2. Academic Validation
  3. PPARγ activation reduces pancreatic beta cell death in type 1 diabetes by decreasing heparanase-dependent insulitis

PPARγ activation reduces pancreatic beta cell death in type 1 diabetes by decreasing heparanase-dependent insulitis

  • Int Immunopharmacol. 2025 Sep 23:162:115183. doi: 10.1016/j.intimp.2025.115183.
Qinyao Zhou 1,  Meiwei Li 2,  Jia Zhang 2,  Xiaohang Zhou 2,  Qi Zhu 3,  Hailing Ni 2,  Yourong Hu 2,  Lei Wang 3,  Yuting Ge 2,  Kunxin Xie 2,  Guanting Li 2,  Yizheng Zhang 3,  Xiaowei Zhu 4,  Xinyuan Cao 5,  Xiao Han 6,  Peng Sun 7
Affiliations

Affiliations

  • 1 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China; Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China; National Demonstration Center for Experimental Basic Medical Education, Nanjing Medical University, Nanjing, China.
  • 2 Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
  • 3 National Demonstration Center for Experimental Basic Medical Education, Nanjing Medical University, Nanjing, China.
  • 4 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
  • 5 National Demonstration Center for Experimental Basic Medical Education, Nanjing Medical University, Nanjing, China. Electronic address: xinyuancao@njmu.edu.cn.
  • 6 Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China; Department of Endocrinology, the Third Affiliated Hospital with Nanjing Medical University, Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China. Electronic address: hanxiao@njmu.edu.cn.
  • 7 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China; Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. Electronic address: sunpeng@njmu.edu.cn.
PMID: 40628043 DOI: 10.1016/j.intimp.2025.115183
Abstract

While the majority of individuals with type 1 diabetes (T1D) receives lifelong exogenous Insulin replacement therapy, a clinically significant subset remains refractory to achieving optimal glycemic targets, necessitating the exploration of novel adjunctive medications to enhance T1D treatment strategies. The aim of this study was to explore the efficacy of rosiglitazone (ROZ), a typical thiazolidinedione as selective agonists of the Peroxisome Proliferator-activated Receptor gamma (PPARγ), in the therapeutic management of T1D. The pharmacological effects of ROZ in different T1D mouse models induced by either multiple-low-dose (MLD) or single-high-dose (SHD) streptozotocin (STZ). Further morphological, bioinformatic, and in vitro experiments using cultured bone marrow-derived monocytes, were performed to explore the possible underlying mechanisms. In vivo findings revealed that ROZ primarily showed therapeutic effects in the MLD-STZ model, which is characterized by inflammatory damage to pancreatic beta cells, rather than SHD-STZ model. Mechanistically, PPARγ activation, mediated by ROZ, downregulates the macrophage expression of heparanase, a specific endoglycosidase of the glycosaminoglycan heparan sulfate. This downregulation inhibits the degradation of intra-islet extracellular heparan sulfate, thereby enhancing the integrity of the physical barrier within the islets. Consequently, PPARγ activation reduces the infiltration of inflammatory immune cells into the islets, thereby suppressing the damage to pancreatic beta cells associated with T1D. Our data emphasize the importance of sustained inflammation in the upregulation of heparanase in macrophages, while also underscoring the pivotal role played by the PPARγ-heparanase axis. This study provides novel evidence for the potential targeting of PPARγ-heparanase as an adjunctive treatment strategy for T1D.

Keywords

Heparanase; Macrophages; PPARγ; Pancreatic beta cells; Type 1 diabetes.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16578
    99.79%, PPARγ Antagonist