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