Molsidomine ameliorates DEXA-induced insulin resistance: Involvement of HMGB1/JAK1/STAT3 signaling pathway

Abstract

Insulin resistance (IR) is a serious clinical syndrome that establishes the basis for illnesses like type 2 diabetes (T2D). In this study, the effectiveness of molsidomine (MOLS) which is a nitric oxide (NO) doner, on dexamethasone (DEXA)- induced IR in rats was examined. Male Wistar rats were managed with MOLS (5 and 10 mg/kg) orally once daily for 7 days before DEXA injection (1 mg/kg, intraperitoneally (i.p.)) and 7 days concurrent with DEXA injection. The findings showed that MOLS reduced low-density lipoprotein cholesterol (LDL-C), fasting serum glucose and insulin, homeostatic model assessment of insulin resistance (HOMA-IR), alanine transaminase (ALT), aspartate transaminase (AST), oral glucose tolerance test (OGTT), and triglycerides (TGs). These findings revealed that MOLS was successful in reducing DEXA-induced IR. Moreover, MOLS was associated with a large increase in reduced glutathione (GSH) and superoxide dismutase (SOD) activity as well as a significant decrease in the levels of malondialdehyde (MDA) in hepatic and aortic tissues. When compared to rats treated with DEXA, MOLS significantly decreased the levels of pro-inflammatory cytokine interlukin-6 (IL-6), high mobility group box 1 (HMGB1), phosphorylated Janus kinase1/phosphorylated signal transducer and activator of transcription 3 (p-JAK1/p-STAT3), and nuclear factor kappa-B-p65 subunit (NF-κB-p65) in hepatic tissues. Additionally, MOLS reduced inflammation and necrosis and increased B cell/lymphoma 2 (BCL-2) and lowered caspase-3 levels and attenuated liver histopathological changes. Moreover, aortic expression levels of NF-κB-p65 and IL-6 were reduced upon MOLS treatment. All these findings show that MOLS protects rats from DEXA-induced IR by inhibiting HMGB1/JAK1/STAT3 signaling, regulating oxidative stress and inflammatory pathways, and having an antioxidant and anti-inflammatory effect.