Oral delivery of glucagon-like peptide-1 in a modified polymer preparation normalizes basal glycaemia in diabetic db/db mice.
OBJECTIVE
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 8h 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.


CONCLUSIONS
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.
Joseph
J W
JW
Department of Physiology, University of Toronto, Ontario, Canada.
Kalitsky
J
J
St-Pierre
S
S
Brubaker
P L
PL
D019325:3-O-Methylglucose / Q000008:administration & dosage; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004337:Drug Carriers; D005260:Female; D005934:Glucagon / Q000008:administration & dosage* / Q000097:blood; D052216:Glucagon-Like Peptide 1; D005951:Glucose Tolerance Test; D006801:Humans; D007700:Kinetics; D051379:Mice; D008863:Microspheres; D000069463:Olive Oil; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000097:blood; D010938:Plant Oils; D011108:Polymers; D011498:Protein Precursors / Q000008:administration & dosage* / Q000097:blood
D001786:Blood Glucose; D004337:Drug Carriers; D000069463:Olive Oil; D010446:Peptide Fragments; D010938:Plant Oils; D011108:Polymers; D011498:Protein Precursors; D019325:3-O-Methylglucose; D052216:Glucagon-Like Peptide 1; D005934:Glucagon