Heparanase Levels Are Elevated in the Urine and Plasma of Type 2 Diabetes Patients and Associate with Blood Glucose Levels

Abstract

Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains of heparan sulfate proteoglycans. Utilizing an ELISA method capable of detection and quantification of heparanase, we examined heparanase levels in the plasma and urine of a cohort of 29 patients diagnosed with type 2 diabetes mellitus (T2DM), 14 T2DM patients who underwent kidney transplantation, and 47 healthy volunteers. We provide evidence that heparanase levels in the urine of T2DM patients are markedly elevated compared to healthy controls (1162±181 vs. 156±29.6 pg/ml for T2DM and healthy controls, respectively), increase that is statistically highly significant (P<0.0001). Notably, heparanase levels were appreciably decreased in the urine of T2DM patients who underwent kidney transplantation, albeit remained still higher than healthy individuals (P<0.0001). Increased heparanase levels were also found in the plasma of T2DM patients. Importantly, urine heparanase was associated with elevated blood glucose levels, implying that glucose mediates heparanase upregulation and secretion into the urine and blood. Utilizing an in vitro system, we show that insulin stimulates heparanase secretion by kidney 293 cells, and even higher secretion is observed when insulin is added to cells maintained under high glucose conditions. These results provide evidence for a significant involvement of heparanase in diabetic complications.

High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature

“…25 We have also reported that HG can stimulate the secretion of both latent and active forms of heparanase from EC. 26 As EC behave differently based on their vessel type and environment, 27 in this study, we compared the effects of HG on releasing Hep …”

Heparanase Enhances the Insulin Receptor Signaling Pathway to Activate Extracellular Signal-regulated Kinase in Multiple Myeloma

“…Interestingly, insulin is known to stimulate heparanase secretion from cells (44), raising the possibility that insulin plays a dual role in activating ERK signaling via insulin receptor regulation and by enhancing secretion of heparanase, which further drives insulin receptor signaling and ERK activation. These findings underscore the potential of heparanase inhibitors and insulin receptor pathway inhibitors as anti-cancer drugs and the possibility that they could be used to reverse the aggressive phenotype of some myeloma tumors.…”

Heparanase enzyme in chronic inflammatory bowel disease and colon cancer

“…Presently, it becomes increasingly clear that immunocytes are not the sole source of the enzyme in inflammation. Up-regulation of heparanase, locally expressed (i.e., by epithelial cells, vascular endothelium) at the site of inflammation, was demonstrated in the mouse models of delayed type hypersensitivity [57], chronic colitis [29], psoriasis (our unpublished results), as well as in several auto-immune and auto-inflammatory human disorders, including rheumatoid arthritis [88], type 2 diabetes [89], ulcerative colitis, and Crohn's disease [29,30].…”