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J Biol Chem, Vol. 275, Issue 6, 3827-3834, February 11, 2000

Dipeptidyl Peptidase IV (DPIV/CD26) Degradation of Glucagon
CHARACTERIZATION OF GLUCAGON DEGRADATION PRODUCTS AND DPIV-RESISTANT ANALOGS*

Simon Amadeus HinkeDagger §, J. Andrew PospisilikDagger , Hans-Ulrich Demuth, Susanne Mannhart, Kerstin Kühn-Wache, Torsten Hoffmann, Erica Nishimura||, Raymond A. PedersonDagger , and Christopher H. S. McIntoshDagger **

From the Dagger  Department of Physiology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada, the  Probiodrug Research, Biocenter, Weinberweg 22, D-06120 Halle (Saale), Germany, and the || Department of Diabetes Biochemistry and Metabolism, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark

Over the past decade, numerous studies have been targeted at defining structure-activity relationships of glucagon. Recently, we have found that glucagon1-29 is hydrolyzed by dipeptidyl peptidase IV (DPIV) to produce glucagon3-29 and glucagon5-29; in human serum, [pyroglutamyl (pGlu)3]glucagon3-29 is formed from glucagon3-29, and this prevents further hydrolysis of glucagon by DPIV (H.-U. Demuth, K. Glund, U. Heiser, J. Pospisilik, S. Hinke, T. Hoffmann, F. Rosche, D. Schlenzig, M. Wermann, C. McIntosh, and R. Pederson, manuscript in preparation). In the current study, the biological activity of these peptides was examined in vitro. The amino-terminally truncated peptides all behaved as partial agonists in cyclic AMP stimulation assays, with Chinese hamster ovary K1 cells overexpressing the human glucagon receptor (potency: glucagon1-29 > [pGlu3]glu- cagon3-29 > glucagon3-29 > glucagon5-29 > [Glu9]glu- cagon2-29). In competition binding experiments, [pGlu3]glucagon3-29 and glucagon5-29 both demonstrated 5-fold lower affinity for the receptor than glucagon1-29, whereas glucagon3-29 exhibited 18-fold lower affinity. Of the peptides tested, only glucagon5-29 showed antagonist activity, and this was weak compared with the classical glucagon antagonist, [Glu9]glucagon2-29. Hence, DPIV hydrolysis of glucagon yields low affinity agonists of the glucagon receptor. As a corollary to evidence indicating that DPIV degrades glucagon (Demuth, et al., manuscript in preparation), DPIV-resistant analogs were synthesized. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry was used to assess DPIV resistance, and it allowed kinetic analysis of degradation. Of several analogs generated, only [D-Ser2] and [Gly2]glucagon retained high affinity binding and biological potency, similar to native glucagon in vitro. [D-Ser2]Glucagon exhibited enhanced hyperglycemic activity in a bioassay, whereas [Gly2]glucagon was not completely resistant to DPIV degradation.

* This work was funded in part by Department of Science and Technology of Sachsen Anhalt Grant 9704/00116 (to H. D. and T. H.) by Medical Research Council of Canada Grant 590007 (to C. H. S. M. and R. A. P.) and by the Canadian Diabetes Association.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Funded by a Medical Research Council of Canada Doctoral Research Fellowship.

** To whom correspondence should be addressed: Dept. of Physiology, Faculty of Medicine, 2146 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada. Tel.: 604-822-3088; Fax: 604-822-6048; E-mail: mcintoch@interchange.ubc.ca.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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