The goal of this study was to see how effective subcutaneous (SC) insulin is and two different types of oral insulin‐loaded nanoparticles (INS) including carboxymethyl chitosan nanoparticles (CMCNPs) and gold nanoparticles (AuNPs) separately and compare their effects on glucokinase, pyruvate kinase gene expressions, and other parameters in diabetes type one male Wistar rats. Seven groups of ten male Wistar rats for each group were formed at random including four control groups (n = 10) and three treatment groups (n = 10). The control groups consisted of four control groups (10 rats for each) and three treatment groups (10 rats for each). Normal control rats were not given any treatment, as were diabetic rats that were not given any treatment, and diabetic rats that were given oral nanoparticles (CMCNPs and AuNPs). Diabetic rats were given subcutaneous insulin, oral insulin‐loaded carboxymethyl chitosan nanoparticles (INS‐CMCNPs), and oral insulin‐loaded gold nanoparticles (INS‐AuNPs). The rats were treated for the final 3 weeks of the experiment, which lasted 4 weeks. CMCNPs and AuNPs presented a promising effect on pyruvate kinase and Glucokinase gene expressions compared to subcutaneous insulin. We also discovered that conjugating insulin to CMCNPs and AuNPs protects them from the insulin‐degrading enzyme, which offers managed bioavailability. Furthermore, we investigated the effects of CMCNPs and AuNPs on several parameters and discovered that both have a significant effect in vivo, which enables glucose level regulation, and improves patient organ activity for better glucose consumption. Practical applications In this paper, we discussed the effect of oral INS‐CMCNPs and INS‐AuNPs, and compared their effects on Glucokinase and pyruvate kinase gene expressions and other biochemical parameters in diabetes type one male Wistar rats. On the other hand, we investigated the impact of oral INS and subcutaneous insulin separately on the same parameters and their effect on the histology of the liver and pancreas of diabetic rats. According to our research, as we discussed the different mechanisms of INS‐CMCNPs and INS‐AuNPs, they presented a promising effect compared to SC insulin. They can be used to keep oral insulin safe from the environment of the gastrointestinal system to overcome all the barriers, improve the therapeutic, and clinical outcomes of insulin by maintaining its desired concentration inside the body, ending the panic of the patient from receiving insulin by the SC injection by increasing his satisfaction with receiving accurate oral insulin doses.