title: Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo.
abstract: Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8))GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC(50): 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC(50): 0.37 nM). (Abu(8))GLP-1 and (Val(8))GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. b.green@ulster.ac.uk
authors.forename: B D
authors.initials: BD
authors.lastname: Green
authors.forename: V A
authors.initials: VA
authors.lastname: Gault
authors.forename: M H
authors.initials: MH
authors.lastname: Mooney
authors.forename: N
authors.initials: N
authors.lastname: Irwin
authors.forename: C J
authors.initials: CJ
authors.lastname: Bailey
authors.forename: P
authors.initials: P
authors.lastname: Harriott
authors.forename: B
authors.initials: B
authors.lastname: Greer
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
authors.forename: F P M
authors.initials: FP
authors.lastname: O'Harte
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004798:Enzymes / Q000097:blood; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D008820:Mice, Obese; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D004798:Enzymes; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C055453:glucagon-like peptide 1 (7-36)amide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4