Journal list menu

Volume 214, Issue 3 p. 829-835
Free Access

Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum


Corresponding Author


Anatomisches Institut, Germany

Correspondence to R. Mentlein, Universität Kiel, Anatomisches Institut, Olshausenstrasse 40-60, D-24118 Kiel, Germany
Fax:+49 431 8801557.Search for more papers by this author


Abteilung Allgemeine Innere Medizin der Universität Kiel, Germany

Search for more papers by this author
Wolfgang E. SCHMIDT

Wolfgang E. SCHMIDT

Abteilung Allgemeine Innere Medizin der Universität Kiel, Germany

Search for more papers by this author
First published: June 1993
Citations: 899


Peptides of the glucagon/vasoactive-intestinal-peptide (VIP) peptide family share a considerable sequence similarity at their N-terminus. They either start with Tyr-Ala, His-Ala or His-Ser which might be in part potential targets for dipeptidyl-peptidase IV, a highly specialized aminopeptidase removing dipeptides only from peptides with N-terminal penultimate proline or alanine. Growthhormone-releasing factor(1–29)amide and gastric inhibitory peptide/glucose-dependent insulinotropic peptide (GIP) with terminal Tyr-Ala as well as glucagon-like peptide-1(7–36)amide/insulinotropin [GLP-1(7–36)amide] and peptide histidine methionine (PHM) with terminal His-Ala were hydrolysed to their des-Xaa-Ala derivatives by dipeptidyl-peptidase IV purified from human placenta. VIP with terminal His-Ser was not significantly degraded by the peptidase. The kinetics of the hydrolysis of GIP, GLP-1(7–36)amide and PHM were analyzed in detail. For these peptides Km values of 4–34 μM and Vmax values of 0.6–3.8 μmol · min−1· mg protein−1 were determined for the purified peptidase which should allow their enzymic degradation also at physiological, nanomolar concentrations. When human serum was incubated with GIP or GLP-1(7–36)amide the same fragments as with the purified dipeptidyl-peptidase IV, namely the des-Xaa-Ala peptides and Tyr-Ala in the case of GIP or His-Ala in the case of GLP-1(7–36)amide, were identified as the main degradation products of these peptide hormones. Incorporation of inhibitors specific for dipeptidylpeptidase IV, 1 mM Lys-pyrrolidide or 0.1 mM diprotin A (Ile-Pro-Ilc), completely abolished the production of these fragments by serum. It is concluded that dipeptidyl-peptidase IV initiates the metabolism of GIP and GLP-1(7–36)amide in human serum. Since an intact N-terminus is obligate for the biological activity of the members of the glucagon/VIP peptide family [e. g. GIP(3–42) is known to be inactive to release insulin in the presence of glucose as does intact GIP], dipeptidyl-peptidase-IV action inactivates these peptide hormones. The relevance of this finding for their inactivation and their determination by immunoassays is discussed.


  • DPP IV
  • dipeptidyl-peptidase IV
  • GIP
  • gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide
  • GLP-1(7–36)amide
  • glucagon-like peptide-1(7–36)amide or insulinotropin or preproglucagon(78–107)amide
  • GLP-2
  • glucagon like peptide-2 or preproglucagon(126–159)
  • GRF
  • growth-hormone-releasing factor/hormone
  • PHI
  • peptide histidine isoleucine
  • PHM
  • peptide histidine methionine
  • VIP
  • vasoactive intestinal peptide
  • pituitary adenylate-cyclase-activating polypeptide
  • Enzyme

  • Dipeptidyl peptidase IV (EC