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.

乙酰肝素酶是切割硫酸乙酰肝素的主要酶，硫酸乙酰肝素是细胞外基质中的主要多糖。尽管乙酰肝素酶在维持自身免疫性糖尿病病理过程中的作用已得到充分证明，但其与代谢综合征/ 2型糖尿病的关系引起了较少的关注。我们的研究旨在阐明乙酰肝素酶在代谢综合征和早期2型糖尿病中葡萄糖代谢受损的重要性。在这里，我们报道乙酰肝素酶在胰岛素产生（即胰岛）与胰岛素靶标（即骨骼肌）区室中发挥相反的作用，根据作用部位维持或阻碍葡萄糖稳态的适当调节。我们观察到该酶在小鼠代谢综合征模型中促进巨噬细胞向胰岛的浸润，并促进由糖尿病/肥胖环境（即脂肪酸）的成分在体外激活的巨噬细胞的β细胞破坏特性。另一方面，在骨骼肌（胰岛素样靶组织）中，乙酰肝素酶对于确保胰岛素敏感性至关重要。因此，尽管乙酰肝素酶对胰岛的巨噬细胞浸润具有有害作用，但该酶似乎在代谢综合征的葡萄糖稳态中具有有益作用。在考虑将乙酰肝素酶靶向治疗糖尿病的策略时，应考虑到该酶在维持血糖控制中的二分作用。尽管乙酰肝素酶对胰岛的巨噬细胞浸润具有有害作用，但该酶似乎在代谢综合征中对葡萄糖稳态具有有益作用。在考虑将乙酰肝素酶靶向治疗糖尿病的策略时，应考虑到该酶在维持血糖控制中的二分作用。尽管乙酰肝素酶对胰岛的巨噬细胞浸润具有有害作用，但该酶似乎在代谢综合征中对葡萄糖稳态具有有益作用。在考虑将乙酰肝素酶靶向治疗糖尿病的策略时，应考虑到该酶在维持血糖控制中的二分作用。