Background: Insulin resistance, persistent hyperglycemia, and β-cell dysfunction are the hallmarks of Type 2 Diabetes Mellitus (T2DM), a metabolic disease. The molecular mediators that connect hyperglycemia to vascular damage, chronic inflammation, and metabolic dysregulation are still not fully known despite a great deal of research. According to recent research on human, Netrin-1 levels are changed in type 2 diabetes and are strongly linked to indicators of vascular problems, inflammation, insulin resistance, and endothelial dysfunction. While chronic and complex diseases have elevated levels of Netrin-1, which may be the result of compensatory or maladaptive overexpression, early-stage type 2 diabetes is frequently accompanied by lower circulating Netrin-1. According to these results, Netrin-1 has two functions: it is protective during early metabolic stress and dysregulated during chronic inflammatory injury. Conclusion: Netrin-1 may serve as both a biomarker and modulator of T2DM progression and its vascular complications. Understanding its mechanistic involvement could be a new diagnostic and therapeutic strategy aimed at mitigating inflammation and preserving endothelial integrity in diabetes.