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.