Metabolic profiling of frailty, associations with type 2 diabetes and interaction with genetic susceptibility.

IF 8.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Cardiovascular Diabetology Pub Date : 2025-05-24 DOI:10.1186/s12933-025-02776-8

Yuxiang Wang, Shuang Chen, Yue Li, Qi Lu, Rui Li, Jun-Xiang Chen, Ji-Juan Zhang, Hancheng Yu, Hanrui Xu, Jinchi Xie, Xianli Li, Gang Liu, An Pan, Tingting Geng, Yun-Fei Liao

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Abstract

Background: Individuals with frailty are at increased risk of type 2 diabetes (T2D), but the underlying mechanisms are unclear. We aimed to investigate whether the frailty-T2D association is mediated by alterations in the metabolome and assess potential interaction with genetic susceptibility to diabetes.

Methods: This retrospective analysis, using data from a large prospective population-based cohort, included a total of 197,502 adults with baseline metabolomics data from the UK Biobank. Frailty was defined using the Fried frailty phenotype according to five components. Elastic net regression was applied to create a frailty-related metabolic signature. We assessed hazard ratios (HR) and its 95% confidence interval (CI) of incident T2D in relation to the baseline metabolic signature of frailty and examined the mediating role of the metabolic signature in the effect of frailty on T2D. Additive interaction between the metabolic signature and polygenic risk score for T2D (PRS-T2D) on the incidence of T2D was assessed as relative excess risk due to interaction (RERI).

Results: Compared with non-frailty, the HR (95% CI) of incident T2D in pre-frailty and frailty was 1.33 (1.26, 1.40) and 1.59 (1.46, 1.74), respectively. The metabolic signature of frailty (comprised of 53 metabolites) was positively associated with T2D risk (HR per standard deviation increment: 1.45; 95% CI: 1.42, 1.48), and explained 31.0% (95% CI: 25.8, 36.8) of the association between frailty and T2D. An additive interaction between metabolic signature of frailty and PRS-T2D was found (RERI: 9.43; 95% CI: 6.06, 12.80).

Conclusions: The increased risk of T2D in individuals with frailty may be mediated through effects on the metabolome, and the influence of such metabolic alterations on diabetes risk may be amplified in individuals with genetic susceptibility to T2D.

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虚弱的代谢谱，与2型糖尿病的关联以及与遗传易感性的相互作用。

背景：身体虚弱的个体患2型糖尿病（T2D）的风险增加，但其潜在机制尚不清楚。我们的目的是研究衰弱与t2d的关联是否由代谢组的改变介导，并评估其与糖尿病遗传易感性的潜在相互作用。方法：本回顾性分析使用来自大型前瞻性人群队列的数据，包括来自英国生物银行的197,502名成年人的基线代谢组学数据。根据五个组成部分，使用Fried脆弱表型来定义脆弱性。弹性网回归应用于创建一个脆弱相关的代谢特征。我们评估了发生T2D的风险比（HR）及其95%置信区间（CI）与虚弱基线代谢特征的关系，并检查了代谢特征在虚弱对T2D影响中的中介作用。代谢特征和T2D多基因风险评分（PRS-T2D）对T2D发病率的加性相互作用被评估为相互作用的相对过量风险（rei）。结果：与非衰弱组相比，衰弱前期和衰弱期发生T2D的HR （95% CI）分别为1.33（1.26,1.40）和1.59（1.46,1.74）。虚弱的代谢特征（由53种代谢物组成）与T2D风险呈正相关(每标准差增量HR: 1.45；95% CI: 1.42, 1.48)，并解释了31.0% （95% CI: 25.8, 36.8）的虚弱和T2D之间的关联。虚弱的代谢特征与PRS-T2D之间存在加性相互作用(rei: 9.43；95% ci: 6.06, 12.80)。结论：体弱多病个体T2D风险的增加可能是通过代谢组的影响介导的，这种代谢改变对糖尿病风险的影响可能在T2D遗传易感性个体中被放大。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cardiovascular Diabetology 医学-内分泌学与代谢

CiteScore

12.30

自引率

15.10%

发文量

240

审稿时长

1 months

期刊介绍： Cardiovascular Diabetology is a journal that welcomes manuscripts exploring various aspects of the relationship between diabetes, cardiovascular health, and the metabolic syndrome. We invite submissions related to clinical studies, genetic investigations, experimental research, pharmacological studies, epidemiological analyses, and molecular biology research in this field.