Abstract
Background and Purpose Intra-islet heparan sulfate (HS) plays
an important role in the maintenance of the pancreatic islet function.
The aim of this study was to investigate the effect mechanism of HS loss
on the functioning of islets in diabetic mice.
Experimental Approach The hypoglycemic effect of a heparanase
inhibitor, OGT2115, was tested in a streptozotocin-induced diabetic mice
model. The islets of pancreas sections were also stained to reveal their
morphology. An insulinoma MIN6 cell line and primary isolated murine
islets were used to investigate the effect of OGT2115 in vitro .
Key Results Intra-islet HS was clearly lost in
streptozotocin-induced diabetic mice due to the increased heparanase
expression in damaged islets. OGT2115 prevented intra-islet HS loss to
improve the glucose profile and insulin secretion in
streptozotocin-treated mice. The apoptosis of pancreatic beta cells, the
infiltration of mononuclear macrophages, CD4 and CD8 positive T-cells in
islets was reduced by OGT2115 in streptozotocin-treated mice, but
OGT2115 did not alter the direct streptozotocin-induced damage in vitro.
The expression of heparanase was increased in high glucose-treated
isolated islets but not in response to direct streptozotocin
stimulation. Further experiments showed that high glucose stimuli could
decrease the expression of peroxisome proliferator-activated receptor
gamma (PPARγ) in cultured islets, thereby relieving the PPARγ-induced
inhibition of heparanase gene expression.
Conclusion and Implications Hyperglycemia could cause
intra-islet HS loss by elevating the expression of heparanase, thereby
aggravating inflammatory cell infiltration and islet damage. Inhibition
of heparanase might provide benefit for pancreatic beta cell protection
in type 1 diabetes.
Keywords: heparan sulfate, islet beta cells, heparanase,
OGT2115, PPARγ, type 1 diabetes