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Exocrine proteins including Trypsin(ogen) as a key biomarker in type 1 diabetes

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Version 2 2023-02-01, 17:27
Version 1 2023-01-26, 16:44
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posted on 2023-02-01, 17:27 authored by Lilianna Bakinowska, Tanwi Vartak, Thato Phuthego, Michelle Taylor, Kyla Chandler, Samual T Jerram, Steven Williams, Marc Feldmann, Desmond G Johnson, Kashyap A Patel, Alistair JK Williams, Anna E Long, R David Leslie, Kathleen M Gillespie, The Action LADA Consortium, The BOX Study Group

  

Objective

Proteomic profiling can identify useful biomarkers. Monozygotic(MZ) twins, discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well characterised cohorts.

Research Design and Methods

A broad, multiplex analysis of 4068 proteins in sera from MZ twins concordant (n=43) and discordant for type 1 diabetes (n=27) identified major differences which were subsequently validated by a trypsin(ogen) assay in MZ pairs concordant (n=39) and discordant (n=42) for type 1 diabetes, individuals at-risk (n=195) and with type 1 diabetes (n=990), as well as with non-insulin requiring adult-onset diabetes diagnosed as either autoimmune (n=96) or type 2 (n=291).

Results

Proteomic analysis identified major differences between exocrine enzyme levels in discordant MZ twin pairs despite strong correlation between twins, whether concordant or discordant for type 1 diabetes (p<0.01 for both). In validation experiments, trypsin(ogen) levels were lower in twins with diabetes compared with non-diabetic co-twins (p<0.0001) and healthy controls (p<0.0001). In recently-diagnosed cases, trypsin(ogen) levels were lower than in controls across a broad age range. In at-risk relatives, levels <15 ng/ml were associated with increased risk of progression (uncorr. p=0.009). Multiple linear regression in recently-diagnosed cases showed that trypsin(ogen) levels were associated with insulin dose and diabetic ketoacidosis while age and BMI were confounders.

Conclusions

Type 1 diabetes is associated with altered exocrine function, even before onset. Twin data suggest roles for genetic and non-genetically determined factors. Exocrine/endocrine interactions are important under-investigated factors in type 1 diabetes.

Funding

This project has been supported by several grants from Diabetes UK; LB is funded by a PhD scholarship (19/0006108); the Bristol Laboratory is a core facility for the T1DUK Immunotherapy Consortium (15/0005232 and 15/0005233); the BOX study is funded by Diabetes UK (14/0004869). AEL is jointly funded as a Diabetes UK & JDRF RD Lawrence Fellow (18/0005778 and 3-APF-2018-591-A-N). The Twins and Adult-Onset Diabetes studies are supported by the British Diabetic Twin Trust, Barts Charity and EU(FP7). SomaLogic performed the SomaScan assays at its own cost. We are grateful for helpful conversations with Professor Emeritus Liz Trimble, Queen’s University Belfast about trypsin(ogen). We are indebted to all the study participants who contributed data and samples without whom this work would not have been possible.

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