Oral delivery of glucagon-like peptide-1 in a modified polymer preparation normalizes basal glycaemia in diabetic db/db mice

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-ala(2) by dipeptidylpeptidase IV, D-ala(2)-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-ala(2)-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-ala(2)-glucagon-like peptide-1 that could be given orally was developed. Methods. We encapsulated D-ala(2)-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 = 0h followed by repeated oral glucose tolerance tests at t = 0, 4 and 8 h. Results. The D-ala(2)-glucagon-like peptide-1-microspheres lowered the glycaemic response to the 4h 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 t 1 mmol/l and was reduced further 8h after treatment from 12+/-1 mmol/l to 8 +/- 1 mmol/l (p < 0.05). Giving D-ala(2)-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.