; volunteer

The consequences of insulin resistance (IR) include not only type 2 diabetes mellitus but also a cluster of metabolic abnormalities that double the risk of developing life-threatening complications of atherosclerosis including myocardial infarction, ischemic strokes, and peripheral arterial disease. The prevalence IR is increasing at an alarming rate as western populations become heavier and more sedentary. When one further considers the ongoing epidemiological transitions in developing countries in addition to the obesity epidemic in developed countries, the worldwide public health impact of IR is undoubtedly profound. Few pharmacological options exist that improve one’s insulin sensitivity and decrease the risk of complications from IR and recent genomic studies of surrogate measures of IR have yielded a disappointing number of new leads. Furthermore, a critical need exists for the development of more accurate blood-based diagnostic tests for IR. The long-term objective of the proposed research is to discover and validate novel protein markers of IR circulating in the blood of individuals who have undergone either one of the two ‘gold standard’ direct measures of insulin sensitivity: an insulin suppression test (IST) or a euglycemic clamp (EC). This information will be used to identify novel molecular pathways of IR that can be targeted pharmacologically and to develop statistical models that correlate highly with the degree of IR as estimated by direct measures of insulin sensitivity. In aim 1 of this proposal, the blood of 2100 white/European subjects who have undergone an IST at Stanford or an EC in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) and the Uppsala Longitudinal Study of Adult Men (ULSAM) studies will be measured for the presence of 981 proteins using an emerging platform that leverages novel technology referred to as the proximity extension assay. This technology allows for the accurate and reliable quantification of proteins in plasma down to the femtomolar or attomolar level. We will further validate the top signals identified in these subjects in an additional ~300 non- European subjects and a subset of 300 subjects from Stanford who underwent a second IST after weight loss or use of a thiazolidinedione. In aim 2, we will examine validated signals from Aim 1 for causality using the principal of Mendelian randomization, and we will quantify improvements afforded by validated markers over conventional measures in identifying subjects at risk of complications from IR. In aim 3, validated associations between proteins that appear causal in nature will be further examined through knockdown of the genes producing these proteins in human cell lines relevant to IR. These cell lines will include adipocytes, hepatocytes, and skeletal myocytes. This study is the largest study of the plasma proteome in relation to direct measures of insulin sensitivity ever proposed. Findings are expected to yield important mechanistic insights into the molecular basis of IR and provide the foundation for the development of a blood-based diagnostic test that can very reliably detect subjects at low or high risk of complications from IR.

胰岛素抵抗（IR）的后果不仅包括2型糖尿病，还包括一群 代谢异常，使动脉粥样硬化生命并发症的风险增加一倍 包括心肌梗塞，缺血性中风和周围动脉疾病。患病率是 随着西方人口变得更重，更久坐的速度，以惊人的速度增加。又一个 考虑了发展中国家正在进行的流行病学转变，除了肥胖症流行 发达国家，IR在全球范围内的公共卫生影响无疑是深远的。很少有药物 存在可以提高胰岛素敏感性并降低IR和最近的并发症风险的选择 IR替代措施的基因组研究产生了令人失望的新线索。此外， 对于开发IR的更准确的血液诊断测试而存在至关重要的需求。长期 拟议的研究的目的是发现和验证IR循环的新型蛋白质标记物 经历了两个“金标准”胰岛素的两个“黄金标准”中的一个人的血液 敏感性：胰岛素抑制检验（IST）或euglycemic夹（EC）。此信息将用于 识别可以针对药物靶向并发展统计的新型IR分子途径 通过直接测量胰岛素敏感性估算的IR程度高度相关的模型。目标 该提案中有1个，在斯坦福大学经历IST的2100名白人/欧洲受试者的血液或 EC在胰岛素敏感性与心血管疾病（RISC）与乌普萨拉（Uppsala）之间的关系中 将测量成人男性（ULSAM）研究的纵向研究，用于使用981种蛋白 利用新技术称为接近扩展测定法的新兴平台。这 技术允许对血浆中的蛋白质进行准确，可靠的量化，直至femtoloral或 大气压水平。我们将进一步验证这些受试者在其他〜300个非 - 欧洲受试者和斯坦福大学的300名受试者的子集，他们在减肥后进行了第二次IST 或使用噻唑烷二酮。在AIM 2中，我们将使用AIM 1的验证信号进行使用 孟德尔随机化的负责人，我们将量化经过验证的标记提供的改进 识别IR并发症风险的受试者的常规措施。在AIM 3中，经过验证的关联 在本质上出现因果的蛋白质之间，将通过敲低基因进一步研究 在与IR相关的人类细胞系中产生这些蛋白质。这些细胞系将包括脂肪细胞， 肝细胞和骨骼肌细胞。这项研究是血浆蛋白质组最大的研究 提出的胰岛素敏感性的度量。期望发现会产生重要的机械见解 进入IR的分子基础，为开发基于血液的诊断测试提供了基础 这可以非常可靠地检测出IR并发症的低或高风险的受试者。