Circulating metabolite profile in young adulthood identifies long-term diabetes susceptibility: the Coronary Artery Risk Development in Young Adults (CARDIA) study,Diabetologia

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Circulating metabolite profile in young adulthood identifies long-term diabetes susceptibility: the Coronary Artery Risk Development in Young Adults (CARDIA) study
Diabetologia ( IF 8.2 ) Pub Date : 2022-01-18 , DOI: 10.1007/s00125-021-05641-x
Venkatesh L Murthy ₁ , Matthew Nayor ₂ , Mercedes Carnethon ₃ , Jared P Reis ₄ , Donald Lloyd-Jones ₃ , Norrina B Allen ₃ , Robert Kitchen ₅ , Paolo Piaggi ₆ , Lyn M Steffen ₇ , Ramachandran S Vasan _{8,

9} , Jane E Freedman ₁₀ , Clary B Clish ₁₁ , Ravi V Shah ₁₀

Affiliation

Department of Medicine and Radiology, University of Michigan, Ann Arbor, MI, USA.
Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Northwestern University, Chicago, IL, USA.
National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Simches Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Department of Information Engineering, University of Pisa, Pisa, Italy.
University of Minnesota School of Public Health, Minneapolis, MN, USA.
Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, MA, USA.
Framingham Heart Study, Framingham, MA, USA.
Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Aims/hypothesis

The aim of this work was to define metabolic correlates and pathways of diabetes pathogenesis in young adults during a subclinical latent phase of diabetes development.

Methods

We studied 2083 young adults of Black and White ethnicity in the prospective observational cohort Coronary Artery Risk Development in Young Adults (CARDIA) study (mean ± SD age 32.1 ± 3.6 years; 43.9% women; 42.7% Black; mean ± SD BMI 25.6 ± 4.9 kg/m²) and 1797 Framingham Heart Study (FHS) participants (mean ± SD age 54.7 ± 9.7 years; 52.1% women; mean ± SD BMI 27.4 ± 4.8 kg/m²), examining the association of comprehensive metabolite profiles with endophenotypes of diabetes susceptibility (adipose and muscle tissue phenotypes and systemic inflammation). Statistical learning techniques and Cox regression were used to identify metabolite signatures of incident diabetes over a median of nearly two decades of follow-up across both cohorts.

Results

We identified known and novel metabolites associated with endophenotypes that delineate the complex pathophysiological architecture of diabetes, spanning mechanisms of muscle insulin resistance, inflammatory lipid signalling and beta cell metabolism (e.g. bioactive lipids, amino acids and microbe- and diet-derived metabolites). Integrating endophenotypes of diabetes susceptibility with the metabolome generated two multi-parametric metabolite scores, one of which (a proinflammatory adiposity score) was associated with incident diabetes across the life course in participants from both the CARDIA study (young adults; HR in a fully adjusted model 2.10 [95% CI 1.72, 2.55], p<0.0001) and FHS (middle-aged and older adults; HR 1.33 [95% CI 1.14, 1.56], p=0.0004). A metabolite score based on the outcome of diabetes was strongly related to diabetes in CARDIA study participants (fully adjusted HR 3.41 [95% CI 2.85, 4.07], p<0.0001) but not in the older FHS population (HR 1.15 [95% CI 0.99, 1.33], p=0.07).

Conclusions/interpretation

Selected metabolic abnormalities in young adulthood identify individuals with heightened diabetes risk independent of race, sex and traditional diabetes risk factors. These signatures replicate across the life course.

Graphical abstract

中文翻译：

青年期循环代谢物谱可确定长期糖尿病易感性：青年期冠状动脉风险发展 (CARDIA) 研究

目标/假设

这项工作的目的是确定糖尿病发展的亚临床潜伏期期间年轻人糖尿病发病机制的代谢相关性和途径。

方法

我们在前瞻性观察队列年轻人冠状动脉风险发展 (CARDIA) 研究中研究了 2083 名黑人和白人年轻人（平均 ± SD 年龄 32.1 ± 3.6 岁；43.9% 女性；42.7% 黑人；平均 ± SD BMI 25.6 ± 4.9 kg/m ² ) 和 1797 名 Framingham 心脏研究 (FHS) 参与者（平均 ± SD 年龄 54.7 ± 9.7 岁；52.1% 女性；平均 ± SD BMI 27.4 ± 4.8 kg/m 2 ），检查综合代谢物^概况与糖尿病易感性的内表型（脂肪和肌肉组织表型和全身炎症）。统计学习技术和 Cox 回归被用于在两个队列中近二十年的中位数随访中识别新发糖尿病的代谢物特征。

结果

我们确定了与内表型相关的已知和新型代谢物，这些内表型描述了糖尿病的复杂病理生理结构，涵盖肌肉胰岛素抵抗、炎症脂质信号传导和 β 细胞代谢的机制（例如生物活性脂质、氨基酸和微生物和饮食衍生的代谢物）。将糖尿病易感性的内表型与代谢组相结合产生了两个多参数代谢物评分，其中一个（促炎性肥胖评分）与来自 CARDIA 研究（年轻人；完全调整的 HR）的参与者的整个生命过程中的糖尿病事件相关模型 2.10 [95% CI 1.72, 2.55], p <0.0001) 和 FHS（中年和老年人；HR 1.33 [95% CI 1.14, 1.56], p=0.0004）。在 CARDIA 研究参与者中，基于糖尿病结果的代谢物评分与糖尿病密切相关（完全调整后的 HR 3.41 [95% CI 2.85, 4.07]，p <0.0001），但在老年 FHS 人群中则不然（HR 1.15 [95 % CI 0.99, 1.33], p = 0.07)。