Background: The increased accumulation of advanced glycation end products (AGEs) under diabetes conditions can promote oxidative stress and inflammation in vasculature and contribute to endothelial dysfunction. Naringin, a flavonoid compound that occurs naturally in citrus fruits, has been shown to have anti-diabetic and anti-oxidant properties.
Objective: To investigate the efficacy of naringin in the improvement of diabetes-induced leukocyte adhesion to cerebral endothelium through AGEs-RAGE-NF-κB pathway.
Materials and Methods: Six-week-old Sprague-Dawley were divided into three groups; normal group (CON: n=8), type 2 diabetes group (DM2: n=8), and type 2 diabetes group with naringin supplementation (DM2-NG: n=8). Rats were fed with high-fat diet for four weeks, followed by a single STZ injection to induce type 2 diabetes. Naringin was supplemented daily by oral gavage feeding (50 mg/kg BW). Twelve weeks after STZ injection with or without naringin supplementation, fasting blood glucose (FBG), serum insulin and calculated homeostatic model assessment of insulin resistance (HOMA-IR) were examined. Leukocyte adhesion at postcapillary venule was carried out by using intravital fluorescence microscopy. AGEs, RAGE and TNF-α were detected by ELISA whereas NF-κB, ICAM-1 were investigated using Western blot analysis and MDA was determined by TBARs assay.
Results: After 12 weeks of naringin feeding into DM2-NG rats, the FBG levels decreased 62.8% compared to those without
supplementation. Moreover, the β-cell function was improved by reducing serum insulin levels and HOMA-IR. Not only the endothelial function was improved by reducing the number of leukocyte adhesion, but the expression of ICAM-1 was also decreased. Naringin supplementation also attenuated inflammation and oxidative stress by reducing the levels of AGEs, RAGE, and its downstream molecules, NF-κB-TNF-α.
Conclusion: It is suggested that supplementation with naringin in type 2 diabetes rat model can reduce leukocyte adhesion to vascular endothelium via anti-hyperglycemic, anti-oxidant and anti-inflammatory effects through AGEs-RAGE-NF-κB-TNF-α-ICAM-1 signaling pathway.

Keywords: Type 2 diabetic rats; Naringin; Leukocyte adhesion; Endothelial dysfunction