Hepatic modulation of apelin and galectin-3 by darbepoetin-alpha in Dexamethasone induced insulin-resistant rats

Insulin resistance (IR) is a central pathological mechanism underlying metabolic syndrome and associated disorders, including type 2 diabetes and non-alcoholic fatty liver disease. This study investigated the therapeutic effects of darbepoetin alfa (DA), an erythropoietin analogue, in a dexamethasone (Dexa)-induced IR model, focusing on its impact on metabolic regulation (apelin) and inflammatory pathways (galectin-3) in liver tissue. Thirty-two male Wistar rats were divided into four groups (n = 8/group): (saline 1 ml/kg/day intraperitoneal [ip] for 5 days), IR (Dexa 1 mg/kg/day ip for 5 days), DA (single 5 µg/kg ip dose on day 6), and IR + DA (Dexa followed by DA). Body weight, fasting glucose, insulin levels, and HOMA-IR were assessed. Liver function was evaluated via AST/ALT levels, while histopathological changes (hydropic degeneration, necrosis, fibrosis via Masson’s trichrome) and immunohistochemical expression of apelin and galectin-3 were analyzed. There were no significant differences in body weights between groups; only the IR group experienced weight loss. Fasting glucose and HOMA-IR levels were significantly higher in the IR group (p < 0.001, p = 0.008), while insulin levels showed no significant change. Darbepoetin treatment reduced glucose and HOMA-IR. Histologically, the IR group displayed marked hepatocyte degeneration, lipid accumulation, necrosis, and disorganized hepatic cords. Masson’s Trichrome staining showed increased collagen deposition around vessels in the IR group, which was reduced after darbepoetin. Immunohistochemically, apelin expression was significantly decreased and galectin-3 increased in the IR group compared to SHAM (p < 0.001). These changes were reversed in the IR + DA group. The SHAM and DA groups exhibited normal liver architecture without pathological alterations. DA attenuated Dexa-induced IR by improving glycemic control, reducing hepatic injury, and modulating key metabolic (apelin↑) and inflammatory (galectin-3↓) markers. The restoration of liver histopathology and reduction in fibrosis suggest DA’s potential as a multifunctional agent against IR-associated complications. Further studies are needed to validate these findings in chronic models and clinical settings.