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: 10376278
• 负责人: THEMISTOCLES LEONARD ASSIMES
• 金额: $ 68.92万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376278
• 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; 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; Longitudinal Studies; Malignant Neoplasms; Measures; Mediating; Mendelian randomization; 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; 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; fatty liver disease; follow-up; genome editing; genome wide association study; genomic data; glucose uptake; high risk; improved; insight; insulin sensitivity; knock-down; lipid biosynthesis; male; men; multi-ethnic; 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，还包括一系列 代谢异常使发生危及生命的动脉粥样硬化并发症的风险加倍 包括心肌梗塞、缺血性中风和外周动脉疾病。 IR 患病率是 随着西方人口变得更重、更久坐，这一数字正以惊人的速度增长。当进一步 除了发展中国家的肥胖流行之外，还考虑了发展中国家正在发生的流行病学转变 对于发达国家来说，IR对全球公共卫生的影响无疑是深远的。药理作用很少 存在提高胰岛素敏感性并降低 IR 和近期并发症风险的选择 IR 替代指标的基因组研究得出的新线索数量令人失望。此外， 迫切需要开发更准确的 IR 血液诊断测试。长期来看 拟议研究的目的是发现并验证 IR 中循环的新蛋白质标记物 接受过两种“金标准”直接胰岛素测量之一的个体的血液 敏感性：胰岛素抑制试验（IST）或正常血糖钳夹试验（EC）。该信息将用于 确定可药理学靶向的 IR 的新分子途径并开发统计数据 与通过直接测量胰岛素敏感性估计的 IR 程度高度相关的模型。瞄准目标 该提案的第 1 项，是 2100 名在斯坦福大学接受过 IST 或接受过 IST 治疗的白人/欧洲受试者的血液。 胰岛素敏感性与心血管疾病 (RISC) 和乌普萨拉之间关系的 EC 成年男性纵向研究 (ULSAM) 将使用 利用称为邻近延伸测定的新技术的新兴平台。这 该技术可以对血浆中的蛋白质进行准确可靠的定量，低至飞摩尔或 阿摩尔水平。我们将在另外约 300 个非非研究对象中进一步验证在这些受试者中识别出的主要信号。 欧洲受试者和来自斯坦福大学的 300 名受试者在减肥后接受了第二次 IST 或使用噻唑烷二酮。在目标 2 中，我们将使用以下方法检查目标 1 中经过验证的信号的因果关系： 孟德尔随机化的原理，我们将量化经过验证的标记所提供的改进 识别有 IR 并发症风险的受试者的常规措施。在目标 3 中，验证关联 自然界中出现因果关系的蛋白质之间的关系将通过基因敲低得到进一步检查 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。这项研究是与直接相关的血浆蛋白质组的最大研究 曾经提出的胰岛素敏感性测量方法。研究结果预计将产生重要的机制见解 深入了解 IR 的分子基础，并为基于血液的诊断测试的开发奠定基础 可以非常可靠地检测出 IR 并发症风险低或高的受试者。