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.

糖尿病是全球主要的健康问题，与死亡率显着增加和高刺激性有关 赖氨酸衍生的代谢物α-氨基酸（2-AAA）的合并症。 Framingham心脏研究（FHS）参与者和验证样本的糖尿病发育（n〜2,000） 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），在调整已知危险因素后识别高危个人事件。 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 未知数。 但是，目前尚未表明2-AAA的遗传决定因素与糖尿病和糖尿病汇编有关 清楚2-AAA是糖尿病发育中的因果关系，还是改变代谢的生物标志物 流程。 2-AAA的决定因素，通过研究赖氨酸-2-AAA代谢在具有极高水平的2-AAA的受试者中 饮食干预后（目标1）； 2-AAA和疾病的建筑（目标3）。 了解2-AAA的决定因素，并建立2-AAA和相关途径的实用性作为一种新型治疗 糖尿病目标。

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.

• 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