Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

The autoimmune type 1 diabetes (T1D) that arises spontaneously in NOD mice is considered to be a model of T1D in humans. It is characterized by the invasion of pancreatic islets by mononuclear cells (MNCs), which ultimately leads to destruction of insulin-producing beta cells. Although T cell dependent, the molecular mechanisms triggering beta cell death have not been fully elucidated. Here, we report that a glycosaminoglycan, heparan sulfate (HS), is expressed at extraordinarily high levels within mouse islets and is essential for beta cell survival. In vitro, beta cells rapidly lost their HS and died. beta Cell death was prevented by HS replacement, a treatment that also rendered the beta cells resistant to damage from ROS. In vivo, autoimmune destruction of islets in NOD mice was associated with production of catalytically active heparanase, an HS-degrading enzyme, by islet-infiltrating MNCs and loss of islet HS. Furthermore, in vivo treatment with the heparanase inhibitor PI-88 preserved intraislet HS and protected NOD mice from T1D. Our results identified HS as a critical molecular requirement for islet beta cell survival and HS degradation as a mechanism for beta cell destruction. Our findings suggest that preservation of islet HS could be a therapeutic strategy for preventing T1D.