Metabolomic predictors of insulin resistance and diabetes

胰岛素抵抗和糖尿病的代谢组预测因子

• 批准号: 10693948
• 负责人: Clary B Clish
• 金额: $ 62.13万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693948
• 关键词: Acetylation; Acids; Adenosine Monophosphate; African American population; Amino Acids; Aromatic Amino Acids; Award; Base Sequence; Biochemical Markers; Biological Markers; Biological Models; Biology; Blood Chemical Analysis; Caucasians; Cells; Classification; Clinical; Clinical Trials; Collaborations; Communities; Complement; Cytosine; Data; Diabetes Mellitus; Diagnosis; Disease; Enzymes; Ethnic Population; Etiology; Fatty acid glycerol esters; Framingham Heart Study; Funding; Future; Genes; Genetic; Glutamates; Glutamine; Glycosylated hemoglobin A; Goals; Health; Heterogeneity; High Prevalence; Human; Hyperglycemia; Imidazole; Incidence; Individual; Institution; Insulin; Insulin Resistance; Jackson Heart Study; Laboratories; Life Style; Lipids; Liver; Maps; Mass Spectrum Analysis; Mendelian randomization; Meta-Analysis; Metabolic; Metabolic Diseases; Metformin; Muscle; Names; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pancreas; Participant; Pathway interactions; Phospholipids; Predictive Value of Tests; Propionates; Proteins; Randomized; Recording of previous events; Resources; Risk; Risk Factors; Stratification; Taurine; Techniques; Testing; Time; Tissues; Triglycerides; Variant; Work; bioinformatics tool; causal variant; clinical risk; cohort; diabetes prevention program; diet and cancer; disorder risk; experimental study; fasting glucose; gain of function; genetic architecture; genetic variant; genome wide association study; genome-wide; glucose tolerance; high risk; improved; loss of function; metabolome; metabolomics; multi-ethnic; n-pentanoic acid; new technology; novel; novel strategies; offspring; population based; preventive intervention; risk variant; solute; sphinganine; trait; uptake; whole genome; young adult

Project Summary/Abstract During prior funding periods we have identified and validated novel metabolite profiles of those destined to develop overt T2D. These metabolites were elevated up to 12 years before the onset of T2D in individuals who were initially glucose-tolerant; improved prediction of T2D beyond clinical risk factors and established biochemical markers; and have been validated by other groups. We have now extended our studies to participants in the Jackson Heart Study (JHS), an African American (AA) population with a high prevalence of T2D and its complications. We have also tested the predictive value of metabolites in a key clinical trial, the Diabetes Prevention Program (DPP). Our renewal will leverage critical advances made during the first 12 years of this award. Beyond the named metabolites that we have associated with incident T2D, our recent “whole metabolome” analyses of T2D and related traits in JHS have nominated hundreds of unknown compounds that are uncorrelated with existing biochemical markers for unambiguous identification. We will use novel, in-house mass spectrometry (MS) and bioinformatics tools to unambiguously identify these compounds. To complement the MS work, genome wide association studies (GWAS) and genetic correlation analyses of metabolites and proteins will be used to assign metabolite peaks to pathways (e.g., based on association with known metabolites or with enzymes or solute carriers) that inform their identity. Finally, fine mapping of metabolite-associated genetic variants, co- localization studies with established T2D-associated variants, and Mendelian Randomization experiments will be used to assess causality of metabolite-associated variants for T2D. Putative causal variants that emerge from these analyses will be validated in model systems, using techniques that are well established in our laboratory as well as novel approaches. In Specific Aim 1, we will establish the identity of unknown metabolite peaks that are associated with T2D and related traits, using state-of-the-art mass spectrometry, and informed by GWAS and genetic correlation analyses. In Specific Aim 2, we will refine the genetic architecture of metabolites associated with T2D and related traits (fasting glucose, insulin, lipids, HbA1c, and HOMA-IR) in multi-ethnic cohorts and test whether the likely causal variants are also risk variants for T2D and these same traits. In Specific Aim 3, we will functionally examine key metabolite-related variants in model systems. We will use both gain- and loss-of-function approaches to recapitulate metabolite profiles seen in humans and test for effects on key metabolic functions (e.g., insulin release) in metabolically active tissues (e.g., pancreas). Initial studies will focus on the novel T2D biomarker, ACY-1, a circulating enzyme most highly expressed by the liver which cleaves endogenous N- acetylated amino acids to their free circulating forms. All data from this multi-institutional collaboration will be made publicly available in real time for the entire scientific community.

项目摘要/摘要 在以前的资助期间，我们已经确定并验证了那些注定为 开发公开的T2D。在T2D发作之前，这些代谢产物在 最初是耐葡萄糖的；改进了T2D超出临床风险因素并建立的预测 生化标记；并已由其他群体验证。我们现在将研究扩展到 杰克逊心脏研究（JHS）的参与者是非裔美国人（AA）人口，患病率很高 T2D及其并发症。我们还测试了代谢物在关键临床试验中的预测价值， 糖尿病预防计划（DPP）。 我们的续约将利用本奖项的前12年中取得的重要进展。超越命名 与事件T2D相关的代谢产物，我们最近对T2D的“整个代谢组”分析 JHS中的相关特征提名了数百种与现有的未知化合物 明确鉴定的生化标记。我们将使用新颖的内部质谱法（MS）和 明确识别这些化合物的生物信息学工具。为了完成MS工作，基因组宽 结合研究（GWAS）以及代谢物和蛋白质的遗传相关分析将用于 将代谢产物峰分配到途径（例如，基于与已知代谢物或酶的关联或 溶质载体），以告知其身份。最后，代谢物相关的遗传变异的精细映射，共同 通过已建立的T2D相关变体和Mendelian随机化实验的本地化研究将 用于评估T2D代谢物相关变体的因果关系。出现的推定因果变体 从这些分析中，将在模型系统中验证，使用我们在我们的 实验室以及新颖的方法。 在特定目标1中，我们将建立与T2D和T2D相关的未知代谢峰的身份 相关性状，使用最先进的质谱法，并通过GWA和遗传相关性告知 分析。在特定目标2中，我们将完善与T2D和T2D和 多族裔队列中的相关性状（禁食葡萄糖，胰岛素，脂质，HBA1C和HOMA-IR），并测试是否是否测试 可能的因果变异也是T2D和这些相同特征的风险变体。在特定的目标3中，我们将在功能上 检查模型系统中与代谢物相关的关键变体。我们将同时使用功能丧失 概括人类中看到的代谢产物特征并测试对关键代谢功能的影响的方法 （例如，胰岛素释放）在代谢活性组织（例如胰腺）中。最初的研究将重点放在新型T2D上 生物标志物，ACY-1，一种循环的酶，肝脏裂解内源性N- 乙酰化氨基酸的自由循环形式。来自此多机构合作的所有数据将是 为整个科学界实时公开提供。