Dietary eriodictyol ameliorates hyperglycemia and multi-organ damage in streptozotocin-induced diabetic mice: involvement of insulin signaling and antioxidant responses.

Diabetes mellitus affects hundreds of millions of people worldwide and remains a leading cause of multi-organ morbidity. Eriodictyol (Eri), a natural flavonoid enriched in edible plants and other citrus fruits, exhibits antioxidant, anti-inflammatory, and glucose-lowering properties in vitro. However, its systemic efficacy against diabetic hyperglycemia and tissue injury in vivo has not been systematically examined. Dietary supplementation with Eri (100 mg kg-1 day-1 for 6 weeks) attenuated body-weight loss, polydipsia, and organ hypertrophy in low-dose streptozotocin-induced diabetic mice. Treatment improved glucose tolerance and insulin sensitivity, lowered fasting glucose and homeostatic model assessment of insulin resistance (HOMA-IR), and ameliorated islet injury while restoring the insulin/glucagon balance. Eri upregulated glucose transporters (Glut2, Glut4) and suppressed insulin-signaling inhibitors (Ptpn1, Pten, Socs3). In the liver, it shifted metabolism from gluconeogenesis (G6pc, Pck1) toward glycolysis (Gck, Pklr) and glycogen synthesis. In skeletal muscle, Eri rescued locomotor impairment, reduced histopathology, increased glycogen content, and restored mitochondrial biogenesis genes (Sirt1, Tfam, Ppargc1a). Systemically, Eri lowered pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), hepatorenal markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CRE), and blood urea nitrogen (BUN), and lactic acid. Furthermore, Eri suppressed inflammatory genes (Tnf, Il1b, Nos2), activated antioxidant genes (Nfe2l2, Hmox1, Nqo1), and restored glutathione (GSH) content and antioxidant enzymes, including catalase (CAT) and superoxide dismutase (SOD), while reducing lipid peroxidation (MDA) in both the liver and muscle. Dietary Eri supplementation ameliorates hyperglycemia and multi-organ injury in diabetic mice through coordinated regulation of insulin signaling, glucose metabolism, mitochondrial biogenesis, and inflammatory/antioxidant responses. These results support its development as a natural, food-derived hypoglycemic nutraceutical for diabetes management. © 2026 Society of Chemical Industry.