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

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.