DIPEPTIDYLPEPTIDASE-IV HYDROLYZES GASTRIC-INHIBITORY POLYPEPTIDE, GLUCAGON-LIKE PEPTIDE-1(7-36)AMIDE, PEPTIDE HISTIDINE METHIONINE AND IS RESPONSIBLE FOR THEIR DEGRADATION IN HUMAN SERUM

Peptides of the glucagon/vasoactive-intestinal-peptide (VIP) peptide f amily share a considerable sequence similarity at their N-terminus. Th ey either start with Tyr-Ala, His-Ala or His-Ser which might be in par t potential targets for dipeptidyl-peptidase IV, a highly specialized aminopeptidase removing dipeptides only from peptides with N-terminal penultimate proline or alanine. Growth-hormone-releasing factor(l -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-X aa-Ala derivatives by dipeptidyl-peptidase IV purified from human plac enta. 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 K(m) values of 4- 34 muM and V(max) values of 0.6-3.8 mumol . min-1 . mg protein-1 were determined for the purified peptidase which should allow their enzymic degradation also at physiological, nanomolar concentrations. When hum an 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 thes e peptide hormones. Incorporation of inhibitors specific for dipeptidy l-peptidase IV, 1 mM Lys-pyrrolidide or 0.1 mM diprotin A (Ile-Pro-Ile ), 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 i s 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-pe ptidase-IV action inactivates these peptide hormones. The relevance of this finding for their inactivation and their determination by immuno assays is discussed.