Quantitative Differences in the Urinary Proteome of Siblings Discordant for Type 1 Diabetes Include Lysosomal Enzymes

Individuals with type 1 diabetes
(T1D) often have higher than normal
blood glucose levels, causing advanced glycation end product formation
and inflammation and increasing the risk of vascular complications
years or decades later. To examine the urinary proteome in juveniles
with T1D for signatures indicative of inflammatory consequences of
hyperglycemia, we profiled the proteome of 40 T1D patients with an
average of 6.3 years after disease onset and normal or elevated HbA1C levels, in comparison with a cohort of 41 healthy siblings.
Using shotgun proteomics, 1036 proteins were identified, on average,
per experiment, and 50 proteins showed significant abundance differences
using a Wilcoxon signed-rank test (FDR q-value ≤
0.05). Thirteen lysosomal proteins were increased in abundance in
the T1D versus control cohort. Fifteen proteins with functional roles
in vascular permeability and adhesion were quantitatively changed,
including CD166 antigen and angiotensin-converting enzyme 2. α-N-Acetyl-galactosaminidase and α-fucosidase 2, two
differentially abundant lysosomal enzymes, were detected in western
blots with often elevated quantities in the T1D versus control cohort.
Increased release of proteins derived from lysosomes and vascular
epithelium into urine may result from hyperglycemia-associated inflammation
in the kidney vasculature.