Diabetes mellitus (DM) prevalence is rising worldwide. Current therapies comprising subcutaneous insulin injections can cause adverse effects such as lipodystrophy, local reactions like redness and swelling, fluid retention, and allergic reactions. Nanoparticle carriers for oral insulin are groundbreaking compared to existing methods because they are non-invasive treatments, showing operational convenience, controlled release profile, and ability to simulate the physiological delivery route into the bloodstream. These systems improve patient adherence and have demonstrated the potential to lower blood glucose levels in DM. We present a systematic review and meta-analysis aimed at compiling relevant data to pave the way for developing innovative nano- and microparticles for the oral delivery of insulin. Our analysis of 85 articles revealed that the diminution of glucose levels is not proportional to the administered insulin dosage, which ranged from 1 to 120 International Units (IU). The meta-analysis data indicated that 25 IU of encapsulated porcine insulin did not produce a statistically significant outcome (p = 0.93). In contrast, a dosage of 30 IU was efficacious in eliciting an optimal hypoglycemic effect compared to excipient controls. Parameters such as a high degree of encapsulation (~ 90%), particle size (200–400 nm), and polydispersity index (0.086–0.3) are all associated with lower blood glucose levels. These parameters were also significant in the linear regression analysis. Among the excipients employed, chitosan emerged as a prevalent excipient in formulations due to its biocompatible and biodegradable properties and its ability to establish stable polymeric matrices. Even though oral insulin administration is a promising therapeutic method, it cannot guarantee preclinical safety and therapeutic efficacy yet in regulating glucose levels in diabetic conditions.
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