Naja Khaled, Elashi Asma A, Anwardeen Najeha, Razzaq Aleem, Hedaya Laila, Almuraikhy Shamma, Diboun Ilhame, Suhre Karsten, AlBagha Omar, Elrayess Mohamed A
Biomedical Research Center, QU Health, Qatar University, Doha, Qatar.
Department of Human Genetics, Sidra Medicine, Doha, Qatar.
Diabetes Obes Metab. 2025 Oct;27(10):5793-5804. doi: 10.1111/dom.16633. Epub 2025 Jul 22.
N-lactoyl amino acids (Lac-AA) are emerging as crucial players in metabolic research, with potential implications for disease mechanisms and therapeutic interventions. This study exploress the role of Lac-AA in insulin resistance, type 2 diabetes (T2D), and its complications.
A cross-sectional study was conducted using data from 2918 participants from Qatar Biobank. After quality control, 2907 individuals were retained and randomly divided into discovery (n = 1990) and validation (n = 917) cohorts. Untargeted metabolomics was employed to profile serum metabolites, and analysis was focused on three Lac-AA species. Participants were stratified into insulin-sensitive, insulin-resistant, T2D without complications and T2D with complications. Associations with clinical traits were assessed using linear regression and Spearman correlation. Diagnostic performance was evaluated using Receiver Operating Characteristic (ROC) analysis in an independent cohort (n = 60). One-sample Mendelian randomisation was performed to assess causality between genetic predisposition to T2D and Lac-AA levels. Network analysis explored metabolic pathways linked to Lac-AA.
Lac-AA levels were significantly higher in individuals with insulin resistance and diabetic complications. These findings were robustly replicated in the validation cohort. These metabolites showed strong positive correlations with markers of poor glycaemic control independent of metformin use. ROC analysis demonstrated that Lac-AA could discriminate between insulin-resistant and insulin-sensitive individuals. Mendelian randomisation analysis indicated a potential causal association between genetic risk for T2D and increased Lac-AA, particularly in patients with complications, supporting their role as downstream biomarkers of metabolic disease severity. Gaussian graphical model analysis revealed Lac-AA as central nodes in metabolic networks, showing strong associations with mitochondrial dysfunction biomarkers.
Lac-AA may serve as integrative biomarkers of metabolic dysfunction and diabetic complications. Further longitudinal and interventional studies are needed to clarify their mechanistic roles and clinical utility.
N-乳酰氨基酸（Lac-AA）正在成为代谢研究中的关键因素，对疾病机制和治疗干预具有潜在影响。本研究探讨了Lac-AA在胰岛素抵抗、2型糖尿病（T2D）及其并发症中的作用。
采用卡塔尔生物银行2918名参与者的数据进行横断面研究。经过质量控制后，保留了2907名个体，并将其随机分为发现队列（n = 1990）和验证队列（n = 917）。采用非靶向代谢组学对血清代谢物进行分析，重点关注三种Lac-AA种类。参与者被分为胰岛素敏感、胰岛素抵抗、无并发症的T2D和有并发症的T2D。使用线性回归和Spearman相关性评估与临床特征的关联。在一个独立队列（n = 60）中使用受试者工作特征（ROC）分析评估诊断性能。进行单样本孟德尔随机化以评估T2D遗传易感性与Lac-AA水平之间的因果关系。网络分析探索了与Lac-AA相关的代谢途径。
胰岛素抵抗和糖尿病并发症患者的Lac-AA水平显著更高。这些发现在验证队列中得到了有力验证。这些代谢物与血糖控制不佳的标志物呈强正相关，且与二甲双胍的使用无关。ROC分析表明，Lac-AA可以区分胰岛素抵抗和胰岛素敏感个体。孟德尔随机化分析表明，T2D的遗传风险与Lac-AA升高之间存在潜在因果关联，尤其是在有并发症的患者中，支持它们作为代谢疾病严重程度下游生物标志物的作用。高斯图形模型分析显示Lac-AA是代谢网络中的中心节点，与线粒体功能障碍生物标志物有很强的关联。
Lac-AA可能作为代谢功能障碍和糖尿病并发症的综合生物标志物。需要进一步的纵向和干预性研究来阐明它们的作用机制和临床应用。
