In silico and in vivo study: chamazulene and/or cinnamic acid modulate IRS2/GLUT4, HNF4α, GLUT2, redox system, DNA damage, and lipid profile signifying their potential antidiabetic effect

Abstract Background Diabetes mellitus is a multifactorial metabolic disorder characterized by chronic hyperglycemia resulting from defects in insulin secretion and/or action. Oxidative stress, impaired insulin signaling, and dysregulated glucose transport are central to its pathogenesis. Given the limitations and side effects of current pharmacotherapies, attention has shifted toward natural compounds with multitargeted mechanisms of action. Purpose of the study This study aimed to explore the antidiabetic potential of Chamazulene (Cham) and Cinnamic Acid (CA), natural bioactive compounds, through in silico and in vivo approaches, targeting key molecular pathways including IRS2/GLUT4, HNF4α, and GLUT2, as well as assessing their effects on oxidative stress, DNA integrity, and lipid metabolism. Methods and results Male Wistar rats were assigned into eight groups: three control groups (C, C+Cham, C+CA) and five streptozotocin-induced diabetic groups (DM, DM + Cham, DM+CA, DM+Cham + CA, and DM+Gli. Our study highlighted the inhibitory α-amylase effect of both nutraceuticals. Biochemically, DM+Cham+CA surpassed the single treatments effects on lowering blood glucose, improving lipid profile, balancing redox system evidenced by improving GPx and GR activity. Moreover, using flow cytometry and Comet test, the used treatments extended their beneficial effects to inhibit reactive oxygen species and DNA damage, respectively. Using qRT-PCR, the treated groups upregulated skeletal muscle IRS2, GLUT4 gene expression, downregulated hepatic GLUT2 and HNF4α. Notably, natural compounds outperformed the standard drug in several parameters. Conclusion The findings support the therapeutic promise of Chamazulene and Cinnamic Acid as natural alternatives or adjuncts to conventional antidiabetic drugs. Further studies involving diverse models and clinical validation are warranted to confirm efficacy and safety in humans.