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Inhibition of heparanase protects against pancreatic β-cell death in streptozotocin-induced diabetic mice via reducing inflammatory cell infiltration
  • +9
  • Wen-Yu Song,
  • Xiao-Han Jiang,
  • Kai Li,
  • Yan Wang,
  • Yun Xia,
  • Ming-Xuan Zhou,
  • Chen-Yu Zhang,
  • Chong-Chong Yin,
  • Chen Qiu,
  • Ying Ding,
  • Peng Sun,
  • Xiao Han
Wen-Yu Song
Nanjing Medical University
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Xiao-Han Jiang
Nanjing Medical University
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Kai Li
Nanjing Medical University
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Yan Wang
Nanjing Medical University
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Yun Xia
Nanjing Medical University
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Ming-Xuan Zhou
Nanjing Medical University
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Chen-Yu Zhang
Nanjing Medical University
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Chong-Chong Yin
Nanjing Medical University
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Chen Qiu
Nanjing Medical University
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Ying Ding
Nanjing Medical University
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Peng Sun
Nanjing Medical University
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Xiao Han
Nanjing Medical University
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Peer review status:ACCEPTED

20 Feb 2020Submitted to British Journal of Pharmacology
20 Feb 2020Submission Checks Completed
20 Feb 2020Assigned to Editor
25 Feb 2020Reviewer(s) Assigned
21 Mar 2020Editorial Decision: Revise Minor
02 Jun 20201st Revision Received
03 Jun 2020Assigned to Editor
03 Jun 2020Submission Checks Completed
04 Jun 2020Reviewer(s) Assigned
16 Jun 2020Editorial Decision: Revise Minor
18 Jun 20202nd Revision Received
22 Jun 2020Submission Checks Completed
22 Jun 2020Assigned to Editor
22 Jun 2020Review(s) Completed, Editorial Evaluation Pending
22 Jun 2020Editorial Decision: Accept

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.