Early intensive insulin therapy alleviates aortic oxidative stress and inflammatory responses through the AGEs/RAGE pathway in diabetes mellitus

PAN Xinyan; ZHU Yajun; ZHANG Zhimei

doi:10.3969/j.issn.1002-7386.2025.06.007

Abstract：Objective To investigate the effects and underlying mechanisms of early intensive insulin therapy on aortic glycation reactions,oxidative stress,and inflammatory responses in rats with diabetes mellitus.Methods A type 2 diabetes mellitus(T2DM)rat model was created.A total of 40 rats were divided into four groups:normal control group(NC group),T2DM group(DC group),T2DM with early intensive insulin therapy(DI group),and T2DM with gliclazide(DG group),with 10 rats in each group.After a 4-week intervention,fasting blood glucose(FBG),fasting serum insulin(FINS),C-peptide(C-P),blood lipids,superoxide dismutase(SOD),advanced glycation end products(AGEs),malondialdehyde(MDA),and glutathione peroxidase(GSH-PX)levels were measured.The insulin sensitivity index(ISI)was calculated.Aortic structure was examined via electron microscopy,and immunohistochemical analysis was performed to assess the expression of AGEs,the receptor for advanced glycation end products(RAGE),and NF-κBp65 in the aorta.Additionally,Western-blotting was used to evaluate the protein expressions of RAGE and NF-κBp65 in the aorta.Results Rats in the DC group presented the highest FBG,and lowest FINS and C-P than other groups,which were comparable among the remaining three groups(P＞0.05).Blood lipids were lower in the DI and DG groups than DC group,although there were no significant differences(P＞0.05).Serum AGEs,MDA,RAGE level in the aorta,and protein level of NF-κB p65 were significantly higher in the DC,DI,and DG group than the NC group.After treatment,they were significantly lower in the DI and DG groups than DC group,which were significantly lower in the DI group than DG group(P＜0.05).SOD and GSH-PX levels were significantly higher in the DI and DG group than the DC group,which were significantly higher in the DI group than the DG group(P＜0.05).Serum AGEs were positively correlated with FBG and MDA,but negatively correlated with FIN,SOD and GSH-PX.Immunohistochemical analysis revealed significantly lower expression of RAGE,AGEs,and NF-κBp65 in the aorta of the DI group compared to the DG group.Electron microscopy further demonstrated alleviated endothelial pathological damage in the DI group compared to the DG group.Conclusion Early intensive insulin therapy effectively mitigates oxidative stress and inflammatory responses in the aorta of diabetic rats by downregulating the activation of the AGEs/RAGE signaling axis.