Revisiting the Platelet-β-Cell Axis: Insights into How Platelet-Derived Mediators, Lipid Signaling, and DOC2B Pathways Converge to Drive β-Cell Dysfunction in Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is a multifactorial disorder where platelet-derived mediators, lipid metabolic pathways, and exocytotic proteins intersect to drive β-cell dysfunction. Activated platelets release serotonin, platelet factor 4 (PF4), sphingosine-1-phosphate (S1P), and microvesicles that trigger oxidative and endoplasmic reticulum (ER) stress in pancreatic islets. CD36-mediated lipid uptake and sphingolipid imbalance intensify ceramide-driven mitochondrial damage. These insults converge on exocytotic failure through disruption of DOC2B, a Ca2+-sensitive mediator of insulin vesicle fusion. Revisiting this axis clarifies how thromboinflammation and lipotoxicity orchestrate β-cell failure and highlights emerging therapeutic targets for T2DM. This review introduces a novel integrative perspective linking platelet-derived mediators, lipid dysregulation, and DOC2B-mediated exocytotic failure as a unified model of β-cell dysfunction in T2DM.