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Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes distinguishes markers of disease and C-peptide trajectory.

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Peer-reviewed

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Abstract

AIMS/HYPOTHESIS: There is a growing need for markers that could help indicate the decline in beta cell function and recognise the need and efficacy of intervention in type 1 diabetes. Measurements of suitably selected serum markers could potentially provide a non-invasive and easily applicable solution to this challenge. Accordingly, we evaluated a broad panel of proteins previously associated with type 1 diabetes in serum from newly diagnosed individuals during the first year from diagnosis. To uncover associations with beta cell function, comparisons were made between these targeted proteomics measurements and changes in fasting C-peptide levels. To further distinguish proteins linked with the disease status, comparisons were made with measurements of the protein targets in age- and sex-matched autoantibody-negative unaffected family members (UFMs). METHODS: Selected reaction monitoring (SRM) mass spectrometry analyses of serum, targeting 85 type 1 diabetes-associated proteins, were made. Sera from individuals diagnosed under 18 years (n=86) were drawn within 6 weeks of diagnosis and at 3, 6 and 12 months afterwards (288 samples in total). The SRM data were compared with fasting C-peptide/glucose data, which was interpreted as a measure of beta cell function. The protein data were further compared with cross-sectional SRM measurements from UFMs (n=194). RESULTS: Eleven proteins had statistically significant associations with fasting C-peptide/glucose. Of these, apolipoprotein L1 and glutathione peroxidase 3 (GPX3) displayed the strongest positive and inverse associations, respectively. Changes in GPX3 levels during the first year after diagnosis indicated future fasting C-peptide/glucose levels. In addition, differences in the levels of 13 proteins were observed between the individuals with type 1 diabetes and the matched UFMs. These included GPX3, transthyretin, prothrombin, apolipoprotein C1 and members of the IGF family. CONCLUSIONS/INTERPRETATION: The association of several targeted proteins with fasting C-peptide/glucose levels in the first year after diagnosis suggests their connection with the underlying changes accompanying alterations in beta cell function in type 1 diabetes. Moreover, the direction of change in GPX3 during the first year was indicative of subsequent fasting C-peptide/glucose levels, and supports further investigation of this and other serum protein measurements in future studies of beta cell function in type 1 diabetes.

Description

Funder: Sigrid Juséliuksen Säätiö; doi: http://dx.doi.org/10.13039/501100006306


Funder: Juvenile Diabetes Research Foundation United Kingdom; doi: http://dx.doi.org/10.13039/100008664


Funder: Jane ja Aatos Erkon Säätiö; doi: http://dx.doi.org/10.13039/501100004012


Funder: European Federation of Pharmaceutical Industries and Associations; doi: http://dx.doi.org/10.13039/100013322


Funder: Leona M. and Harry B. Helmsley Charitable Trust; doi: http://dx.doi.org/10.13039/100007028


Funder: Medicinska Understödsföreningen Liv och Hälsa; doi: http://dx.doi.org/10.13039/100010116


Funder: Diabetestutkimussäätiö; doi: http://dx.doi.org/10.13039/501100013500


Funder: Helsingin Yliopiston Tiedesäätiö; doi: http://dx.doi.org/10.13039/100007798


Funder: University of Turku (UTU) including Turku University Central Hospital

Keywords

C-peptide, Glutathione peroxidase 3, Serum proteomics, Type 1 diabetes, Humans, Adolescent, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, C-Peptide, Proteomics, Cross-Sectional Studies, Fasting, Glucose, Insulin, Blood Glucose

Journal Title

Diabetologia

Conference Name

Journal ISSN

0012-186X
1432-0428

Volume Title

66

Publisher

Springer Science and Business Media LLC
Sponsorship
Academy of Finland (677943)
Innovative Medicines Initiative 2 (No 115797 (INNODIA), No 945268 (INNODIA HARVEST)
European Research Council ERC (677943)
Academy of Finland (310561, 314443, 329278, 335434, 335611, 341342)