Mangiferin mitigates dexamethasone-induced insulin resistance in rats: insight on vascular dysfunction and hepatic steatosis

Abdullah Q Alsaedi^1,2Manar Nader^1,2Dalia H. El-Kashef^1,2Marwa Abdelmageed^1,2*

• ¹Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
• ²Faculty of Pharmacy, Mansoura University, Mansoura, Egypt

Aim: Insulin resistance (IR), the ultimate potential hazard to human health, in which peripheral insulin-target organs, like liver, are less sensitive to normal levels of insulin. Dexamethasone (DEX)-induced IR is a distinct model that represents IR. Hence, the present study investigates the efficacy of Mangiferin (Mang) in the reversal of DEX-induced IR in liver and aorta of rats.Main methods: Rats were randomly assigned into six groups; control (CTRL), Mang, DEX and three pretreated groups (received Mang; 25, 50 or 100 mg/kg, orally for 14 days, DEX (1mg/kg) was injected from day8 to day14), on day 15, serum, liver and aorta tissues were obtained and examined using biochemical, histological and immunohistochemical assessments. Key findings: Mang administration attenuated DEX-induced IR evidenced by decreased oral glucose tolerance test (OGTT) and fasting serum insulin level beside improving the DEXinduced hepatic and aortic histopathological alterations. Additionally, Mang attenuated DEXinduced alterations in liver function parameters and improved serum lipid profile, oxidative stress and antioxidant biomarkers. Mang also markedly increased hepatic and aortic levels of insulin receptor substrate1 (IRS1) and protein kinase B (AKT), AMP-activated protein kinase (AMPK) and Peroxisome proliferator-activated receptor-gamma (PPAR-γ) levels and lowered hepatic and aortic tumor necrosis factor alpha (TNF-α), forkhead box protein O1 (FOXO-1) and hepatic NOD-like Receptor Family Pyrin Domain Containing3 (NLRP3), phosphoenol pyruvate carboxy kinase (PEPCK) and glucose 6-phosphatase (G6Pase) and elevated hepatic glycogen synthase kinase3 (GSK3α) and glycogen synthase (GS2) levels. Furthermore, Mang ameliorated aortic expression levels of endothelin-1 (ET-1), vascular cell adhesion molecule-1 (VCAM), c-Jun N-terminal kinase (JNK), and nuclear factor kappa B (NF-κB) and vascular endothelial growth factor (VEGF) and increased endothelial nitric oxide synthase (eNOS) and prostacyclin (PGI2) levels.Conclusions: Mang administration could confer hepato-and vasculo-protective activity via its hypolipidemic, hepatoprotective, anti-inflammatory and antioxidant efficacy.