^aMolecular Physiology Division, Zoology Department, Faculty of Science, Beni- Suef University, Egypt

^bCell Biology, Histology and Genetics Division, Zoology Department, Faculty of Science, Beni-Suef University, Egypt

^cMaterials Science and Nanotechnology Department, Faculty of Postgraduate

Studies for Advanced Sciences (PSAS), Beni-Suef University, Egypt

Nanotechnology can offer various non-invasive and efficient alternative delivery strategies for insulin injections to enhance the quality of life of diabetic patients. The current research was aimed to fabricate a de novo oral formula of insulin-loaded chitosan nanoparticles coated with dextrin and pectin (INS-CN/DP) to improve the bioavailability and therapeutic efficiency of oral insulin. INS-CN/DP nano-formula was prepared using ionic gelation technique and characterized by XRD, FTIR, SEM, EDX, and DLS. Insulin loading capacity and entrapment efficiency (LC%, EE%), release profile, and kinetic study was conducted for INS-CN/DP nano-formula. Next, hypoglycemic and antidiabetic efficiency of INS-CN/DP nano-formula were studied in streptozotocin-induced diabetic rats by measuring fasting and postprandial glucose, the activities of carbohydrate metabolizing enzymes, liver glycogen content, and gene expression levels of glucokinase and Glucose transporter-2. Characterization results confirmed the formation of INS- CN/DP nanoparticles with LC% =26.2 ± 0.56 and EE% 69.3 ± 2.75, respectively. Size average was 282.8 nm and nearly 25% of loaded insulin released after 4 hrs vs 48% for unloaded insulin. In vivo results displayed that oral administration of INS-CN/DP nanoparticles showed highly significant hypoglycemic and antidiabetic efficacy in diabetic rats compared to unloaded oral insulin. Oral INS-CN/DP nano-formula is promising alternative for insulin injections and can be suggested as non-invasive and effective diabetes therapy.