Type 1 diabetes (T1D) results from an autoimmune attack of the pancreatic β cells that progresses to dysglycemia and symptomatic hyperglycemia. Current biomarkers to track this evolution are limited, with development of islet autoantibodies marking the onset of autoimmunity and metabolic tests used to detect dysglycemia. Therefore, additional biomarkers are needed to better track disease initiation and progression. Multiple clinical studies have used proteomics to identify biomarker candidates. However, most of the studies were limited to the initial candidate identification, which needs to be further validated and have assays developed for clinical use. Here we curate these studies to help prioritize biomarker candidates for validation studies and to obtain a broader view of processes regulated during disease development. This systematic review was registered with Open Science Framework ( https://doi.org/10.17605/OSF.IO/N8TSA ). Using PRISMA guidelines, we conducted a systematic search of proteomics studies of T1D in the PubMed to identify putative protein biomarkers of the disease. Studies that performed mass spectrometry-based untargeted/targeted proteomic analysis of human serum/plasma of control, pre-seroconversion, post-seroconversion, and/or T1D-diagnosed subjects were included. For unbiased screening, 3 reviewers screened all the articles independently using the pre-determined criteria. A total of 13 studies met our inclusion criteria, resulting in the identification of 266 unique proteins, with 31 (11.6%) being identified across 3 or more studies. The circulating protein biomarkers were found to be enriched in complement, lipid metabolism, and immune response pathways, all of which are found to be dysregulated in different phases of T1D development. We found 2 subsets: 17 proteins (C3, C1R, C8G, C4B, IBP2, IBP3, ITIH1, ITIH2, BTD, APOE, TETN, C1S, C6A3, SAA4, ALS, SEPP1 and PI16) and 3 proteins (C3, CLUS and C4A) have consistent regulation in at least 2 independent studies at post-seroconversion and post-diagnosis compared to controls, respectively, making them strong candidates for clinical assay development. Biomarkers analyzed in this systematic review highlight alterations in specific biological processes in T1D, including complement, lipid metabolism, and immune response pathways, and may have potential for further use in the clinic as prognostic or diagnostic assays.

中文翻译：

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对 1 型糖尿病生物标志物的系统评价揭示了与补体、脂质代谢和免疫反应相关的循环蛋白的调节

1 型糖尿病 (T1D) 由胰腺 β 细胞的自身免疫攻击导致，并进展为血糖异常和症状性高血糖。目前追踪这种进化的生物标志物是有限的，胰岛自身抗体的发展标志着自身免疫的开始，以及用于检测血糖异常的代谢测试。因此，需要额外的生物标志物来更好地跟踪疾病的发生和进展。多项临床研究已使用蛋白质组学来识别候选生物标志物。然而，大多数研究仅限于最初的候选者识别，需要进一步验证并开发用于临床使用的检测方法。在这里，我们策划这些研究，以帮助优先考虑验证研究的候选生物标志物，并获得对疾病发展过程中监管过程的更广泛的了解。该系统评价已在开放科学框架（https://doi.org/10.17605/OSF.IO/N8TSA）中注册。使用 PRISMA 指南，我们对 PubMed 中 T1D 的蛋白质组学研究进行了系统检索，以确定该疾病的假定蛋白质生物标志物。包括对对照、血清转换前、血清转换后和/或 T1D 诊断受试者的人血清/血浆进行基于质谱的非靶向/靶向蛋白质组学分析的研究。为了进行公正的筛选，3 位评审员使用预先确定的标准独立筛选所有文章。共有 13 项研究符合我们的纳入标准，最终鉴定出 266 种独特蛋白质，其中 31 种 (11.6%) 在 3 项或更多研究中被鉴定。研究发现，循环蛋白生物标志物在补体、脂质代谢和免疫反应途径中富集，所有这些途径在 T1D 发展的不同阶段都出现失调。我们发现了 2 个子集：17 种蛋白质（C3、C1R、C8G、C4B、IBP2、IBP3、ITIH1、ITIH2、BTD、APOE、TETN、C1S、C6A3、SAA4、ALS、SEPP1 和 PI16）和 3 种蛋白质（C3、CLUS 和C4A）在至少两项独立研究中分别与对照相比在血清转换后和诊断后具有一致的调节，使它们成为临床检测开发的有力候选者。本系统综述中分析的生物标志物强调了 T1D 特定生物过程的变化，包括补体、脂质代谢和免疫反应途径，并且可能有潜力在临床中进一步用作预后或诊断分析。