Coumarin-loaded chitosan nanoparticles alleviate high-fructose diet-induced diabetes by modulating insulin and eNOS/NO signaling

Objective: To evaluate the therapeutic potential of coumarin-loaded chitosan nanoparticles (CNNPs) in managing high-fructose diet-induced diabetes and associated complications. Methods: CNNPs were synthesized using an ionic gelation method with chitosan coating and characterized. Rats with a high-fructose diet-induced diabetes were treated with coumarin and CNNPs (30, 70, and 100 mg/kg) for 6-12 weeks. Metabolic, inflammatory, oxidative stress, organ function, and cardiovascular parameters were assessed, and qRT-PCR studies were carried out for measuring the mRNA expression of glucose transporter-4 ( GLUT-4 ), sirtuin-1 ( S1RT1 ), pyrin domain containing-3 ( NLRP3 ), sterol regulatory element binding protein 1c ( SREBP-1c ), forkhead box O3 ( FOXO3 ), and endothelial nitric oxide synthase ( eNOS ) genes. Results: Nanoparticle characterization revealed a Z-average size of 510.8 nm with a +14 mV zeta potential. CNNP treatment was more effective than coumarin, normalizing glycemic markers (glycosylated hemoglobin, serum insulin, and fasting blood glucose), and lipid profiles (total cholesterol, low-density lipoprotein cholesterol, triglycerides, and high-density lipoprotein cholesterol). Significant improvements were also seen in adipokines (adiponectin, chemerin, and leptin), inflammatory cytokines (interleukin-6 and tumor necrosis factor-a), and oxidative stress markers (catalase, superoxide dismutase and malonaldehyde). In addition, both treatments significantly upregulated the gene expression of S1RT1, GLUT-4 , and eNOS , and downregulated FOXO3, SREBP-1c , and NLRP3 . Histopathological studies confirmed that CNNPs ameliorated diabetes-induced structural abnormalities in major organs. Conclusions: CNNPs demonstrate improved bioavailability and therapeutic efficacy, offering a promising strategy for managing high-fructose diet-induced metabolic dysfunction and its complications.