Determinants of alpha-aminoadipic acid (2-AAA) and relationship to diabetes

α-氨基己二酸 (2-AAA) 的决定因素及其与糖尿病的关系

• 批准号: 10164763
• 负责人: Jane F Ferguson
• 金额: $ 46.56万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164763
• 关键词: Acids; Acute; Address; Amino Acids; Animals; Biological; Biological Markers; Biology; Blood; Blood specimen; Cardiometabolic Disease; Catabolism; Cause of Death; Cohort Studies; Communities; Complications of Diabetes Mellitus; Computerized Medical Record; Controlled Study; DNA; Data; Development; Diabetes Mellitus; Diet; Dietary Intervention; Disease; Disease Marker; Early identification; Epidemiology; Fasting; Food Interactions; Framingham Heart Study; Functional disorder; Future; General Population; Genes; Genetic; Genetic Determinism; Genetic Risk; Genotype; Genotype-Tissue Expression Project; Health; Health Care Costs; High Prevalence; Human; Incidence; Individual; Intake; Investigation; Jackson Heart Study; Knowledge; Lysine; Measurement; Measures; Medical Genetics; Meta-Analysis; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Morbidity - disease rate; Outcome Study; Participant; Pathogenesis; Pathway interactions; Patient Self-Report; Phenotype; Plasma; Population; Protocols documentation; Randomized; Research; Risk; Risk Factors; Risk Marker; Role; Sampling; Testing; Tissue-Specific Gene Expression; Tissues; Tracer; Validation; Variant; Women' s Health; biobank; cohort; comorbidity; cost; diabetes pathogenesis; diabetes prevention program; diabetes risk; dietary; falls; follow-up; genetic architecture; genetic predictors; genome wide association study; global health; improved; insight; insulin secretion; men; metabolomics; mortality; multi-ethnic; new therapeutic target; novel; protein intake; recruit; stable isotope; targeted treatment; therapeutic development

Diabetes is a major global health concern, associated with significantly increased mortality and high incidence of co-morbidities. The lysine-derived metabolite α-aminoadipic acid (2-AAA) was identified as a novel predictor of diabetes development in Framingham Heart Study (FHS) participants and validation samples (N~2,000). In these subjects, increased plasma 2-AAA in healthy individuals was associated with increased future risk of diabetes (12-year follow-up), identifying at-risk individuals even after adjustment for known risk factors. Several subsequent studies have confirmed the association between 2-AAA and diabetes, but the mechanisms remain unknown. Preliminary data support a role for 2-AAA in insulin secretion and diabetes pathophysiology, and suggest genetic determinants of 2-AAA relate to diabetes and diabetic complications. However it is not yet clear whether 2-AAA is itself causal in diabetes development, or is a biomarker for altered metabolic processes. Many questions remain as to mechanisms of action. In this proposal, we will examine the determinants of 2-AAA, by studying lysine-2-AAA metabolism in subjects with extreme levels of 2-AAA before and after dietary intervention (Aim 1); identify the genetic predictors of 2-AAA (Aim 2); and examine the genetic architecture of 2-AAA and disease (Aim 3). These aims will advance our long-term research objective, to understand determinants of 2-AAA, and establish utility of 2-AAA and related pathways as a novel therapeutic target in diabetes.

糖尿病是全球主要的健康问题，与死亡率显着增加和高发病率有关 合并症。赖氨酸来源的代谢产物α-氨基丙酸（2-AAA）被确定为一种新型预测指标 Framingham心脏研究（FHS）参与者和验证样本中的糖尿病发育（n〜2,000）。在 这些受试者，健康个体中血浆2-AAA的增加与未来的风险增加有关 糖尿病（12年的随访），即使在调整已知危险因素后，也可以确定高危人群。一些 随后的研究已经证实了2-AAA和糖尿病之间的关联，但这些机制仍然存在 未知。初步数据支持2-AAA在胰岛素分泌和糖尿病生理学中的作用，以及 建议2-AAA的遗传决定剂与糖尿病和糖尿病并发症有关。但是还没有 清楚2-AAA本身是糖尿病发育中的因果，还是改变代谢的生物标志物 过程。关于行动机制仍然存在许多问题。在此提案中，我们将研究 2-AAA的决定因素，通过研究赖氨酸-2-AAA代谢的2-AAA代谢。 饮食干预后（目标1）；确定2-AAA的遗传预测因子（AIM 2）；并检查遗传 2-AAA和疾病的结构（AIM 3）。这些目标将促进我们的长期研究目标，以 了解确定2-AAA，并确定2-AAA和相关途径的实用性作为一种新的疗法 糖尿病目标。