Inhibition of heparanase protects against pancreatic beta cell death in streptozotocin‐induced diabetic mice via reducing intra‐islet inflammatory cell infiltration

Abstract

Background and Purpose Intra‐islet heparan sulfate (HS) plays an important role in the maintenance of 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 hypoglycaemic effect of a heparanase inhibitor, OGT2115, was tested in a streptozotocin‐induced diabetic mouse model. The islets in pancreatic sections were also stained to reveal their morphology. An insulinoma cell line (MIN6) 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 and improved the glucose profile and insulin secretion in streptozotocin‐treated mice. The apoptosis of pancreatic beta cells and 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 decreased expression of PPARγ in cultured islets, thereby relieving the PPARγ‐induced inhibition of heparanase gene expression. Conclusion and Implications Hyperglycaemia 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.

Integrative biology of extracellular vesicles in diabetes mellitus and diabetic complications

“…Notably, heparanase derived from insulitis leukocytes can degrade heparan sulfate of β cells and thus promote islet cell death in T1D. In mice, inhibition of heparanase can effectively delay the onset of T1D induced by STZ and NOD 155 - 158 . Also, the level of heparanase in the circulation and urine is positively correlated with glucose and HbA1c 159 - 161 and is also closely associated with albuminuria in DM, indicating its crucial role in diabetic renal injury 162 - 167 .…”

Identification of Heparan Sulfate in Dilated Cardiomyopathy by Integrated Bioinformatics Analysis

“…In addition, our previous work reported an anti-diabetic effect by targeting HS. OGT2115 protected islet β cells against streptozotocin-induced inflammation and apoptosis in mice by regulating intra-islet HS ( 23 ). Moreover, inhibition of HS was reported to protect against fibrosis in kidney ( 24 ), lung ( 25 ), and cornea ( 26 ).…”

Importance of Heparan Sulfate Proteoglycans in Pancreatic Islets and β-Cells

“…In the pancreatic β-cells of spontaneous T1DM model mice, HS protects against the promotion of the autoimmune response to β-cell-destructive insulitis [ 12 ]. Furthermore, OGT2115, an inhibitor of heparanase, avoided a decrease in pancreatic β-cell HS and impaired insulin secretion in a mouse model of T1DM induced by streptozotocin (STZ), which causes pancreatic β-cell damage [ 17 ]. Moreover, insulin secretion is also reportedly impaired in hereditary multiple exostoses patients with mutations in the EXT1 or EXT2 genes [ 13 ], and a reduction of pancreatic β-cell HS in T1DM patients decreased the protection against hydrogen peroxide-induced β-cell death [ 15 ].…”

“…Thus, STZ-induced damage to pancreatic β-cells appears to be more severe in SDC4-KO mice than in wild-type ICR mice. Hyperglycemia following pancreatic β-cell injury through STZ treatment suppresses the expression of the transcription factor PPARγ, resulting in the cancellation of the inhibition of heparanase expression by PPARγ and the promotion of HS degradation on pancreatic islets by heparanase [ 17 ]. STZ-treated SDC4-KO mice also showed an increased gene expression of heparanase compared to the control group, suggesting the existence of a molecular mechanism similar to that described above.…”

“…Further, multiple issues have yet to be addressed regarding the maintenance and improvement of GSIS function in isolated islets derived from organ donors. Several recent attempts to analyze the function of pancreatic β-cells from the viewpoint of glycobiology have been reported, and the connection between diverse roles of high-molecular-weight polysaccharides and the maintenance of islet homeostasis and insulin secretion has been analyzed [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]; this has increased the demand for glycobiology studies in the field of diabetes research.…”