Heparanase-Inhibiting Glycans Protect Pancreatic β-Cells from Oxidative and Inflammatory Injuries and Preserve Insulin Production in Human Islets

Abstract Inflammatory destruction of pancreatic β-cells is a central driver of diabetes progression and is closely associated with heparanase (HPSE)-mediated degradation of heparan sulfate (HS), oxidative stress, and amplification of inflammatory signaling. However, whether selective HPSE inhibition can simultaneously modulate the inflammatory microenvironment and preserve intrinsic β-cell function remains poorly understood. Here, we investigated the protective effects and underlying mechanisms of two sulfated aminoglycoside-derived HPSE inhibitors, L15 and L17, in inflammatory β-cell injury models and human islets. Notably, we demonstrate that the heparanase-inhibiting glycans suppress pro-inflammatory M1 macrophage polarization within the pancreatic inflammatory microenvironment, thereby reducing cytokine production and disrupting inflammatory feedback signaling. In MIN6 pancreatic β-cells, L15 and L17 reduce mitochondrial reactive oxygen species (ROS), preserve cytoskeletal organization, and inhibit apoptosis induced by HPSE and inflammatory cytokines. Mechanistic studies further reveal that oxidative stress precedes cytoskeletal disruption, supporting the role of ROS accumulation as an upstream driver of β-cell injury. Importantly, in ex vivo human pancreatic islets, both compounds preserve intra-islet HS, reduce oxidative stress, and maintain glucose-stimulated insulin secretion under inflammatory conditions, with L17 consistently exhibiting greater protective efficacy. Unlike most current therapeutic strategies for type 1 diabetes that primarily focus on systemic immune modulation or suppression of autoimmune responses, sulfated aminoglycoside-derived HPSE inhibitors simultaneously attenuate inflammatory amplification and intrinsic β-cell vulnerability. Collectively, these findings identify HPSE as a central regulator linking inflammatory signaling, oxidative stress, and β-cell dysfunction. They also suggest that selectively inhibiting HPSE is a mechanistically distinct strategy for reprogramming the inflammatory-β-cell axis and preserving functional insulin-secreting human islets during diabetes progression.