AIMS/HYPOTHESIS Previous metabolomics studies suggest that type 1 diabetes is preceded by specific metabolic disturbances. The aim of this study was to investigate whether distinct metabolic patterns occur in peripheral blood mononuclear cells (PBMCs) of children who later develop pancreatic beta cell autoimmunity or overt type 1 diabetes. METHODS In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who (1) progressed to type 1 diabetes (PT1D, n = 34), (2) seroconverted to ≥1 islet autoantibody without progressing to type 1 diabetes (P1Ab, n = 27) or (3) remained autoantibody negative during follow-up (CTRL, n = 10). RESULTS During the first year of life, levels of most lipids and polar metabolites were lower in the PT1D and P1Ab groups compared with the CTRL group. Pathway over-representation analysis suggested alanine, aspartate, glutamate, glycerophospholipid and sphingolipid metabolism were over-represented in PT1D. Genome-scale metabolic models of PBMCs during type 1 diabetes progression were developed by using publicly available transcriptomics data and constrained with metabolomics data from our study. Metabolic modelling confirmed altered ceramide pathways, known to play an important role in immune regulation, as specifically associated with type 1 diabetes progression. CONCLUSIONS/INTERPRETATION Our data suggest that systemic dysregulation of lipid metabolism, as observed in plasma, may impact the metabolism and function of immune cells during progression to overt type 1 diabetes. DATA AVAILABILITY The GEMs for PBMCs have been submitted to BioModels (www.ebi.ac.uk/biomodels/), under accession number MODEL1905270001. The metabolomics datasets and the clinical metadata generated in this study were submitted to MetaboLights (https://www.ebi.ac.uk/metabolights/), under accession number MTBLS1015.

中文翻译：

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免疫细胞的代谢改变与1型糖尿病的发展有关。

目的/假设以前的代谢组学研究表明1型糖尿病先于特定的代谢紊乱。这项研究的目的是调查是否在后来发展为胰腺β细胞自身免疫性或明显的1型糖尿病的儿童的外周血单核细胞（PBMC）中发生不同的代谢方式。方法在纵向队列研究中，PBMC代谢组学分析适用于（1）进展为1型糖尿病（PT1D，n = 34），（2）血清转化为≥1胰岛自身抗体而未进展为1型糖尿病（P1Ab，n）的儿童= 27）或（3）在随访期间自身抗体阴性（CTRL，n = 10）。结果在生命的第一年中，与CTRL组相比，PT1D和P1Ab组的大多数脂质和极性代谢产物的水平较低。通路过度表达分析表明，PT1D中丙氨酸，天冬氨酸，谷氨酸，甘油磷脂和鞘脂代谢过多。PBMC在1型糖尿病进展过程中的基因组规模代谢模型是通过使用可公开获得的转录组学数据并受本研究的代谢组学数据约束而开发的。代谢模型证实了神经酰胺途径的改变，已知在免疫调节中起着重要作用，特别是与1型糖尿病的进展有关。结论/解释我们的数据表明，如在血浆中观察到的，脂质代谢的系统性失调可能会影响向1型糖尿病的发展过程中免疫细胞的代谢和功能。数据可用性PBMC的GEM已提交给BioModels（www.ebi.ac.uk/biomodels/），登录号为MODEL1905270001。这项研究中产生的代谢组学数据集和临床元数据已提交给MetaboLights（https://www.ebi.ac.uk/metabolights/），登录号为MTBLS1015。