Introduction
Type 1 diabetes is characterized by direct and specific pancreatic beta cell destruction that causes an absolute deficiency of insulin secretion and hyperglycemia (Noble, 2015). The autoimmune inflammatory response of beta cells is widely considered to underlie the mechanism of beta cell dysfunction in type 1 diabetes. Following inflammatory injury of prophase beta cells, an accumulation of mononuclear cells (MNCs) and lymphocytes occurs around the pancreatic islets, and these MNCs produce cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), and interferon (IFN-γ), that trigger beta cell apoptosis (Mallone et al. , 2011). Once the beta cell destruction has occurred, specific T cells, like CD4+ T cells and CD8+ T cells, are activated and further damage beta cells (Ferris et al. , 2014) Overall, the immune inflammatory reaction is a key element in the process of the beta cell dysfunction in type 1 diabetes.
Heparan sulfate (HS) is a linear polysaccharide expressed broadly on cell surfaces and in the cell matrix. HS is attached to a core protein to form heparan sulfate proteoglycan (HSPG), and highly associated with various biological processes, such as angiogenesis, invasion, and metastasis of tumors (Iozzo, 1998). A role for HS in diabetes has been indicated in recent years. The lack of HS in the human glomerular basement membrane affects the permeability of endothelial cells in diabetic nephropathy (Edge et al. , 2000).And in gestational diabetes mellitus, the reduction of HS expression in the placenta affects early embryonic development (Ginath et al. , 2015). In type 1 diabetes, HS that localized in the peri-islet basement membrane may act as a physical barrier that protects beta cells from attack by immune inflammatory reactions (Irving-Rodgers et al. , 2008). Loss of intra-islet HS is directly related to the apoptosis of beta cells in non-obese diabetic (NOD) mice characterized by autoimmune beta cell damage (Ziolkowski et al. , 2012). Further studies confirmed that a decrease of HS in the islets aggravates the oxidative stress damage by free radicals (Simeonovic et al. , 2018). Thus, further exploration of the possible involvement of intra-islet HS in the maintenance of the function and survival of the islets, together with an in-depth understanding of the underlying mechanism, could improve knowledge regarding the development of islet dysfunction during type 1 diabetes.
The aim of the present study was to investigate the role of intra-islet HS in a type 1 diabetes mouse model. This model is established by multiple injections of low doses of streptozotocin (STZ) to C57BL/6 mice; these injections damage a few islet beta cells and induce further immune injury (Lin et al. , 2010). Intra-islet HS level and the expression of heparanase, the key enzyme that hydrolyzes HS (Whiteheadet al. , 2018), in the islets were investigated in STZ mice. The effect of a small molecule inhibitor of heparanase, OGT2115, on the glucose profile, insulin secretion, morphological alteration of the islets in the STZ mice was investigated. Further experiments studied the effect of OGT2115 in vitro and the regulation of heparanase expression in pancreatic beta cells.