Cyanidin‐3‐O‐Glucoside Supplementation Ameliorates Metabolic Insulin Resistance via Restoration of Nitric Oxide‐Mediated Endothelial Insulin Transport

Scope Anthocyanin cyanidin‐3‐O‐glucoside (Cy3G) possesses a great potential in prevention of diabetes and its vascular complications while the underlying mechanisms are still far from clear. Accumulating evidence suggests that endothelial insulin transport plays a critical role in regulating metabolic insulin sensitivity. Whether Cy3G can modulate metabolic insulin resistance via regulating endothelial insulin transport is not reported yet. Methods and Results Palmitic acid (PA)‐treated mouse aortic endothelial cells (MAECs) model and high‐fat diet (HFD) fed mice model are used. Compared with HFD mice, Cy3G supplementation decrease exogenous insulin content in skeletal muscle and ameliorate metabolic insulin resistance. In culture, Cy3G can directly ameliorate PA‐induced impairment on FITC‐insulin uptake in MAECs. Mechanistically, Cy3G can effectively decrease inflammatory cytokines and toll‐like receptor 4 (TLR4)/nuclear factor‐kappa‐B inhibitor alpha (IκBα) activation, and restore the attenuated Akt/eNOS signaling pathway. Blunted nitric oxide (NO) synthase with N‐nitro‐l‐arginine methyl ester (L‐NAME) can effectively abolish the protective role of Cy3G on endothelial insulin transport and insulin‐stimulated glucose utilization in HFD‐fed mice. Conclusions These findings suggest that Cy3G supplementation can directly restore the attenuated nitic oxide‐mediated endothelial insulin transport and thereby ameliorate metabolic insulin resistance. Our finding can provide a novel explanation for the anti‐diabetic effects of Cy3G. Palmitic acid (PA) or high fat diet (HFD) activates TLR4/IκBα signaling in endothelium and blunts endothelial insulin transport via impairing Akt/eNOS signaling and that result in decrease of metabolic actions of insulin in target organ (indicated by the red solid arrow). Cyanidin‐3‐O‐glucoside (Cy3G) supplementation ameliorates metabolic insulin resistance via restoration of Akt/eNOS mediated endothelial insulin transport (indicated by the blue solid arrow).