scholarly journals Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs

2002 ◽  
Vol 172 (2) ◽  
pp. 355-362 ◽  
Author(s):  
CF Deacon ◽  
S Wamberg ◽  
P Bie ◽  
TE Hughes ◽  
JJ Holst
Keyword(s):  
Plasma Concentrations ◽  
Dipeptidyl Peptidase ◽  
Feedback Mechanism ◽  
Dipeptidyl Peptidase Iv ◽  
Biologically Active ◽  
Incretin Hormones ◽  
Dpp Iv ◽  
Incretin Secretion ◽  
Glucagon Like Peptide 1

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are degraded by dipeptidyl peptidase IV (DPP IV), thereby losing insulinotropic activity. DPP IV inhibition reduces exogenous GLP-1 degradation, but the extent of endogenous incretin protection has not been fully assessed, largely because suitable assays which distinguish between intact and degraded peptides have been unavailable. Using newly developed assays for intact GLP-1 and GIP, the effect of DPP IV inhibition on incretin hormone metabolism was examined. Conscious dogs were given NVP-DPP728, a specific DPP IV inhibitor, at a dose that inhibited over 90% of plasma DPP IV for the first 90 min following treatment. Total and intact incretin concentrations increased (P<0.0001) following a mixed meal, but on control days (vehicle infusion), intact peptide concentrations were lower (P<0.01) than total peptide concentrations (22.6 +/- 1.2% intact GIP; 10.1 +/- 0.4% intact GLP-1). Following inhibitor treatment, the proportion of intact peptide increased (92.5 +/- 4.3% intact GIP, P<0.0001; 99.0 +/- 22.6% intact GLP-1, P<0.02). Active (intact) incretins increased after NVP-DPP728 (from 4797 +/- 364 to 10 649 +/- 106 pM x min for GIP, P<0.03; from 646 +/- 134 to 2822 +/- 528 pM x m in for GLP-1, P<0.05). In contrast, total incretins fell (from 21 632 +/- 654 to 12 084 +/- 1723 pM x min for GIP, P<0.002; from 5145 +/- 677 to 3060 +/- 601 pM x min for GLP-1, P<0.05). Plasma glucose, insulin and glucagon concentrations were unaltered by the inhibitor. We have concluded that DPP IV inhibition with NVP-DPP728 prevents N-terminal degradation of endogenous incretins in vivo, resulting in increased plasma concentrations of intact, biologically active GIP and GLP-1. Total incretin secretion was reduced by DPP IV inhibition, suggesting the possibility of a feedback mechanism.

scholarly journals 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

2003 ◽  
Vol 31 (3) ◽  
pp. 529-540 ◽  
Author(s):  
BD Green ◽  
VA Gault ◽  
MH Mooney ◽  
N Irwin ◽  
CJ Bailey ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Biological Activities ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Glucose Lowering ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

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 Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8))GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC(50): 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC(50): 0.37 nM). (Abu(8))GLP-1 and (Val(8))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 (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.

IN VIVO INHIBITION OF DIPEPTIDYL PEPTIDASE IV (DPP IV) BY PRO-PRO-DIPHENYL PHOSPHONATE (DIPROFEN)

1996 ◽  
Vol 24 (4) ◽  
pp. 630S-630S ◽  
Author(s):  
I. De Meester ◽  
AM. Lambeir ◽  
A. Belyaev ◽  
M. Borloo ◽  
GRY. De Meyer ◽  
...  
Keyword(s):  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Dpp Iv

scholarly journals Dipeptidyl-Peptidase IV Converts Intact B-Type Natriuretic Peptide into Its des-SerPro Form

2006 ◽  
Vol 52 (1) ◽  
pp. 82-87 ◽  
Author(s):  
Inger Brandt ◽  
Anne-Marie Lambeir ◽  
Jean-Marie Ketelslegers ◽  
Marc Vanderheyden ◽  
Simon Scharpé ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Ex Vivo ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Amino Terminal ◽  
Dpp Iv

Abstract Background: Analysis of plasma B-type natriuretic peptide (BNP) has suggested the in vivo formation of a truncated form, BNP (3–32), also called des-SerPro-BNP. The objectives of this study were to investigate (a) whether BNP and other natriuretic peptides are truncated by dipeptidyl-peptidase IV (DPP IV/CD26; EC 3.4.14.5) and (b) whether this truncation affects the susceptibility to cleavage by neutral endopeptidase (NEP; EC 3.4.24.11). Methods: Human BNP (1–32), A-type natriuretic peptide 1–28 (ANP 1–28), and related peptides were incubated with purified DPP IV and with human plasma. In addition, BNP (1–32), BNP (3–32), and ANP (1–28) were subjected to hydrolysis by NEP. Cleavage products were analyzed by mass spectrometry. Results: BNP (1–32) was cleaved by purified DPP IV with a specificity constant of 0.37 × 106 L · mol−1 · s−1. The DPP IV activity in EDTA-plasma was able to truncate BNP (1–32) ex vivo. Addition of Vildagliptin, a specific DPP IV inhibitor, prevented this truncation in a concentration-dependent manner. Under in vitro circumstances in which ANP was hydrolyzed extensively, BNP (1–32) and BNP (3–32) were very resistant to NEP-mediated cleavage. Conclusions: DPP IV cleaves BNP (1–32) with an efficiency higher than or comparable to several known in vivo substrates of the enzyme. Even after loss of the amino-terminal dipeptide, BNP remains highly resistant to cleavage by NEP.

In vitro dipeptidyl peptidase IV inhibitory activity and in situ insulinotropic activity of milk and egg white protein digests

2021 ◽  
Author(s):  
Marta Santos-Hernandez ◽  
Maria Cermeno ◽  
Isidra Recio ◽  
Richard J. FitzGerald
Keyword(s):  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Food Protein ◽  
Protein Digestion ◽  
Egg White Protein ◽  
Dpp Iv ◽  
Protein Digests ◽  
Incretin Secretion

Dietary proteins are involved in the regulation of glucose homeostasis by different mechanisms. Food protein digestion products are reported to inhibit dipeptidyl peptidase IV (DPP-IV), induce incretin secretion or directly...

Evaluation of some plants for potential dipeptidyl peptidase IV inhibitory effects in vitro

2015 ◽  
Vol 40 (3) ◽  
Author(s):  
Ali Zeytünlüoğlu ◽  
Figen Zihnioğlu
Keyword(s):  
Inhibitory Activity ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Vitis Vinifera L ◽  
Aqueous Extracts ◽  
Inhibitory Effects ◽  
Dpp Iv ◽  
Ic50 Values ◽  
Glucagon Like Peptide 1

AbstractObjective: Dipeptidyl peptidase IV (DPP IV) is a serine amino (exo) peptidase which regulates various processes most notably plasma glucose homeostasis by cleaving incretin peptide hormones as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin releasing polypeptide (GIP). Realization of the inhibition of this enzyme in controlling diabetes is one of the strategies adopted in recent years. The present study was designed to investigate the DPP IV inhibitory effects of sixteen plant having antidiabetic property in aqueous extracts in correlation with their protein content.Methods: In vitro DPP IV inhibition was evaluated by the specific inhibitory activity of plant aqueous extracts prepared without and with heat (60°C) treatment.Results: Among the tested plants Vitis vinifera L., Artemisia dracunculus L., Prunus laurocerasus L., Rubus caesius L. and Olea europaea L. extracts showed DPP IV inhibitory activity with respect to IC50 values of 0.04-0.09 mg protein/ml. Kinetic analysis indicated that the inhibitor potency of A. dracunculus extract was stronger than the other extracts.Conclusion: The present study is the first report on screening and preliminary characterization of DPP IV inhibitory activity in aqueous extracts of selected antidiabetic medicinal food. This study could provide a new insight into DPP IV inhibitors from plants that could be useful for treatment of Type 2 diabetes.

Hepatische Elimination und First-Pass-Effekt von Glucagon-Like Peptide-1 (GLP-1)

2006 ◽  
Vol 34 (02) ◽  
pp. 132-137
Author(s):  
A. Greischel ◽  
W. Roth ◽  
J.P. Sandel
Keyword(s):  
Diabetes Mellitus ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Diabetes Mellitus Typ 2 ◽  
Klinische Relevanz ◽  
Dpp Iv ◽  
First Pass ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Zusammenfassung Gegenstand und Ziel: Ein neuer, innovativer Ansatz in der humanmedizinischen Behandlung des nichtinsulinabhängigen Diabetes mellitus (Typ 2) zielt auf die Hemmung der Dipeptidyl-Peptidase IV (DPP-IV) ab, um die Plasmakonzentration an Glucagon-Like Peptide-1 (GLP-1) zu erhöhen, wodurch wiederum die Insulininkretion in Abhängigkeit von erhöhten Blutzuckerspiegeln gesteigert wird. Material und Methoden: In der vorliegenden Studie wurde der Anteil der hepatischen Elimination des GLP-1 an der Gesamtkörper-Elimination mit und ohne DPP-IV-Hemmung mithilfe des rezirkulierenden Modells der isolierten perfundierten Rat- tenleber (IPRL) quantifiziert. Ergebnisse: Die Leberelimination hat bei der Ratte einen Anteil von 57% an der totalen Clearance des GLP-1. Der niedrige hepatische Extraktionsquotient von 30 ± 11% erlaubt sieben von zehn vom Darm abgegebenen GLP-1-Molekülen den Eintritt in den systemischen Kreislauf (70% Bioverfügbarkeit). Die Halbwertszeit der GLP-1-Amid-Isoform (7–36 amid) in der IPRL beträgt 5,0 ± 1,3 Minuten und unterscheidet sich statistisch nicht signifikant (p = 0,114) von der Halbwertszeit der Glycin-Isoform (7–37) mit 6,1 ± 1,6 Minuten. Schlussfolgerung und klinische Relevanz: DPP-IV-Inhibitoren verlängern erfolgreich die Halbwertszeit und damit die Wirkdauer von GLP-1, was den Einsatz von Insulin bei Katzen mit Diabetes mellitus verzichtbar machen könnte.

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