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. 2025 Jun;68(6):1108-1114.
doi: 10.1007/s00125-025-06394-7. Epub 2025 Feb 28.

Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes affirms markers of disease

Robert Moulder  1   2 , M Karoliina Hirvonen  3   4 , Tommi Välikangas  3   4 , Tomi Suomi  3   4 , Lut Overbergh  5 , Mark Peakman  6 , Søren Brunak  7 , Chantal Mathieu  5 , Mikael Knip  8   9   10 , Laura L Elo  11   12   13 , Riitta Lahesmaa  14   15   16 ; INNODIA consortium
Affiliations

Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes affirms markers of disease

Robert Moulder et al. Diabetologia. 2025 Jun.

Abstract

Aims/hypothesis: While investigating markers for declining beta cell function in type 1 diabetes, we previously demonstrated 11 statistically significant protein associations with fasting C-peptide/glucose ratios in longitudinal serum samples from newly diagnosed (ND) individuals (n=86; 228 samples in total) participating in the INNODIA (Innovative approaches to understanding and arresting type 1 diabetes) study. Furthermore, comparison with protein measurements from age- and sex-matched autoantibody-negative unaffected family members (UFMs, n=194) revealed differences in the serum levels of 13 target proteins. To further evaluate these findings, we analysed longitudinal serum drawn during the first year after diagnosis from a new group of ND individuals subsequently enrolled in the study, together with samples from additional UFMs.

Methods: To validate the previously reported statistically significant protein associations with type 1 diabetes progression, selected reaction monitoring (SRM) MS analyses were carried out. Sera from individuals diagnosed with type 1 diabetes under the age of 18 years (n=146) were collected within 6 weeks of diagnosis and at 3, 6 and 12 months after diagnosis (560 samples in total). The resulting SRM data were compared with fasting C-peptide/glucose measurements, which were used as a proxy for beta cell function. The protein data were further compared with cross-sectional SRM measurements from age- and sex-matched UFMs (n=272).

Results: Our results confirmed the presence of significant (p<0.05) inverse associations between fasting C-peptide/glucose ratios and peptides from apolipoprotein B-100, apolipoprotein M and glutathione peroxidase 3 (GPX3) in ND individuals. Additionally, we observed consistent differences in the levels of ten of the 13 targeted proteins between individuals with type 1 diabetes and UFMs. These proteins included GPX3, transthyretin, prothrombin, apolipoprotein C1 and afamin.

Conclusions/interpretation: The validated results reflect the landscape of biological changes accompanying type 1 diabetes. For example, the association of the targeted apolipoproteins with fasting C-peptide/glucose ratios in the first year after diagnosis is likely to relate to lipid abnormalities observed in individuals with type 1 diabetes, and reiterates the connection of apolipoproteins with the underlying changes accompanying the disease. Further research is needed to explore the clinical value and relevance of these targets.

Keywords: C-peptide; Markers; Serum proteomics; Targeted proteomics; Type 1 diabetes.

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Conflict of interest statement

Acknowledgements: We are grateful to staff at the University of Cambridge Department of Paediatrics laboratory, particularly A. Qureshi, for their contributions to the management of the samples. M. Hakkarainen and S. Heinonen at Turku Bioscience are thanked for their excellent technical assistance. We thank the personnel of the Turku Proteomics Facility at Turku Bioscience, which is supported by the University of Turku, Åbo Akademi University and Biocenter Finland. Data availability: Access to these person-sensitive data is only through secure environment by application to the INNODIA Data Access Committee (see https://www.innodia.eu/ ). Funding: Open Access funding provided by University of Turku (including Turku University Central Hospital). This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (IMI2-JU) under grant agreement no. 115797 (INNODIA) and no. 945268 (INNODIA HARVEST). This IMI2-JU receives support from the European Union’s Horizon 2020 research and innovation programme, EFPIA, Breakthrough T1D (formerly known as JDRF) and The Leona M. and Harry B. Helmsley Charitable Trust. The views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the IMI2-JU, and the IMI2-JU cannot be held responsible for them. RL received funding from the Academy of Finland (grants 31444, 329277, 331793) and Business Finland and grants from the JDRF, Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, Finnish Diabetes Foundation and Finnish Cancer Foundation. LLE reports grants from the European Research Council ERC (677943), Academy of Finland (310561, 329278, 335434, 335611 and 341342) and Sigrid Jusélius Foundation during the conduct of the study. MK has also received grants supported by the Sigrid Jusélius Foundation, Helsinki University Hospital Research Funds and Liv and Hälsa Fund. Research at the Turku Bioscience Centre (LLE and RL) was supported by the University of Turku Graduate School (UTUGS), Biocenter Finland, ELIXIR Finland and the InFLAMES Flagship Programme of the Academy of Finland (decision no. 337530). TV is supported by the Doctoral Programme in Mathematics and Computer Sciences (MATTI) of the University of Turku. MKH was supported by the Turku Doctoral Programme of Molecular Medicine (TuDMM), Päivikki and Sakari Sohlberg Foundation and Yrjö Jahnsson Foundation. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: RM prepared the samples, conducted the analyses, prepared the tables and figures, evaluated and interpreted the data and co-wrote the manuscript. MKH automated and performed the sample preparation, evaluated and interpreted the data, prepared the figures and co-wrote the manuscript. TV analysed the data, prepared the figures and co-wrote the manuscript. TS supervised the analysis of the data. CM, LO, MP and SB initiated, designed and supervised the study. MK, LLE and RL designed and supervised the study. All authors edited, reviewed and approved the final version of the manuscript. RL is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis

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