Inhibition of heparanase protects against pancreatic β-cell death in
streptozotocin-induced diabetic mice via reducing inflammatory cell
infiltration
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
streptozotocin-induced diabetic mice. 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.