Abstract
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-characterized cohorts.
RESEARCH DESIGN AND METHODS: A broad, multiplex analysis of 4,068 proteins in serum samples from MZ twins concordant (n = 43) and discordant (n = 27) for type 1 diabetes identified major differences that 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 for (n = 195) and with (n = 990) type 1 diabetes, as well as individuals with noninsulin-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 a 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 than in the cotwin without diabetes (P < 0.0001) and healthy control participants (P < 0.0001). In recently diagnosed participants, trypsin(ogen) levels were lower than in control participants across a broad age range. In at-risk relatives, levels <15 ng/mL were associated with an increased risk of progression (uncorrected P = 0.009). Multiple linear regression in recently diagnosed participants 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 nongenetically determined factors. Exocrine/endocrine interactions are important underinvestigated factors in type 1 diabetes.
| Original language | English |
|---|---|
| Article number | dc221317 |
| Pages (from-to) | 714–721 |
| Number of pages | 8 |
| Journal | Diabetes Care |
| Volume | 46 |
| Issue number | 4 |
| Early online date | 26 Jan 2023 |
| DOIs | |
| Publication status | E-pub ahead of print - 26 Jan 2023 |
Bibliographical note
Funding Information:Acknowledgments. The authors acknowledge helpful conversations with Prof. Emeritus Liz Trimble, Queen’s University Belfast, about trypsin(ogen). We are indebted to all the study participants who contributed data and samples, without which this work would not have been possible. A.J.K.W. is deceased. Funding. This project was supported by Diabetes UK PhD scholarship 19/0006108 (to L.B.) and grant 14/0004869 (BOX study). The Bristol Laboratory is a core facility for the T1DUK Immunotherapy Consortium (grants 15/0005232 and 15/0005233). A.E.L. is jointly funded as a Diabetes UK fellow (grant 18/ 0005778) and JDRF RD Lawrence Fellow (grant 3-APF-2018-591-A-N). R.D.L. has been recently funded by the European Foundation for the Study of Diabetes (MMBP1C3R), the European Union (QLGi-CT-2002-01886), and (EU-FP7: 282510), Bart’s
Funding Information:
This project was supported by Diabetes UK PhD scholarship 19/0006108 (to L.B.) and grant 14/0004869 (BOX study). The Bristol Laboratory is a core facility for the T1DUK Immunotherapy Consortium (grants 15/0005232 and 15/0005233). A.E.L. is jointly funded as a Diabetes UK fellow (grant 18/ 0005778) and JDRF RD Lawrence Fellow (grant 3-APF-2018-591-A-N). R.D.L. has been recently funded by the European Foundation for the Study of Diabetes (MMBP1C3R), the European Union (QLGi-CT-2002-01886), and (EU-FP7: 282510), Bart’s Charity (MGU0513), British Twin Trust, and Diabetes UK (MMBG1K9R/S).
Publisher Copyright:
© 2023 by the American Diabetes Association.
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