caa a22 4500 475772202 CHVBK 20180406123620.0 cr unu---uuuuu 170329e20001001xx s 000 0 eng 10.1007/s001250051529 doi (NATIONALLICENCE)springer-10.1007/s001250051529 Oral delivery of glucagon-like peptide-1 in a modified polymer preparation normalizes basal glycaemia in diabetic db/db mice [Elektronische Daten] [J. W. Joseph, J. Kalitsky, S. St-Pierre, P. L. Brubaker] 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] Springer-Verlag Berlin Heidelberg, 2000 Keywords OGTT, peptide delivery system, GLP-1, analog, PLGA-COOH, oral microspheres nationallicence Joseph J. W. Department of Physiology, University of Toronto, Toronto, Ontario, Canada, CA aut Kalitsky J. Department of Physiology, University of Toronto, Toronto, Ontario, Canada, CA aut St-Pierre S. Department of Chemistry, University of Quebec in Montreal, Montreal, Quebec, Canada, CA aut Brubaker P. L. Department of Physiology, University of Toronto, Toronto, Ontario, Canada, CA aut https://doi.org/10.1007/s001250051529 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s001250051529 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Joseph J. W. Department of Physiology, University of Toronto, Toronto, Ontario, Canada, CA aut NATIONALLICENCE 700 1- Kalitsky J. Department of Physiology, University of Toronto, Toronto, Ontario, Canada, CA aut NATIONALLICENCE 700 1- St-Pierre S. Department of Chemistry, University of Quebec in Montreal, Montreal, Quebec, Canada, CA aut NATIONALLICENCE 700 1- Brubaker P. L. Department of Physiology, University of Toronto, Toronto, Ontario, Canada, CA aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer