Yangyang Wang, Yan He, Zhiming Xiu, Huiyan Wang
Disorders of glucose metabolism, particularly type 2 diabetes and obesity, remain major therapeutic challenges because they involve dysfunction across multiple tissues, including pancreatic β-cells, peripheral insulin-sensitive tissues, and immune cells. ADP-ribosylation factor 6 (ARF6) is a regulator of membrane trafficking and cytoskeletal dynamics and may represent a mechanistically relevant link across these compartments. In this review, we summarise evidence suggesting that ARF6 may contribute to sustained second-phase insulin secretion, glucose transporter type 4 trafficking and recycling, and metabolic inflammation through effects on receptor and membrane trafficking. We also discuss pharmacological and nucleic acid-based approaches targeting ARF6 or its regulatory network. Current evidence suggests that direct systemic inhibition may be difficult to translate because of off-target risks, including possible disruption of endothelial barrier integrity. In addition, because cellular uptake of some delivery systems depends on endocytic pathways associated with ARF6, broad inhibition may also interfere with drug entry. Given these limitations, tissue-targeted and microenvironment-responsive nanodelivery systems may provide a more feasible strategy for modulating the ARF6 axis with greater spatial and temporal control. Overall, this review presents ARF6 as a potentially important mechanistic and translational entry point within the broader network that regulates glucose homeostasis, rather than as a single master regulator.