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 125I-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.This study was supported by Project 863 of China (2008AA02Z205).
Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, Tianjin, P. R. China.
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Ma
Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, Tianjin, P. R. China.
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Hu
Food Science & Human Nutrition Department, University of Florida, Gainesville, FL, USA.
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Zhao
Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, Tianjin, P. R. China.
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Zhang
Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, Tianjin, P. R. China.
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Li
Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, Tianjin, P. R. China.
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Ma
Food Science & Human Nutrition Department, University of Florida, Gainesville, FL, USA.
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Abbas
Tianjin Institute of Pharmaceutical Sciences, Tianjin, P. R. China.
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Chen
Tianjin Institute of Pharmaceutical Sciences, Tianjin, P. R. China.
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Qu
Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, Tianjin, P. R. China.
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Li
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D014018:Tissue Distribution
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011994:Recombinant Proteins; D052216:Glucagon-Like Peptide 1