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

Abstract

Anatomisches Institut andPeptides of the glucagodvasoactive-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 peptidefglucose-dependent insulinotropic peptide (GIP) with terminal Tyr-Ala as well as glucagon-like peptide-1 (7 -36)amidehnsulinotropin [GLP-l(7 -36)amidel 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 K, values of 4-34 pM and V,,, values of 0.6-3.8 pmol . min-' . mg protein-' 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-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 is obligate for the biological activity of the members of the glucagonNIP peptide family [e. g. ) is known to be inactive to release insulin in the presence of glucose as does intact GIP], dipeptidylpeptidase-IV action inactivates these peptide hormones. The relevance of this finding for their inactivation and their determination by immunoassays is discussed.

Exploration of replicative senescence-associated genes in human dermal fibroblasts by cDNA microarray technology

“…DPP4 is identical to T-cell activation antigen CD26 (Koch and Shows, 1980) and to adenosine deaminase complexing protein 2 (Morrison et al, 1993). DPP4 is a serine exopeptidase and has been implicated in the regulation of the biological activity of multiple hormones and chemokines, including the insulinotropic peptides glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (Mentlein et al, 1993). The CD26/DPP4-null mice showed normal blood glucose levels in the fasted state (Marguet et al, 2000) and were refractory to the development of obesity and hyperinsulinemia when administered a high fat diet (Conarello et al, 2003).…”

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

“…20,21,51 As a result, current GLP-1-receptor agonist therapies require repeated injections to maintain therapeutic plasma concentrations. As an alternative means of raising plasma GLP-1 levels, DPP-IV inhibitors have recently been developed and are now in clinical use for treatment of type-2 diabetes.…”

“…5,18,19 Native GLP-1, as well as currently available GLP-1-receptor agonists, have short biological half-lives. [20][21][22][23] Native GLP-1 is degraded within minutes by dipeptidylpeptidase (DPP)-IV, 20,21 rendering it unfit for use as a subcutaneously administered therapeutic. The synthetic GLP-1-receptor agonists exenatide and liraglutide are resistant to DPP-IV, exhibiting half-lives of approximately 2 and 12 h, respectively.…”

Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7?36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships

“…min-1 (highest dose), which is higher than that during intravenous infusion (approximately 12-14ml.kg -~" min-1 [3,4,7]) and, therefore, may indicate incomplete delivery of GLP-1 [7-36 amide] into the vascular compartment. In addition, partial degradation might occur also in subcutaneous tissue, as has been demonstrated after prolonged incubation in plasma via dipeptidyl-peptidase IV [17]. This would not alter GLP-1 immunoreactivity, but could reduce biological effects of subcutaneous GLP-1 [7-36 amide].…”