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

Green, B.D., Gault, V.A., Mooney, M.H., Irwin, N., Bailey, C.J., Harriott, P., Greer, B., Flatt, P.R. and O'Harte, F.P.M. (2003). 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. Journal of Molecular Endocrinology, 31 (3), pp. 529-540.

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 Ala8-substituted analogues of GLP-1, (Abu8)GLP-1 and (Val8)GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu8)GLP-1 and (Val8)GLP-1 exhibited moderate affinities (IC50: 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC50: 0.37 nM). (Abu8)GLP-1 and (Val8)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 (Val8)GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu8 )GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val8)GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala8 in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val8)GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.

Publication DOI: https://doi.org/10.1677/jme.0.0310529
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Uncontrolled Keywords: Endocrinology
Full Text Link: http://jme.endo ... ontent/31/3/529
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2003-12
Authors: Green, B.D.
Gault, V.A.
Mooney, M.H.
Irwin, N.
Bailey, C.J. ( 0000-0002-6998-6811)
Harriott, P.
Greer, B.
Flatt, P.R.
O'Harte, F.P.M.

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