A conceptual framework linking platelet activation, adaptive FGF21-GDF15 signaling, and islet vascular dysfunction in progressive β-cell failure of type 2 diabetes.

Platelet activation, endothelial dysfunction, and stress-responsive endocrine signaling have emerged as important components of the complex biological processes underlying type 2 diabetes mellitus (T2DM), extending beyond the classical concepts of glucotoxicity and lipotoxicity. This review proposes a hypothesis-generating conceptual framework in which platelet activation, fibroblast growth factor 21 (FGF21), and growth differentiation factor 15 (GDF15) represent partly independent yet biologically interconnected stress-response pathways that may converge within the pancreatic islet microenvironment during disease progression. Activated platelets contribute to vascular inflammation and endothelial dysfunction through soluble mediators and extracellular vesicles, whereas FGF21 and GDF15 are induced by oxidative stress, mitochondrial dysfunction, and activation of integrated cellular stress responses as adaptive endocrine signals that promote mitochondrial homeostasis, endothelial integrity, and cellular resilience. Under persistent metabolic stress, sustained vascular injury, impaired adaptive signaling, and progressive endothelial dysfunction may collectively reduce the capacity of these protective mechanisms to preserve β-cell function. Rather than representing a proven transition point, the pancreatic islet microenvironment is proposed as a biologically plausible convergence site where vascular injury, adaptive endocrine responses, and intrinsic β-cell stress may interact. Although direct mechanistic evidence linking these pathways remains limited, this conceptual framework integrates current experimental and clinical evidence, identifies important mechanistic knowledge gaps, and provides a foundation for future mechanistic studies, integrated biomarker development, disease stratification, and precision medicine strategies in T2DM.