scholarly journals New Molecular Insights into the Inhibition of Dipeptidyl Peptidase-4 by Natural Cyclic Peptide Oxytocin

Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 3887
Author(s):  
Veera C. S. R. Chittepu ◽  
Poonam Kalhotra ◽  
Tzayhri Osorio-Gallardo ◽  
Cristian Jiménez-Martínez ◽  
Raúl René Robles-de la Torre ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Serine Protease ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Dipeptidyl Peptidase ◽  
Dependent Manner ◽  
Protease Inhibition ◽  
Dipeptidyl Peptidase 4 ◽  
Glucose Levels ◽  
Dpp4 Inhibition

Protease inhibition has led to treating many diseases and has been successful in producing many commercial drugs by pharmaceutical companies. Among many proteases, serine protease has been attractive in treating metabolic disorder diabetes mellitus (DM). Gliptins have been proven to inhibit dipeptidyl peptidase-4 (DPP4), a serine protease, and are an emerging therapeutic drug target to reduce blood glucose levels, but until now there is no natural cyclic peptide proven to inhibit serine protease DPP4. This study demonstrates the potential mechanism of natural cyclic peptide oxytocin (OXT) as a DPP4 inhibitor. To achieve this, initially, activity atlas and field-based models of DPP4 inhibitors were utilized to predict the possible features of positive and negative electrostatic, hydrophobic, and activity shapes of DPP4 inhibition. Oxytocin binding mode, flexibility, and interacting residues were studied using molecular docking simulations studies. 3D-RISM calculations studies revealed that the stability of water molecules at the binding site are favorable. Finally, an experimental study using fluorescence assay revealed OXT inhibits DPP4 in a concentration-dependent manner in a significant way (p < 0.05) and possess IC50 of 110.7 nM. These new findings significantly expand the pharmaceutical application of cyclic peptides, and in specific OXT, and implicate further optimization of OXT inhibition capacity to understand the effect of DPP4 inhibition. This work highlights the development of natural cyclic peptides as future therapeutic peptides to reduce glucose levels and treat diabetes mellitus.

scholarly journals Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Yuko Ohara-Nemoto ◽  
Manami Nakasato ◽  
Yu Shimoyama ◽  
Tomomi T. Baba ◽  
Takeshi Kobayakawa ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Dipeptidyl Peptidase ◽  
Oral Glucose ◽  
Content Type ◽  
Dipeptidyl Peptidase 4 ◽  
Glucose Levels ◽  
Flight Mass Spectrometry ◽  
Blood Glucose Levels ◽  
Molecular Events

ABSTRACT Severe periodontitis is known to aggravate diabetes mellitus, though molecular events related to that link have not been fully elucidated. Porphyromonas gingivalis, a major pathogen of periodontitis, expresses dipeptidyl peptidase 4 (DPP4), which is involved in regulation of blood glucose levels by cleaving incretins in humans. We examined the enzymatic characteristics of DPP4 from P. gingivalis as well as two other periodontopathic bacteria, Tannerella forsythia and Prevotella intermedia, and determined whether it is capable of regulating blood glucose levels. Cell-associated DPP4 activity was found in those microorganisms, which was effectively suppressed by inhibitors of human DPP4, and molecules sized 73 kDa in P. gingivalis, and 71 kDa in T. forsythia and P. intermedia were immunologically detected. The k cat/Km values of recombinant DPP4s ranged from 721 ± 55 to 1,283 ± 23 μM−1s−1 toward Gly-Pro-4-methylcoumaryl-7-amide (MCA), while those were much lower for His-Ala-MCA. Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) analysis showed His/Tyr-Ala dipeptide release from the N termini of incretins, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, respectively, with the action of microbial DPP4. Moreover, intravenous injection of DPP4 into mice decreased plasma active GLP-1 and insulin levels, accompanied by a substantial elevation in blood glucose over the control after oral glucose administration. These results are the first to show that periodontopathic bacterial DPP4 is capable of modulating blood glucose levels the same as mammalian DPP4; thus, the incidence of periodontopathic bacteremia may exacerbate diabetes mellitus via molecular events of bacterial DPP4 activities.

Linagliptin: A Novel Xanthine-Based Dipeptidyl Peptidase-4 Inhibitor for Treatment of Type II Diabetes Mellitus

2011 ◽  
Vol 7 (5) ◽  
pp. 325-335 ◽  
Author(s):  
Somsuvra B. Ghatak ◽  
Devang S. Patel ◽  
Neeraj Shanker ◽  
Ambrish Srivastava ◽  
Shrikalp S. Deshpande ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type Ii Diabetes ◽  
Type Ii Diabetes Mellitus ◽  
Dipeptidyl Peptidase ◽  
Type Ii ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitor

Dipeptidyl peptidase‐4 inhibitor‐related bullous pemphigoid: A comparative study of 100 patients with bullous pemphigoid and diabetes mellitus

2021 ◽  
Vol 48 (4) ◽  
pp. 486-496 ◽  
Author(s):  
Kumutnart Chanprapaph ◽  
Nathathai Pratumchart ◽  
Preeyachat Limtong ◽  
Suthinee Rutnin ◽  
Chonlaphat Sukasem ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Comparative Study ◽  
Bullous Pemphigoid ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitor

scholarly journals Association between Dipeptidyl Peptidase-4 Inhibitor Prescription and Erythropoiesis-Stimulating Agent Hyporesponsiveness in Hemodialysis Patients with Diabetes Mellitus

2021 ◽  
pp. 1-10
Author(s):  
Takeshi Hasegawa ◽  
Junhui Zhao ◽  
Brian Bieber ◽  
Jarcy Zee ◽  
Ronald L. Pisoni ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Iron Deficiency ◽  
Interaction Analysis ◽  
Conditional Logistic Regression ◽  
Resistance Index ◽  
Dipeptidyl Peptidase ◽  
Repeated Measurements ◽  
Study Phase ◽  
Dipeptidyl Peptidase 4 ◽  
Patients With Diabetes

<b><i>Introduction:</i></b> Dipeptidyl peptidase-4 (DPP-4) has been hypothesized to improve responsiveness to erythropoiesis-stimulating agent (ESA). We aimed to describe the trend in DPP-4 inhibitor prescription patterns and assess the association between DPP-4 inhibitor prescription and ESA hyporesponsiveness (eHypo) in Japanese hemodialysis (HD) patients with diabetes mellitus (DM). <b><i>Methods:</i></b> We analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study phase 4–6 (2009–2017) on patients with DM who underwent HD thrice per week for at least 4 months. The primary exposure of interest was having a DPP-4 inhibitor prescription. The primary analysis outcomes were a binary indicator of eHypo (mean hemoglobin &#x3c;10 and mean ESA dose &#x3e;6,000 units/week over 4 months) and the natural log-transformed ESA resistance index (ERI). We used conditional logistic regression to compare within-patient changes in eHypo before and after initial DPP-4 inhibitor prescription. We used linear generalized estimating equation models to compare continuous ERI outcomes while accounting for within-patient repeated measurements with an exchangeable correlation structure. <b><i>Results:</i></b> There was a monotonic increase in DPP-4 inhibitor prescription according to study year up to 20% in 2017. Moreover, 12.8% of patients with a DPP-4 inhibitor prescription were ESA hyporesponsive before the initial DPP-4 inhibitor prescription. After DPP-4 inhibitor prescription, the odds of eHypo and mean log-ERI remained unchanged in the whole cohort of our study. The interaction analysis of DPP-4 inhibitor and sideropenia showed that DPP-4 inhibitors attenuated eHypo in the patients without iron deficiency. <b><i>Conclusion:</i></b> Our findings indicate a recent increase in DPP-4 inhibitor prescription among Japanese HD patients with DM. DPP-4 inhibitors could improve ERI in patients undergoing HD without iron deficiency.

scholarly journals Risk of morbidity and mortality in patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitor and/or dipeptidyl peptidase-4 inhibitor: a nationwide study

2021 ◽  
Vol 9 (1) ◽  
pp. e001765
Author(s):  
Gábor Sütő ◽  
Gergő A Molnár ◽  
Gyorgy Rokszin ◽  
Ibolya Fábián ◽  
Zoltan Kiss ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Propensity Score ◽  
Propensity Score Matching ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4 ◽  
Sodium Glucose Cotransporter ◽  
Dipeptidyl Peptidase 4 Inhibitor ◽  
All Cause Mortality

IntroductionMortality and disability in diabetes mellitus are determined mostly by cardiovascular complications and cancer. The impact of dipeptidyl peptidase-4 inhibitor (DPP-4i) and sodium-glucose cotransporter-2 inhibitor (SGLT2i) monotherapy or combination on long-term complications of type 2 diabetes mellitus was studied.Research design and methodsPatients with type 2 diabetes treated with DPP-4i or SGLT2i during a 3-year period were identified in the database of the National Institute of Health Insurance Fund in Hungary. All-cause mortality, acute myocardial infarction, stroke, hospitalization for heart failure (HHF), lower limb amputation (LLA) and cancer were assessed. Outcomes of add-on SGLT2i to DPP-4i treatment in comparison with switching DPP-4i therapy to SGLT2i were also evaluated. After propensity score matching, survival analysis was performed with a Cox proportional hazards model.ResultsAfter propensity score matching, both SGLT2i and DPP-4i groups included 18 583 patients. All-cause mortality (HR, 0.80; 95% CI 0.68 to 0.94; p=0.0057), HHF (HR, 0.81; 95% CI 0.71 to 0.92; p=0.0018), and risk of cancer (HR, 0.75; 95% CI 0.66 to 0.86; p<0.0001) were lower in the SGLT2i population compared with DPP-4i. Risk of LLA was higher in the SGLT2i group (HR, 1.35; 95% CI 1.03 to 1.77; p=0.0315). SGLT2i in combination with DPP-4i results in lower all-cause mortality (HR, 0.46; 95% CI 0.31 to 0.67; p=0.0001), with a lower trend in stroke, LLA, HHF and cancer, but without any statistical difference.ConclusionsSGLT2i treatment leads to a lower risk of overall mortality, HHF and cancer when compared with DPP-4i treatment. Adding SGLT2i to DPP-4i instead of switching from DPP-4i to SGLT2i further lowers the risk of all-cause mortality.

scholarly journals Effect of Dipeptidyl-Peptidase 4 Inhibitors on Circulating Oxidative Stress Biomarkers in Patients with Type 2 Diabetes Mellitus

Antioxidants ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 233
Author(s):  
Elisabetta Bigagli ◽  
Cristina Luceri ◽  
Ilaria Dicembrini ◽  
Lorenzo Tatti ◽  
Francesca Scavone ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Propensity Score ◽  
Oxidative Damage ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitors

Pre-clinical studies suggested potential cardiovascular benefits of dipeptidyl peptidase-4 inhibitors (DPP4i), however, clinical trials showed neither beneficial nor detrimental effects in patients with type 2 diabetes mellitus (T2DM). We examined the effects of DPP4i on several circulating oxidative stress markers in a cohort of 32 T2DM patients (21 males and 11 post-menopausal females), who were already on routine antidiabetic treatment. Propensity score matching was used to adjust demographic and clinical characteristics between patients who received and who did not receive DPP4i. Whole-blood reactive oxygen species (ROS), plasma advanced glycation end products (AGEs), advanced oxidation protein products (AOPP), carbonyl residues, as well as ferric reducing ability of plasma (FRAP) and leukocyte DNA oxidative damage (Fpg sites), were evaluated. With the exception of Fpg sites, that showed a borderline increase in DPP4i users compared to non-users (p = 0.0507), none of the biomarkers measured was affected by DPP4i treatment. An inverse correlation between estimated glomerular filtration rate and AGEs (p < 0.0001) and Fpg sites (p < 0.05) was also observed. This study does not show any major effect of DPP4i on oxidative stress, assessed by several circulating biomarkers of oxidative damage, in propensity score-matched cohorts of T2DM patients.

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