Heparan sulfate and heparanase play key roles in mouse [Beta] 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.