Abstract
Background: Type 2 diabetes mellitus represents a global health challenge, with chronic hyperglycemia leading to a spectrum of microvascular and macrovascular complications. This narrative review provides a comprehensive and integrated analysis of the nerve growth factor (NGF) axis as a key, yet underrecognized, pathogenic mechanism. Methods: This narrative review was conducted in accordance with scholarly standards for non-systematic syntheses (SANRA). We included both clinical and preclinical studies focusing on NGF/proNGF biology and interventions across major diabetes complications. Discussion: Growing evidence highlights NGF as a pivotal mediator at the crossroads of neuronal, vascular and metabolic pathways. In diabetes, a disrupted balance between mature NGF and its precursor proNGF, favors the detrimental p75NTR pathway, leading to increased cellular stress, inflammation and apoptosis. In this narrative review, we examine how a decline in mature NGF and a relative excess of proNGF contribute to the pathophysiology of diabetic complications across various organ systems. We highlight the dual role of the NGF axis: while NGF-TrkA signaling consistently confers neuroprotective and vasculoprotective benefits, unchecked proNGF-p75NTR activity amplifies tissue damage. Conclusions: Collectively, the evidence identifies NGF as a candidate biomarker for both early tissue distress and therapeutic monitoring. We conclude by outlining key priorities for future research, including the development of standardized assays and the initiation of well-designed clinical trials to translate these promising strategies for early detection and treatment of diabetes-related complications.