Pharmacokinetics, Pharmacodynamics, and Cytotoxicity of Recombinant Orally-administrated long-lasting GLP-1 and its Therapeutic Effect on db/db Mice

Recombinant orally long-acting glucagon-like peptide 1 (rolGLP-1), a novel analog of native GLP-1 that can stimulate insulin secretion, was constructed via site-directed mutagenesis by our laboratory. This study was designed to investigate the pharmacokinetics, pharmacodynamics, and the cytotoxicity of rolGLP-1. Diabetic db/db mice were given I-125-rolGLP-1 through a single dose of oral administration to evaluate the pharmacokinetics of rolGLP-1 by trichloroacetic acid-Radioactive assay (TCA-RA). Separately, rolGLP-1 was orally administered to the db/db mice daily for 28 days to evaluate its therapeutic effect. In addition, the safety of rolGLP-1 was assessed based on cytotoxicity testing on the cell line SH-SY5Y by both the MTT assay and the cell counts method. The results showed that the half-life of rolGLP-1 in db/db mice was 68.2 h, which is longer than that of native GLP-1. Results after the 28 day treatment showed glucose homeostasis was improved. Furthermore, rolGLP-1 was also proved to mitigate insulin resistance, alleviate hyperinsulinemia and decreased glycosylated hemoglobin content. Lastly, no visible adverse events were observed in cytotoxicity treatments on SH-SY5Y. Our results revealed that oral administration of rolGLP-1 harbored a longer half-life and a good therapeutic effect for type 2 db/db mice. All the results suggest the capacity and safety of rolGLP-1 for further use as an anti-diabetic agent for type 2 diabetes.