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: 10447054
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447054
• 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.

糖尿病是一个主要的全球健康问题，与死亡率显着增加和发病率高相关 的合并症。赖氨酸衍生的代谢物 α-氨基己二酸 (2-AAA) 被确定为一种新的预测因子 弗雷明汉心脏研究 (FHS) 参与者和验证样本 (N~2,000) 的糖尿病发展情况。在 在这些受试者中，健康个体血浆 2-AAA 的增加与未来风险的增加有关 糖尿病（12 年随访），即使在调整已知风险因素后也能识别出高危个体。一些 随后的研究证实了 2-AAA 与糖尿病之间的关联，但其机制仍然存在 未知。初步数据支持 2-AAA 在胰岛素分泌和糖尿病病理生理学中的作用，以及 表明 2-AAA 的遗传决定因素与糖尿病和糖尿病并发症有关。然而现在还没有 明确 2-AAA 本身是否是糖尿病发生的原因，或者是代谢改变的生物标志物 流程。关于作用机制仍然存在许多问题。在本提案中，我们将研究 2-AAA 的决定因素，通过研究 2-AAA 极端水平受试者的赖氨酸-2-AAA 代谢 以及饮食干预后（目标 1）；确定 2-AAA 的遗传预测因子（目标 2）；并检查遗传 2-AAA 的结构和疾病（目标 3）。这些目标将推进我们的长期研究目标， 了解 2-AAA 的决定因素，并确定 2-AAA 和相关途径作为新型治疗方法的效用 糖尿病的目标。

项目成果

Branched-chain amino acids and type 2 diabetes: a bidirectional Mendelian randomization analysis.

• DOI: 10.1002/oby.23951
• 发表时间: 2024-01
• 期刊: Obesity
• 影响因子: 6.9
• 作者: Jonathan D. Mosley;Mingjian Shi;David Agamasu;N. Vaitinadin;V. Murthy;Ravi V Shah;Minoo Bagheri;Jane F. Ferguson

New-onset vegetarian diet shows differences in fatty acid metabolites in European American and African American women.

• DOI: 10.1016/j.numecd.2021.05.013
• 发表时间: 2021-07-22
• 期刊: NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES
• 影响因子: 3.9
• 作者: Wang, Naomi C.;Bagheri, Minoo;Olszewski, Timothy;Friese, Katie A.;Smith, Holly M.;Robles, Michelle E.;Wang, Chuan;Brooks, Andrew;Bordenstein, Seth R.;Ferguson, Jane F.;Silver, Heidi J.
• 通讯作者: Silver, Heidi J.

Metabolomics reveals the impact of Type 2 diabetes on local muscle and vascular responses to ischemic stress.

• DOI: 10.1042/cs20191227
• 发表时间: 2020-09-18
• 期刊: Clinical science (London, England : 1979)
• 作者: Beckman JA;Hu JR;Huang S;Farber-Eger E;Wells QS;Wang TJ;Gerszten RE;Ferguson JF
• 通讯作者: Ferguson JF

Knock-Out of DHTKD1 Alters Mitochondrial Respiration and Function, and May Represent a Novel Pathway in Cardiometabolic Disease Risk.

DHTKD1的敲除改变了线粒体的呼吸和功能，并且可能代表心脏代谢疾病风险的新途径。

• DOI: 10.3389/fendo.2021.710698
• 发表时间: 2021
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Wang C;Calcutt MW;Ferguson JF
• 通讯作者: Ferguson JF