Lys9 for Glu9 substitution in glucagon-like peptide-1(7-36)amide confers dipeptidylpeptidase IV resistance with cellular and metabolic actions similar to those of established antagonists glucagon-like peptide-1(9-36)amide and exendin (9-39).
The incretin hormone glucagon-like peptide-1(7-36)amide (GLP-1) has been deemed of considerable importance in the regulation of blood glucose. Its effects, mediated through the regulation of insulin, glucagon, and somatostatin, are glucose-dependent and contribute to the tight control of glucose levels. Much enthusiasm has been assigned to a possible role of GLP-1 in the treatment of type 2 diabetes. GLP-1's action unfortunately is limited through enzymatic inactivation caused by dipeptidylpeptidase IV (DPP IV). It is now well established that modifying GLP-1 at the N-terminal amino acids, His(7) and Ala(8), can greatly improve resistance to this enzyme. Little research has assessed what effect Glu(9)-substitution has on GLP-1 activity and its degradation by DPP IV. Here, we report that the replacement of Glu(9) of GLP-1 with Lys dramatically increased resistance to DPP IV. This analogue, (Lys(9))GLP-1, exhibited a preserved GLP-1 receptor affinity, but the usual stimulatory effects of GLP-1 were completely eliminated, a trait duplicated by the other established GLP-1-antagonists, exendin (9-39) and GLP-1(9-36)amide. We investigated the in vivo antagonistic actions of (Lys(9))GLP-1 in comparison with GLP-1(9-36)amide and exendin (9-39) and revealed that this novel analogue may serve as a functional antagonist of the GLP-1 receptor.
Green
B D
BD
School of Biomedical Sciences, University of Ulster, Coleraine, Northern, Ireland.
Mooney
M H
MH
Gault
V A
VA
Irwin
N
N
Bailey
C J
CJ
Harriott
P
P
Greer
B
B
Flatt
P R
PR
O'Harte
F P M
FP
D000262:Adenylyl Cyclases / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005934:Glucagon; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides; D018698:Glutamic Acid / Q000737:chemistry*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008239:Lysine / Q000737:chemistry*; D051379:Mice; D008820:Mice, Obese / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; C114437:glucagon-like peptide-1 (9-36)-amide; C061970:glucagon-like peptide 1 (7-36); D018698:Glutamic Acid; C083773:exendin (9-39); D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D000262:Adenylyl Cyclases; D008239:Lysine