Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by Vildagliptin ((2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile)

Brandt, Inger; Joossens, Jurgen; Chen, Xin; Maes, Marie-Berthe; Scharpé, Simon; Meester, Ingrid De; Lambeir, Anne‐Marie

doi:10.1016/j.bcp.2005.04.009

Cited by 107 publications

(63 citation statements)

References 32 publications

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“…5, the inhibitory effects of vildagliptin on DPP-IV activity were notable, giving an IC 50 of 2.1 mM, as observed in previous studies (34). Nateglinide inhibition of DPP-IV activity in vitro resulted in an IC 50 of 17.1 mM, demonstrating less of an inhibitory effect than vildagliptin.…”

Section: Inhibitory Effect Of Vildagliptin On Dpp-iv-mediated Degradasupporting

confidence: 78%

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation

McKillop

Duffy

Lindsay

et al. 2009

European Journal of Endocrinology

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Background: Nateglinide restores early-phase insulin secretion to feeding and reduces postprandial hyperglycaemia in type 2 diabetes. This study evaluated the effects of nateglinide on dipeptidyl peptidase-IV (DPP-IV) activity and glucose-dependent insulinotropic polypeptide (GIP) degradation. Research design and methods: Blood samples were collected from type 2 diabetic subjects (nZ10, fasting glucose 9.36G1.2 mmol/l) following administration of oral nateglinide (120 mg) 10 min prior to a 75 g oral glucose load in a randomised crossover design. Results: Plasma glucose reached 18.2G1.7 and 16.7G1.7 mmol/l at 90 min in control and placebo groups (P!0.001). These effects were accompanied by prompt 32% inhibition of DPP-IV activity after 10 min (19.9G1.6 nmol/ml per min, P!0.05), reaching a minimum of 1.9G0.1 nmol/ml per min at 120 min (P!0.001) after nateglinide. Insulin and C-peptide levels increased significantly compared with placebo, to peak after 90 min at 637.6G163.9 pmol/l (P!0.05) and 11.8G1.4 mg/l (P!0.01) respectively. DPP-IV-mediated degradation of GIP was significantly less in patients receiving nateglinide compared with placebo. Inhibition of DPP-IV activity corresponded with a time-and concentration-dependent inhibitory effect of nateglinide on DPP-IV-mediated truncation of GIP(1-42) to GIP(3-42) in vitro. Comparison of in vitro inhibition of DPP-IV by nateglinide and vildagliptin revealed IC 50 values of 17.1 and 2.1 mM respectively. Conclusions: Although considerably less potent than specified DPP-IV inhibitors, the possibility that some of the beneficial actions of nateglinide are indirectly mediated through DPP-IV inhibition and increased bioavailability of GIP and other incretins merits consideration.

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Section: Inhibitory Effect Of Vildagliptin On Dpp-iv-mediated Degradasupporting

confidence: 78%

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation

McKillop

Duffy

Lindsay

et al. 2009

European Journal of Endocrinology

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“…We used the data in Fig. 3 to estimate an IC 50 for Vildagliptin; the calculated IC 50 was 32 (4) nmol/L, similar to the reported value (18 ).…”

Section: Shown Insupporting

confidence: 66%

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

et al. 2006

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“…3, A and B). The fact that vildagliptin has a high specificity for CD26 (59,60) indicated that CD26 counteracts the expression of these components. In contrast, an inhibitor of granzyme B (IleGlu-Thr-Asp aldehyde), another protease expressed by T cells, did not increase TSP-1 and CD91 expression.…”

Section: Cd26 Influences Cell Surface Expression Of Tsp-1mentioning

confidence: 99%

A CD26-Controlled Cell Surface Cascade for Regulation of T Cell Motility and Chemokine Signals

Liu

Christensson

Forslöw

et al. 2009

The Journal of Immunology

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Chemokines are key regulators of cell trafficking, and dipeptidyl peptidase IV/CD26 (CD26) inactivates chemokines. Here we show that the CD26-processed chemokines SDF1α/CXCL12 and RANTES/CCL5, in contrast to a control chemokine not processed by CD26, are potent inducers of cell surface expression of thrombospondin-1 (TSP-1) in T lymphocytes through a CD26-controlled mechanism and that TSP-1 stimulates expression of lipoprotein receptor related protein/CD91. Accordingly, intact TSP-1 and a peptide mimetic of a sequence in TSP-1 were sufficient to stimulate CD91 expression. The chemokine-induced expression of TSP-1 and CD91 was mimicked by inhibitors of CD26 and CXCL12 and CCL5 as well as inhibitors of CD26 stimulated polarized cytoplasmic spreading and migration through TSP-1. Silencing of CD26 using small interfering RNA or Ab-induced modulation of CD26 also increased TSP-1 expression and enhanced cytoplasmic spreading and T cell migration markedly. These results indicate that CD26 is an endogenous inhibitor of T cell motility through inhibition of TSP-1 expression and that chemokines stimulate cell polarity and migration through abrogation of the CD26-dependent inhibition. This suggests that T cell motility is regulated by a cascade of interacting cell surface molecules.

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Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by Vildagliptin ((2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile)

Cited by 107 publications

References 32 publications

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation

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

A CD26-Controlled Cell Surface Cascade for Regulation of T Cell Motility and Chemokine Signals

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