Levels of Urinary Trypsin Inhibitor and Structure of Its Chondroitin Sulphate Moiety in Type 1 and Type 2 Diabetes

Abstract

Background Diabetes mellitus is a global health problem representing the fifth leading cause of mortality and a major risk factor for cardiovascular diseases. In the last years, we reported an association among urinary trypsin inhibitor (UTI), a small proteoglycan that plays pleiotropic roles in many inflammatory processes, and both type 1 and 2 diabetes and developed a method for its direct quantitation and structural characterization. Methods Urine from 39 patients affected by type 1 diabetes, 32 patients with type 2 diabetes, and 52 controls were analysed. UTI was separated from the main glycosaminoglycans physiologically present in urine by anion exchange chromatography, treated for chondroitin sulphate (CS) chain complete depolymerisation, and analysed for both UTI content and CS structure. UTI identification was performed by nano-LC-MS/MS analysis. Results We evidenced increased UTI levels, as well as reduced sulphation of its CS moiety in association with diabetes, regardless of both age and medium-term glycaemic control. Furthermore, no association between UTI and albumin excretion rate was found. Conclusions Evidences suggest that UTI levels are not directly correlated with renal function or, otherwise, that they may increase before the onset of renal impairment in diabetes, representing a potential marker for the underlying inflammatory condition.

The Inter-α-Trypsin Inhibitor Family: Versatile Molecules in Biology and Pathology

“…113,153 IαI itself is modified during inflammation where the CS chain that is biosynthesized is longer and less sulfated. 63,157,158 This is hypothesized to facilitate the transfer of HCs from IαI to HA. 63 Lesser explored, however, are the roles of the IαI family in cell signaling, extracellular matrix interactions, and protease inhibition in the context of pathology.…”

Major endothelial damage markers identified from hemadsorption filters derived from treated patients with septic shock – endoplasmic reticulum stress and bikunin may play a role

“…According to Kaczmarczyk et al., bikunin is quickly removed from circulation (approximately 7 minutes) not to interfere with tissue reconstitution, which is why excretion via urine as urinary trypsine inhibitor (UTI) or ulinastatin is highly relevant and plasma concentrations do not exceed 5 µg/mL ( 22 ). Inflammatory conditions described significant modifications of the bikunin side chains regarding both sulfation and chain length composition of the CS moiety ( 34 ). Accordingly, free bikunin has been termed a novel acute phase protein ( 24 ).…”

Molecular and pathobiological insights of bikunin/UTI in cancer

“…Because of its proteinase inhibitory activity, bikunin is quickly removed from circulation (approximately 7 min) to prevent a shutdown of repair and healing processes, by both tissue uptake and renal excretion and it is found in urine as UTI or ulinastatin [14]. In human physiological conditions, UTI levels are lower than 5 μg/mL, but they may rise up to tenfold as a consequence of both acute and chronic inflammations including bacterial or viral infections, liver diseases, cancer, type I and II diabetes mellitus, and renal diseases [45][46][47][48][49][50][51][52][53]. Similarly, modifications of both sulfation degree and chain length of CS moiety have been reported following inflammatory conditions [54].…”