ISSN:
1432-0428
Keywords:
Keywords OGTT, peptide delivery system, GLP-1, analog, PLGA-COOH, oral microspheres.
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Aims/hypothesis. The insulinotropic hormone, glucagon-like peptide-1 has been proposed for the treatment of patients with Type II (non-insulin-dependent) diabetes mellitus. As glucagon-like peptide-1 is rapidly cleaved at l-ala2 by dipeptidylpeptidase IV, d-ala2-glucagon-like peptide-1 was synthesized and shown to have dipeptidylpeptidase IV resistance in vitro and enhanced bioactivity in mice during an oral glucose challenge. The actions of d-ala2-glucagon-like peptide-1 were, however, lost within 4 h of injection, thus necessitating frequent and invasive treatment if it is to be used therapeutically. To circumvent this problem, a microsphere of d-ala2-glucagon-like peptide-1 that could be given orally was developed.¶Methods. We encapsulated d-ala2-glucagon-like peptide-1 in poly(lactide-co-glycolide)-COOH with olive oil as a filler, using phase inversion. The microspheres were tested in vivo by oral gavage in mice at t = 0 h followed by repeated oral glucose tolerance tests at t = 0, 4 and 8 h.¶Results. The d-ala2-glucagon-like peptide-1-microspheres lowered the glycaemic response to the 4 h oral glucose challenge in both normal CD1 and diabetic db/db mice, by 41 ± 12 % (p 〈 0.001) and 27 ± 5 % (p 〈 0.001), respectively and by 19 ± 11 % (p 〈 0.05) and 28 ± 4 % (p 〈 0.001), respectively during the 8-h test. At 4 h after the oral gavage, basal glycaemia in the diabetic mice was reduced from 13 ± 1 mmol/l to 10 ± 1 mmol/l and was reduced further 8 h after treatment from 12 ± 1 mmol/l to 8 ± 1 mmol/l (p 〈 0.05). Giving d-ala2-glucagon-like peptide-1 alone orally had no effect on glycaemia.¶Conclusion/interpretation. The data presented here suggest that a similar microsphere preparation could be useful in the delivery of glucagon-like peptide-1 to patients with Type II diabetes. [Diabetologia (2000) 43: 1319–1328]
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s001250051529
Permalink