Heparanase is the predominant
enzyme that cleaves
heparan sulfate, the main
polysaccharide in the extracellular matrix. While the role of
heparanase in sustaining the pathology of
autoimmune diabetes is well documented, its association with
metabolic syndrome/
type 2 diabetes attracted less attention. Our research was undertaken to elucidate the significance of
heparanase in impaired
glucose metabolism in
metabolic syndrome and early
type 2 diabetes. Here, we report that
heparanase exerts opposite effects in
insulin-producing (i.e., islets) vs.
insulin-target (i.e., skeletal muscle) compartments, sustaining or hampering proper regulation of
glucose homeostasis depending on the site of action. We observed that the
enzyme promotes macrophage infiltration into islets in a murine model of
metabolic syndrome, and fosters β-cell-damaging properties of macrophages activated in vitro by components of diabetogenic/obese milieu (i.e.,
fatty acids). On the other hand, in skeletal muscle (prototypic
insulin-target tissue),
heparanase is essential to ensure
insulin sensitivity. Thus, despite a deleterious effect of
heparanase on macrophage infiltration in islets, the
enzyme appears to have beneficial role in
glucose homeostasis in
metabolic syndrome. The dichotomic action of the
enzyme in the maintenance of
glycemic control should be taken into account when considering
heparanase-targeting strategies for the treatment of diabetes.