Inflammatory signaling pathways in pancreatic β-cell: New insights into type 2 diabetes pathogenesis

Type 2 diabetes (T2D) is a complex metabolic disorder with a growing global prevalence, and there is a linking between inflammation in pancreatic β-cell and impaired glucose homeostasis which has emerged as a key player in the pathogenesis of T2D. Recent advances in research have provided new insights into various inflammatory signaling cascades in β-cell among which we focus on Toll-like Receptor 4 (TLR4), Nuclear Factor kappa B (NF-κB), Janus Kinase-Signal Transducer and Activator of Transcription (JAK/STAT), Platelet-Derived Growth Factor Receptor α (PDGFR-α), Stimulator of Interferon Genes (STING), and the death receptor TMEM219. TLR4 activation by pathogen- or damage-associated molecular patterns initiates NF-κB and mitogen-activated protein kinase (MAPK) cascades, promoting pro-inflammatory cytokine release and β-cell apoptosis. NF-κB acts as a central hub, integrating metabolic stress signals (e.g., glucolipotoxicity, ER stress) and amplifying inflammatory responses through crosstalk with JAK/STAT and STING pathways. Meanwhile, JAK/STAT signaling exhibits dual roles in β-cell survival and inflammation, influenced by cytokine milieu and feedback regulation. PDGFR-α, traditionally linked to β-cell proliferation, paradoxically contributes to pathological hyperplasia in obesity, while STING activation by cytosolic DNA triggers β-cell senescence and ferroptosis via IRF3/NF-κB. In this review, we synthesize recent advancements of these inflammatory signaling pathways in β-cells, and current therapeutic strategies targeting TLR4/NF-κB inhibitors, JAK/STAT modulators, STING antagonists, and the death receptor TMEM219 are discussed, alongside challenges in pathway specificity and clinical translation. Understanding these inflammatory signaling pathways and their interactions in pancreatic β-cell is essential for the development of novel therapeutic strategies to prevent or treat T2D.