N-terminally modified glucagon-like peptide-1(7-36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo.
Glucagon-like peptide-1(7-36)amide (tGLP-1) is inactivated by dipeptidyl peptidase (DPP) IV by removal of the NH(2)-terminal dipeptide His(7)-Ala(8). We examined the degradation of NH(2)-terminally modified His(7)99% of His(7)-glucitol tGLP-1 remained intact at 12 h. His(7)-glucitol tGLP-1 was similarly resistant to plasma degradation in vitro. His(7)-glucitol tGLP-1 showed greater resistance to degradation in vivo (92% intact) compared to tGLP-1 (27% intact) 10 min after i.p. administration to Wistar rats. Glucose homeostasis was examined following i.p. injection of both peptides (12 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly reduced and insulin concentrations elevated following peptides administration compared with glucose alone. The area under the curve (AUC) for glucose for controls (AUC 691+/-35 mM/min) was significantly lower after administration of tGLP-1 and His(7)-glucitol tGLP-1 (36 and 49% less; AUC 440+/-40 and 353+/-31 mM/min, respectively; P<0.01). This was associated with a significantly higher AUC for insulin (98-99% greater; AUC 834+/-46 and 838+/-39 ng/ml/min, respectively; P<0.01) after tGLP-1 and His(7)-glucitol tGLP-1 administration compared to controls (421+/-30 ng/ml/min). In conclusion, His(7)-glucitol tGLP-1 resists plasma DPP IV degradation while retaining potent antihyperglycaemic and insulin-releasing activities in vivo.
O'Harte
F P
FP
School of Biomedical Sciences, University of Ulster, Coleraine, UK. fpm.oharte@ulst.ac.uk
Mooney
M H
MH
Lawlor
A
A
Flatt
P R
PR
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D006706:Homeostasis; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013012:Sorbitol / Q000378:metabolism
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; C055453:glucagon-like peptide 1 (7-36)amide; D013012:Sorbitol; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C051322:glucagon-like peptide 1 (7-37)