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

 

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Abstract

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).

• References

• 1 Orskov C. Glucagon-like peptide-1, a new hormone of the entero-insular axis. Diabetologia 1992; 35: 701-711
  PubMedGoogle Scholar
• 2 Kiefer TJ, Habener JF. The glucagon-like peptides. Endocr Rev 1999; 20: 876-913
  CrossrefPubMedGoogle Scholar
• 3 Kreymann B, Williams G, Ghatei MA et al. Glucagon-like-peptide 1 7-36: a physiological incretin in man. Lancet 1987; 2: 1300-1304
  PubMedGoogle Scholar
• 4 Deacon CF. Incretin-based treatment of type 2 diabetes: glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2007; 9: 23-31
  PubMedGoogle Scholar
• 5 Inzucchi SE, McGuire DK. New drugs for the treatment of diabetes. Part II: incretin-based therapy and beyond. Circulation 2008; 117: 574-584
  CrossrefPubMedGoogle Scholar
• 6 Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696-1705
  CrossrefPubMedGoogle Scholar
• 7 Buteau J, EI-Assaad W, Rhodes CJ et al. Glucagon-like peptide-1 prevents beta cell Glucolipotoxicity. Diabetologia 2004; 47: 806-815
  CrossrefPubMedGoogle Scholar
• 8 Edvell A, Lindström P. Initiation of increased pancreatic islet growth in young normoglycaemic mice (Umeå +/?). Endocrinology 1999; 140: 778-783
  CrossrefPubMedGoogle Scholar
• 9 Deacon CF, Nauck MA, Toft-Nielsen M et al. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995; 44: 1126-1131
  CrossrefPubMedGoogle Scholar
• 10 Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagons like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 1995; 80: 952-957
  CrossrefPubMedGoogle Scholar
• 11 Juhl CB, Hollingdal M, Sturis J et al. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes 2002; 51: 424-429
  CrossrefPubMedGoogle Scholar
• 12 Davies SL, Martin L, Castaner RM. CJC-1131. Drugs Fut 2005; 30: 553
  CrossrefPubMedGoogle Scholar
• 13 Kolterman OG, Buse JB, Fineman MS et al. Synthetic exendin-4 (Exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 3082-3089
  CrossrefPubMedGoogle Scholar
• 14 Hou J, Yan R, Ding D et al. Oral administration of a fusion protein containing eight GLP-1 analogues produced in Escherichia coli BL21(DE3) in streptozotocin-induced diabetic rats. Biotechnol Lett 2007; 29: 1439-1446
  CrossrefPubMedGoogle Scholar
• 15 Tang ZM, Liu XW, Xu LP et al. Pharmacokinetics and tissue distribution of human recombinant interleukin-2 in mice. Acta Pharmacologica Sinica 1994; 15: 51-56
  PubMedGoogle Scholar
• 16 Liu YP, Li QS, Huang YR et al. Pharmacokinetics of C-1027 in mice as determined by TCA-RA method. World J Gastroenterol 2005; 11: 717-720
  CrossrefPubMedGoogle Scholar
• 17 Huang YR, Li QS, Liu CX. Pharmacokinetics of recombinant hirudin in rats in vivo. Chinese Traditional and Herbal Drugs 2005; 36: 1352-1356
  PubMedGoogle Scholar
• 18 Gutniak MK, Linde B, Holst JJ et al. Subcutaneous injection of the incretin hormone glucagon-like peptide 1 abolishes postprandial glycemia in NIDDM. Diabetes Care 1994; 17: 1039-1044
  CrossrefPubMedGoogle Scholar
• 19 Shah RB, Ahsan F, Khan MA. Oral delivery of proteins: Progress and prognostication. Crit Rev Ther Drug Carrier Syst 2002; 19: 135-169
  CrossrefPubMedGoogle Scholar
• 20 Fox JA, Hotaling TE, Struble C et al. Tissue distribution and complex formation with IgE of an anti-IgE antibody after intravenous administration in cynomolgus monkeys. J Pharmacol Exp Ther 1996; 279: 1000-1008
  PubMedGoogle Scholar
• 21 Takagi A, Masuda H, Takakura Y et al. Disposition characteristics of recombinant human interleukin-11 after a bolus intravenous administration in mice. J Pharmacol Exp Ther 1995; 275: 537-543
  PubMedGoogle Scholar
• 22 Hu Z, Niu H, Yang X et al. Recombinant human parathyroid hormone 1-34: pharmacokinetics, tissue distribution and excretion in rats. Int J Pharm 2006; 317: 144-154
  CrossrefPubMedGoogle Scholar
• 23 Park CW, Kim HW, Ko SH et al. Long-Term Treatment of Glucagon-Like Peptide-1 Analog Exendin-4 Ameliorates Diabetic Nephropathy through Improving Metabolic Anomalies in db/db Mice. J Am Soc Nephrol 2007; 18: 1227-1238
  CrossrefPubMedGoogle Scholar
• 24 Qin Z, Sun Z, Huang J et al. Mutated recombinant human glucagon-like peptide-1 protects SH-SY5Y cells from apoptosis induced by amyloid-beta peptide (1-42). Neurosci Lett 2008; 444: 217-221
  CrossrefPubMedGoogle Scholar
• 25 Dong CF, Liu XP, Wang MX et al. Effect of advanced glycation end products on oxidative stress and apoptosis of SH-SY5Y cells. Journal of Shandong university (Health science) 2012; 50: 9-14
  PubMedGoogle Scholar

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