Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice

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Waget, Aurélie; Cabou, Cendrine; Masseboeuf, Myriam

2011-01-01

Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expres...

Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria

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Martin Haluzík

2013-01-01

Full Text Available Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculo-protective actions. One of the recently emerged interesting features of dipeptidyl peptidase-4 (DPP-4 inhibitors is its possible protective effect on the diabetic kidney disease. Here, we review the renal effects of DPP-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria, as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complications. Mechanisms underlying possible nephroprotective properties of DPP-4 inhibitors include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction. Effects of DPP-4 inhibitors may be both glucagon-like peptide-1 (GLP-1 dependent and independent. Ongoing prospective studies focused on the nephroprotective effects of DPP-4 inhibitors will further clarify its possible role in the prevention/attenuation of diabetic kidney disease beyond its glucose lowering properties.

Impact of type 1 diabetes mellitus and sitagliptin treatment on the neuropeptide Y system of rat retina

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Campos, Elisa J.; Martins, João; Brudzewsky, Dan

2018-01-01

1 diabetes mellitus (DM) and sitagliptin, a DPP-IV inhibitor, on the NPY system in the retina using an animal model.  Methods: Type 1 DM was induced in male Wistar rats by an intraperitoneal injection of streptozotocin. Starting 2weeks after DM onset, animals were treated orally with sitagliptin (5...... of NPY to all receptors. Sitagliptin alone reduced retinal NPY mRNA levels. The effects of DM on the NPY system were not affected by sitagliptin.  Conclusion: DM modestly affects the NPY system in the retina and these effects are not prevented by sitagliptin treatment. These observations suggest that DPP...

Dipeptidyl-peptidase IV (DPP-IV) inhibitor delays tolerance to anxiolytic effect of ethanol and withdrawal-induced anxiety in rats.

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Sharma, Ajaykumar N; Pise, Ashish; Sharma, Jay N; Shukla, Praveen

2015-06-01

Dipeptidyl-peptidase IV (DPP-IV) is an enzyme responsible for the metabolism of endogenous gut-derived hormone, glucagon-like peptide-1 (GLP-1). DPP-IV is known for its role in energy homeostasis and pharmacological blockade of this enzyme is a recently approved clinical strategy for the management of type II diabetes. Accumulating evidences suggest that enzyme DPP-IV can affect spectrum of central nervous system (CNS) functions. However, little is known about the role of this enzyme in ethanol-mediated neurobehavioral complications. The objective of the present study was to examine the impact of DPP-IV inhibitor, sitagliptin on the development of tolerance to anxiolytic effect of ethanol and anxiety associated with ethanol withdrawal in rats. A dose-response study revealed that sitaglitpin (20 mg/kg, p.o.) per se exhibit anxiolytic effect in the elevated plus maze (EPM) test in rats. Tolerance to anxiolytic effect of ethanol (2 g/kg, i.p.; 8 % w/v) was observed from 7(th) day of ethanol-diet (6 % v/v) consumption. In contrast, tolerance to anxiolytic effect of ethanol was delayed in rats that were treated daily with sitagliptin (20 mg/kg, p.o.) as tolerance was observed from 13(th)day since commencement of ethanol-diet consumption. Discontinuation of rats from ethanol-diet after 15-days of ethanol consumption resulted in withdrawal anxiety between 8 h and 12 h post-abstinence. However, rats on 15-day ethanol-diet with concomitant sitagliptin (20 mg/kg, p.o.) treatment exhibited delay in appearance (24 h post-withdrawal) of withdrawal anxiety. In summary, DPP-IV inhibitors may prove as an attractive research strategy against ethanol tolerance and dependence.

Vildagliptin: the first innovative DDP-4 inhibitor

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Edvin Villkhauer

2010-09-01

Full Text Available A review of the main stages of investigation undertaken by Novartis Pharmaceuticals in search of a new molecule for the treatment of type 2 diabetesmellitus, dipeptidyl peptidase-4 (DPP-4 inhibitor (Vildaglyptin. The data on specificity and selectivity of the action of this molecule are presentedalong with the results of its comparison with another agent of this group (sitagliptin.

Novel combination treatment of type 2 diabetes DPP-4 inhibition + metformin

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Bo Ahrén

2008-04-01

Full Text Available Bo AhrénDepartment of Clinical Sciences, Division of Medicine, Lund University, Lund, SwedenAbstract: Inhibition of dipeptidyl peptidase-4 (DPP-4 as a novel therapy for type 2 diabetes is based on prevention of the inactivation process of bioactive peptides, the most important in the context of treatment of diabetes of which is glucagon-like peptide-1 (GLP-1. Most clinical experience with DPP-4 inhibition is based on vildagliptin (GalvusR, Novartis and sitagliptin (JanuviaR, Merck. These compounds improve glycemic control both in monotherapy and in combination with other oral hyperglycemic agents. Both have also been shown to efficiently improve glycemic control when added to ongoing metformin therapy in patients with inadequate glycemic control. Under that condition, they reduce HbA1c levels by 0.65%–1.1% (baseline HbA1c 7.2–8.7% in studies up to 52 weeks of duration in combination versus continuous therapy with metformin alone. Sitagliptin has also been examined in initial combination therapy with metformin have; HbA1c was reduced by this combination by 2.1% (baseline HbA1c 8.8% after 24 weeks of treatment. Both fasting and prandial glucose are reduced by DPP-4 inhibition in combination with metformin in association with improvement of insulin secretion and insulin resistance and increase in concentrations of active GLP-1. The combination of DPP-4 inhibition and metformin has been shown to be highly tolerable with very low risk of hypoglycemia. Hence, DPP-4 inhibition in combination with metformin is an efficient, safe and tolerable combination therapy for type 2 diabetes.Keywords: DPP-4 inhibition, sitagliptin, vildagliptin, metformin, type 2 diabetes

Synthesis, pharmacological evaluation and molecular docking studies of pyrimidinedione based DPP-4 inhibitors as antidiabetic agents

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Jha, Vibhu; Bhadoriya, Kamlendra Singh

2018-04-01

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of newly developed antidiabetic drugs that bock DPP-4. DPP-4 is responsible for degradation of incretins harmones such as GLP-1 (Glucagon like Peptide) and GIP (Gastric inhibitory polypeptide) that maintain blood-glucose level. Pyrimidinedione based compounds were designed and synthesized for DPP-4 inhibitory activity. These heterocycles were designed by taking Alogliptin as a reference DPP-4 inhibitors and synthesized as N-methylated and N-benzylated pyrimidinediones. These compounds were subjected to DPP-4 assay, five out of nine synthesized compounds have shown in vitro DPP-4 inhibitory activity in significant range. Further, molecular docking studies of these compounds were performed on DPP-4 subunit and compared with natural DPP-4 inhibitors like Flavone, Resveratrol, Quercetin, Diprotin A. Docking studies have led to the conclusion that there are some identical amino acid interactions as Tyr 666 and Tyr 662, seen in both synthesized compounds and natural DPP-4 inhibitors. This study completely gives a good scope for further derivatisation and optimization of synthesized compounds to get clinical candidate as DPP-4 inhibitor for antidiabetic activity.

Effect of dipeptidyl peptidase-4 inhibitors on circulating tumor necrosis factor-α concentrations: A systematic review and meta-analysis of controlled trials.

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Atkin, Stephen L; Katsiki, Niki; Banach, Maciej; Mikhailidis, Dimitri P; Pirro, Matteo; Sahebkar, Amirhossein

2017-09-01

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes mellitus. There are also reports of an effect of these drugs in reducing inflammation through inhibition of tumor necrosis factor-α (TNF-α) that is an important mediator for several inflammatory processes. The present systematic review and meta-analysis were performed to evaluate the effect of DPP-4 inhibitors on circulating TNF-α levels in T2DM patients. A systematic review and a meta-analysis were undertaken on all controlled trials of DPP-4 inhibitors that included measurement of TNF-α. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analysis were performed to assess the modifiers of treatment response. Eight eligible articles (6 with sitagliptin and 2 with vildagliptin) comprising 9 treatment arms were selected for this meta-analysis. Meta-analysis suggested a significant reduction of circulating TNF-α concentrations following treatment with DPP-4 inhibitors (SMD: -1.84, 95% CI: -2.88, -0.80, p=0.001). The effect size was robust in the sensitivity analysis and not mainly driven by a single study. A subgroup analysis did not suggest any significant difference between the TNF-α-lowering activity of sitagliptin (SMD: -1.49, 95% CI: -2.89, -0.10) and vildagliptin (SMD: -2.80, 95% CI: -4.98, -0.61) (p=0.326). This meta-analysis of the 8 available controlled trials showed that DPP-4 inhibition in patients with type 2 diabetes mellitus was associated with significant reductions in plasma TNF-α levels with no apparent difference between sitagliptin and vildagliptin. Copyright © 2017 Elsevier Inc. All rights reserved.

Sitagliptin as combination therapy in the treatment of type 2 diabetes mellitus

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Shannon A Miller

2009-05-01

Full Text Available Shannon A Miller1, Erin L St Onge2, J Roger Accardi31Pharmacotherapy Faculty, Florida Hospital East Family Practice Residency, Orlando, Florida, USA; 2University of Florida College of Pharmacy, Orlando Campus, Florida, USA; 3Accardi Clinical Pharmacy, Orange City, Florida, USAAbstract: The American Diabetes Association and The European Association for the Study of Diabetes recommend metformin as the initial agent of choice in the treatment of type 2 diabetes mellitus. Unfortunately, most patients require multiple medications to obtain glycemic control. One of the newest additions to the antidiabetic armamentarium is the class of drugs known as dipeptidyl-peptidase IV (DPP-IV inhibitors. This novel approach focuses on harnessing the beneficial effects of GLP-1, an incretin hormone released from the gut postprandially. The first DPP-IV inhibitor approved in the United States was sitagliptin. It has been studied in both monotherapy and combination therapy. Combination studies with metformin realize a hemoglobin A1c reduction of 0.65%–1.1%. The combination of the two has a modest positive effect on body weight with the convenience of an oral route of administration. It has also been shown to be highly tolerable, efficacious and with little risk of hypoglycemia. This review will focus on combination therapy with sitagliptin with emphasis on combination with metformin. Keywords: DPP-IV inhibitor, sitagliptin, metformin, type 2 diabetes, incretins

A comparison of effects of DPP-4 inhibitor and SGLT2 inhibitor on lipid profile in patients with type 2 diabetes.

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Cha, Seon-Ah; Park, Yong-Moon; Yun, Jae-Seung; Lim, Tae-Seok; Song, Ki-Ho; Yoo, Ki-Dong; Ahn, Yu-Bae; Ko, Seung-Hyun

2017-04-13

Previous studies suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors have different effects on the lipid profile in patients with type 2 diabetes. We investigated the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile in patients with type 2 diabetes. From January 2013 to December 2015, a total of 228 patients with type 2 diabetes who were receiving a DPP-4 inhibitor or SGLT2 inhibitor as add-on therapy to metformin and/or a sulfonylurea were consecutively enrolled. We compared the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile at baseline and after 24 weeks of treatment. To compare lipid parameters between the two groups, we used the analysis of covariance (ANCOVA). A total of 184 patients completed follow-up (mean age: 53.1 ± 6.9 years, mean duration of diabetes: 7.1 ± 5.7 years). From baseline to 24 weeks, HDL-cholesterol (HDL-C) levels were increased by 0.5 (95% CI, -0.9 to 2.0) mg/dl with a DPP-4 inhibitor and by 5.1 (95% CI, 3.0 to 7.1) mg/dl with an SGLT2 inhibitor (p = 0.001). LDL-cholesterol (LDL-C) levels were reduced by 8.4 (95% CI, -14.0 to -2.8) mg/dl with a DPP-4 inhibitor, but increased by 1.3 (95% CI, -5.1 to 7.6) mg/dl with an SGLT2 inhibitor (p = 0.046). There was no significant difference in the mean hemoglobin A1c (8.3 ± 1.1 vs. 8.0 ± 0.9%, p = 0.110) and in the change of total cholesterol (TC) (p = 0.836), triglyceride (TG) (p = 0.867), apolipoprotein A (p = 0.726), apolipoprotein B (p = 0.660), and lipoprotein (a) (p = 0.991) between the DPP-4 inhibitor and the SGLT2 inhibitor. The SGLT2 inhibitor was associated with a significant increase in HDL-C and LDL-C after 24 weeks of SGLT2 inhibitor treatment in patients with type 2 diabetes compared with those with DPP-4 inhibitor treatment in this study. This study was conducted by retrospective medical record review.

Changes in glucose-induced plasma active glucagon-like peptide-1 levels by co-administration of sodium–glucose cotransporter inhibitors with dipeptidyl peptidase-4 inhibitors in rodents

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Takahiro Oguma

2016-12-01

Full Text Available We investigated whether structurally different sodium–glucose cotransporter (SGLT 2 inhibitors, when co-administered with dipeptidyl peptidase-4 (DPP4 inhibitors, could enhance glucagon-like peptide-1 (GLP-1 secretion during oral glucose tolerance tests (OGTTs in rodents. Three different SGLT inhibitors—1-(β-d-Glucopyranosyl-4-chloro-3-[5-(6-fluoro-2-pyridyl-2-thienylmethyl]benzene (GTB, TA-1887, and canagliflozin—were examined to assess the effect of chemical structure. Oral treatment with GTB plus a DPP4 inhibitor enhanced glucose-induced plasma active GLP-1 (aGLP-1 elevation and suppressed glucose excursions in both normal and diabetic rodents. In DPP4-deficient rats, GTB enhanced glucose-induced aGLP-1 elevation without affecting the basal level, whereas metformin, previously reported to enhance GLP-1 secretion, increased both the basal level and glucose-induced elevation. Oral treatment with canagliflozin and TA-1887 also enhanced glucose-induced aGLP-1 elevation when co-administered with either teneligliptin or sitagliptin. These data suggest that structurally different SGLT2 inhibitors enhance plasma aGLP-1 elevation and suppress glucose excursions during OGTT when co-administered with DPP4 inhibitors, regardless of the difference in chemical structure. Combination treatment with DPP4 inhibitors and SGLT2 inhibitors having moderate SGLT1 inhibitory activity may be a promising therapeutic option for improving glycemic control in patients with type 2 diabetes mellitus.

Sitagliptin versus saxagliptin in decompensated type 2 diabetes mellitus patients

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Antonio Asti

2016-03-01

Full Text Available Sitagliptin and saxagliptin are oral hypoglycemic agents inhibitors of DPP-4, indicated in the treatment of type 2 diabetes mellitus in combination with metformin, in patients who have not achieved adequate glycemic control. In our study we enrolled 128 decompensated type 2 diabetes patients while on metformin maximum dosage. At time 0’ we have detected, body mass index (BMI, total cholesterol, high- and low-density lipoproteins (HDL and LDL, triglycerides, transaminases and pancreatic amylase; patients were randomized to receive sitagliptin or saxagliptin; follow-up was performed after 4 months with the revaluation of the same variables and adverse events. In both sitagliptin and saxagliptin groups we observed a significant reduction in fasting glucose, glycated hemoglobin, weighing, BMI, triglycerides, while the reduction in total cholesterol, LDL cholesterol did not reach statistical significance. There was no suspension of therapy, adverse events appeared minor and temporary. In conclusion, our observations highlight the almost identical efficacy of sitagliptin and saxagliptin. These data reinforce even more the idea that we should think about this class of drugs as the next step in patients failing therapy with metformin.

The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo

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Masako Uchii

2017-11-01

Full Text Available Saxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2 cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibitory potency of saxagliptin on DPP-4 activity persisted after washout, while that of sitagliptin was clearly reduced. In normal rats, a single treatment of saxagliptin or sitagliptin inhibited the plasma DPP-4 activity to similar levels. The inhibitory action of saxagliptin on the renal DPP-4 activity was retained, even when its inhibitory effect on the plasma DPP-4 activity disappeared. However, the inhibitory action of sitagliptin on the renal DPP-4 activity was abolished in correlation with the inhibition of the plasma DPP-4 activity. In situ staining showed that saxagliptin suppressed the DPP-4 activity in both glomerular and tubular cells and its inhibitory effects were significantly higher than those of sitagliptin. Saxagliptin exerted a sustained inhibitory effect on the renal DPP-4 activity in vitro and in vivo. The long binding action of saxagliptin in renal tubular cells might involve the sustained inhibition of renal DPP-4.

Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes

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Kishimoto M

2013-05-01

Full Text Available Miyako KishimotoDepartment of Diabetes and Metabolic Medicine, Center Hospital, Tokyo, Japan; Diabetes and Metabolism Information Center, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, JapanAbstract: Dipeptidyl peptidase-4 (DPP-4 inhibitors have recently emerged as a new class of antidiabetic that show favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. Teneligliptin, a novel DPP-4 inhibitor, exhibits a unique structure characterized by five consecutive rings, which produce a potent and long-lasting effect. Teneligliptin is currently used in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea- or thiazolidine-class drugs. In adults, teneligliptin is orally administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per day. Because the metabolites of this drug are eliminated via renal and hepatic excretion, no dose adjustment is necessary in patients with renal impairment. The safety profile of teneligliptin is similar to those of other available DPP-4 inhibitors. However, caution needs to be exercised when administering teneligliptin to patients who are prone to QT prolongation. One study has reported that the postprandial blood glucose-lowering effects of teneligliptin administered prior to breakfast were sustained throughout the day, and the effects observed after dinner were similar to those observed after breakfast or lunch. Thus, although clinical data for this new drug are limited, this drug shows promise in stabilizing glycemic fluctuations throughout the day and consequently suppressing the progression of diabetic complications. However, continued evaluation in long-term studies and clinical trials is required to evaluate the efficacy and safety of the drug as well as to identify additional indications for its clinical use

Comparison between SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy in type 2 diabetes: a systematic review with indirect comparison meta-analysis.

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Min, Se Hee; Yoon, Jeong-Hwa; Hahn, Seokyung; Cho, Young Min

2017-01-01

Both sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors can be used to treat patients with type 2 diabetes mellitus (T2DM) that is inadequately controlled with insulin therapy, and yet there has been no direct comparison of these two inhibitors. We searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through June 2015. Randomized controlled trials published in English that compare SGLT2 inhibitor plus insulin (SGLT2i/INS) with placebo plus insulin or DPP4 inhibitor plus insulin (DPP4i/INS) with placebo plus insulin in patients with T2DM were selected. Data on the study characteristics, efficacy and safety outcomes were extracted. We compared the efficacy and safety between SGLT2i/INS and DPP4i/INS indirectly with covariates adjustment. Risk of potential bias was assessed. Fourteen eligible randomized controlled trials comprising 6980 patients were included (five SGLT2 inhibitor studies and nine DPP4 inhibitor studies). Covariate-adjusted indirect comparison using meta-regression analyses revealed that SGLT2i/INS achieved greater reduction in HbA 1c [weighted mean difference (WMD) -0.24%, 95% confidence interval (CI) -0.43 to -0.05%], fasting plasma glucose (WMD -18.0 mg/dL, 95% CI -28.5 to -7.6 mg/dL) and body weight (WMD -2.38 kg, 95% CI -3.18 to -1.58 kg) from baseline than DPP4i/INS without increasing the risk of hypoglycaemia (relative risks 1.19, 95% CI 0.78 to 1.82). Sodium glucose cotransporter 2 inhibitors achieved better glycaemic control and greater weight reduction than DPP4 inhibitors without increasing the risk of hypoglycaemia in patients with T2DM that is inadequately controlled with insulin. There has been no direct comparison of SGLT2 inhibitors and DPP4 inhibitors in patients with T2DM inadequately controlled with insulin therapy. In this study, we performed indirect meta-analysis comparing SGLT2 inhibitors and DPP4 inhibitors added to insulin

Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors

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Pissarnitski, Dmitri A.; Zhao, Zhiqiang; Cole, David; Wu, Wen-Lian; Domalski, Martin; Clader, John W.; Scapin, Giovanna; Voigt, Johannes; Soriano, Aileen; Kelly, Theresa; Powles, Mary Ann; Yao, Zuliang; Burnett, Duane A. (Merck)

2016-11-01

Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test.

Oral administration of sitagliptin activates CREB and is neuroprotective in murine model of brain trauma

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Brian Dellavalle

2016-12-01

Full Text Available Introduction: Traumatic brain injury is a major cause of mortality and morbidity. We have previously shown that the injectable glucagon-like peptide-1 (GLP-1 analogue, liraglutide, significantly improved the outcome in mice after severe traumatic brain injury (TBI. In this study we are interested in the effects of oral treatment of a different class of GLP-1 based therapy, dipeptidyl peptidase IV (DPP-IV inhibition on mice after TBI. DPP-IV inhibitors reduce the degradation of endogenous GLP-1 and extend circulation of this protective peptide in the bloodstream. This class has yet to be investigated as a potential therapy for TBI. Methods: Mice were administrated once-daily 50 mg/kg of sitagliptin in a Nutella® ball or Nutella® alone throughout the study, beginning two days before severe trauma was induced with a stereotactic cryo-lesion. At two days post trauma, lesion size was determined. Brains were isolated for immunoblotting for assessment of selected biomarkers for pathology and protection.Results: Sitagliptin treatment reduced lesion size at day 2 post-injury by ~28% (p0.05. Conversely, apoptotic tone (alpha-spectrin fragmentation, Bcl-2 levels and the neuroinflammatory markers IL-6, and Iba-1 were not affected by treatment.Conclusions: This study shows, for the first time, that DPP-IV inhibition ameliorates both anatomical and biochemical consequences of TBI and activates CREB in the brain. Moreover, this work supports previous studies suggesting that the effect of GLP-1 analogues in models of brain damage relates to GLP-1 receptor stimulation in a dose-dependent manner.Keywords: GLP-1, Traumatic Brain Injury, TBI, sitagliptin, liraglutide, CREB, Oxidative Stress, GIP, DPP-IV, DPP-4

Dipeptidyl peptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) agonists

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Madsbad, Sten

2012-01-01

Incretin-based therapies, which include the GLP-1 receptor agonists and DPP-4 inhibitors, use the antidiabetic properties of potentiating the GLP-1 receptor signalling via the regulation of insulin and glucagon secretion, inhibition of gastric emptying and suppression of appetite. Most physicians...... will start antidiabetic treatment with metformin, but adding a GLP-1 receptor agonist as the second drug seems to be optimal since more patients will reach an HbA1c below 7% than with a DPP-4 inhibitor or another oral antidiabetic agents and with minimal risk of hypoglycaemia. The GLP-1 receptor agonists...

DPP4 in Diabetes

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Diana eRöhrborn

2015-07-01

Full Text Available Dipeptidyl peptidase 4 (DPP4 is a glycoprotein of 110 kDa, which is ubiquitously expressed on the surface of a variety of cells. This exopeptidase selectively cleaves N-terminal dipeptides from a variety of substrates, including cytokines, growth factors neuropeptides, and the incretin hormones. Expression of DPP4 is substantially dysregulated in a variety of disease states including inflammation, cancer, obesity and diabetes. Since the incretin hormones GLP-1 and GIP are major regulators of post-prandial insulin secretion, inhibition of DPP4 by the gliptin family of drugs has gained considerable interest for the therapy of type 2 diabetic patients. In this review, we summarise the current knowledge on the DPP4 - incretin axis, and evaluate most recent findings on DPP4 inhibitors.Furthermore, DPP4 as a type II transmembrane protein is also known to be cleaved from the cell membrane involving different metalloproteases in a cell-type specific manner. Circulating, soluble DPP4 has been identified as a new adipokine which exerts both para- and endocrine effects. Recently, a novel receptor for soluble DPP4 has been identified and data are accumulating that the adipokine-related effects of DPP4 may play an important role in the pathogenesis of cardiovascular disease. Importantly, circulating DPP4 is augmented in obese and type 2 diabetic subjects and it may represent a molecular link between obesity and vascular dysfunction. A critical evaluation of the impact of circulating DPP4 is presented and the potential role of DPP4 inhibition at this level is also discussed.

Predicting DPP-IV inhibitors with machine learning approaches

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Cai, Jie; Li, Chanjuan; Liu, Zhihong; Du, Jiewen; Ye, Jiming; Gu, Qiong; Xu, Jun

2017-04-01

Dipeptidyl peptidase IV (DPP-IV) is a promising Type 2 diabetes mellitus (T2DM) drug target. DPP-IV inhibitors prolong the action of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), improve glucose homeostasis without weight gain, edema, and hypoglycemia. However, the marketed DPP-IV inhibitors have adverse effects such as nasopharyngitis, headache, nausea, hypersensitivity, skin reactions and pancreatitis. Therefore, it is still expected for novel DPP-IV inhibitors with minimal adverse effects. The scaffolds of existing DPP-IV inhibitors are structurally diversified. This makes it difficult to build virtual screening models based upon the known DPP-IV inhibitor libraries using conventional QSAR approaches. In this paper, we report a new strategy to predict DPP-IV inhibitors with machine learning approaches involving naïve Bayesian (NB) and recursive partitioning (RP) methods. We built 247 machine learning models based on 1307 known DPP-IV inhibitors with optimized molecular properties and topological fingerprints as descriptors. The overall predictive accuracies of the optimized models were greater than 80%. An external test set, composed of 65 recently reported compounds, was employed to validate the optimized models. The results demonstrated that both NB and RP models have a good predictive ability based on different combinations of descriptors. Twenty "good" and twenty "bad" structural fragments for DPP-IV inhibitors can also be derived from these models for inspiring the new DPP-IV inhibitor scaffold design.

Comparison of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment: a randomised clinical trial.

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Kothny, Wolfgang; Lukashevich, Valentina; Foley, James E; Rendell, Marc S; Schweizer, Anja

2015-09-01

There are limited data comparing dipeptidyl peptidase-4 (DPP-4) inhibitors directly. We compared the safety and efficacy of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment (RI). This study was a parallel-arm, randomised, multicentre, double-blind, 24 week study conducted in 87 centres across Brazil and the USA. Patients with type 2 diabetes, either drug naive or treated with any glucose-lowering agents, who had inadequate glycaemic control (HbA1c 6.5-10.0% [48-86 mmol/mol]) and an estimated GFR vildagliptin 50 mg once daily or sitagliptin 25 mg once daily. These doses are recommended in this patient population and considered maximally effective. Participants, investigators and the sponsor were blinded to group assignment. Efficacy endpoints included change in HbA1c and fasting plasma glucose (FPG) at all visits and the primary safety endpoint was assessment of treatment-emergent adverse events. In total, 148 patients were randomised, 83 to vildagliptin and 65 to sitagliptin. All patients were analysed. After 24 weeks, the adjusted mean change in HbA1c was -0.54% (5.9 mmol/mol) from a baseline of 7.52% (59 mmol/mol) with vildagliptin and -0.56% (6.1 mmol/mol) from a baseline of 7.80% (62 mmol/mol) with sitagliptin (p = 0.874). FPG decreased by 0.47 ± 0.37 mmol/l with vildagliptin and increased by 0.16 ± 0.43 mmol/l with sitagliptin (p = 0.185). Both treatments were well tolerated with overall similar safety profiles. At their recommended doses for severe RI, vildagliptin (50 mg once daily) compared with sitagliptin (25 mg once daily) demonstrated similar efficacy and both drugs were well tolerated. This study provides further support for the use of DPP-4 inhibitors in patients with severe RI. ClinicalTrials.gov NCT00616811 (completed) This study was planned and conducted by Novartis.

Concordance with prescribing information dosage recommendations for dipeptidyl-peptidase-4 inhibitors among type 2 diabetes mellitus patients with moderate to severe chronic kidney disease.

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Huang, Huan; Shetty, Sharash; Bauer, Elise; Lang, Kathleen

2018-06-01

To estimate the proportion of patients with moderate to severe chronic kidney disease (CKD) whose initial dipeptidyl-peptidase-4 inhibitor (DPP4-i) dosage was concordant with prescribing information (label) recommendations in the United States. Adult patients with type 2 diabetes mellitus (T2DM) who initiated a DPP4-i (linagliptin, sitagliptin, saxagliptin) between 1 January 2011 and 30 June 2014 were identified using electronic medical records and administrative claims, with index date being the date of first observed DPP4-i treatment. Patients were required to have chronic kidney disease (CKD) stage 3b, 4 or 5 (estimated Glomerular Filtration Rate [eGFR] value <45 ml/min/1.73 m 2 ) during the 12 month pre-index period. Patients were classified as concordant or not concordant based on whether the first prescribed dose was consistent with label recommendations. Demographics, clinical characteristics, resource use and costs during pre-index were evaluated by DPP4-i concordance status. Of the 492 patients (323 sitagliptin, 57 saxagliptin, 112 linagliptin), 36.2% were prescribed doses that were not concordant with label recommendations (44.9% for sitagliptin, 57.9% for saxagliptin and 0% for linagliptin [which does not require dosage adjustment]). Concordant patients were slightly older (mean age 71 years vs. 68, p = .01) but had similar gender distribution (55% vs. 60% female, p = .31) compared to those who were not concordant. They had lower general health status (Charlson Comorbidity Score 2.6 vs. 2.2, p = .03), and had similar pre-index all-cause total costs ($25,245 vs. $21,972, p = .68) and lower pre-index T2DM-related costs ($1618 vs. $1922, p = .05). More than a third of DPP4-i patients with CKD stage 3b or higher were prescribed doses not concordant with DPP4-i label dosage recommendations.

Oral Administration of Sitagliptin Activates CREB and Is Neuroprotective in Murine Model of Brain Trauma

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DellaValle, Brian; Brix, Gitte S; Brock, Birgitte

2016-01-01

in the effects of oral treatment of a different class of GLP-1 based therapy, dipeptidyl peptidase IV (DPP-IV) inhibition on mice after TBI. DPP-IV inhibitors reduce the degradation of endogenous GLP-1 and extend circulation of this protective peptide in the bloodstream. This class has yet to be investigated...... for immunoblotting for assessment of selected biomarkers for pathology and protection. Results: Sitagliptin treatment reduced lesion size at day 2 post-injury by ~28% (p

Effects of sitagliptin on counterregulatory and incretin hormones during acute hypoglycaemia in patients with type 1 diabetes

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Schopman, J E; Hoekstra, J B L; Frier, B M

2015-01-01

AIMS: Within a few years after onset of type 1 diabetes (T1DM), the glucagon response to hypoglycaemia is severely diminished. Inhibitors of the enzyme dipeptidyl peptidase-4 (DPP-4), which under normal circumstances inactivate the incretin hormones (glucose-dependent insulinotropic polypeptide...... (GIP) and glucagon-like peptide-1 (GLP-1)), have been suggested to enhance glucagon secretion during hypoglycaemia in patients with type 2 diabetes. The aim of this study was to assess whether the DPP-4 inhibitor sitagliptin affects glucagon and other counterregulatory hormone responses...... to hypoglycaemia in patients with T1DM. METHODS: We conducted a single-centre, randomized, double-blind, placebo-controlled, three-period cross-over study. We studied 16 male patients with T1DM aged 18-52 years, with diabetes duration of 5-20 years and intact hypoglycaemia awareness. Participants received...

The effects of GLP-1 analogues, DPP-4 inhibitors and SGLT2 inhibitors on the renal system.

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Schernthaner, Guntram; Mogensen, Carl Erik; Schernthaner, Gerit-Holger

2014-09-01

Diabetic nephropathy (DN) affects an estimated 20%-40% of patients with type 2 diabetes mellitus (T2DM). Key modifiable risk factors for DN are albuminuria, anaemia, dyslipidaemia, hyperglycaemia and hypertension, together with lifestyle factors, such as smoking and obesity. Early detection and treatment of these risk factors can prevent DN or slow its progression, and may even induce remission in some patients. DN is generally preceded by albuminuria, which frequently remains elevated despite treatment in patients with T2DM. Optimal treatment and prevention of DN may require an early, intensive, multifactorial approach, tailored to simultaneously target all modifiable risk factors. Regular monitoring of renal function, including urinary albumin excretion, creatinine clearance and glomerular filtration rate, is critical for following any disease progression and making treatment adjustments. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels without additional risk of hypoglycaemia, and may also reduce albuminuria. Further investigation of the potential renal benefits of DPP-4 and SGLT2 inhibitors is underway. © The Author(s) 2014.

Effect of sitagliptin on hepatic histological activity and fibrosis of nonalcoholic steatohepatitis patients: a 1-year randomized control trial

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Alam S

2018-04-01

Full Text Available Shahinul Alam,1 Jhumur Ghosh,1 Golam Mustafa,1 Mohammad Kamal,2 Nooruddin Ahmad1 1Department of Hepatology, 2Department of Pathology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh Background/purpose: Dipeptidyl peptidase 4 (DPP-4 expression is directly associated with hepatic lipogenesis and liver injury in nonalcoholic steatohepatitis (NASH. This study has been designed to elucidate the histological improvement of NASH with the DPP-4 inhibitor sitagliptin. Materials and methods: In this open-label randomized control trial, paired liver biopsy was taken from 40 NASH patients. Sitagliptin 100 mg was given once daily to the SL group and no sitagliptin was given to the L group for 1 year. Patients from both groups were encouraged to exercise moderately and advised to avoid saturated fat, excessive sugar, soft drinks, fast food, and refined carbohydrates to reduce weight. Results: Steatosis improved in the SL group (from 2.3±0.6 to 1.2±0.8; P=0.000 and the L group (from 2.1±0.6 to 1.6±0.9; P=0.008, ballooning decreased from 1.8±0.6 to 1.3±06 (P=0.002 in the SL group, but not in the L group. Nonalcoholic fatty liver disease activity score (NAS attenuated in both groups: the SL group (from 5.8±0.9 to 3.9±1.4; P=0.000 and the L group (from 5.3±0.6 to 4.6±1.2; P=0.009. NAS improvement was much higher in the SL group (1.9±1.4 than in the L group (0.7±1.1 (P=0.006, with NAS improving by ≥2 in 13 patients from the SL group and five patients from the L group (P=0.01. Improvement was irrespective of diabetes. Regression analysis explored that sitagliptin had odds of 6.38 and weight reduction had odds of 4.51 for NAS reduction. Conclusion: Sitagliptin 100 mg once daily for 1 year ameliorates NAS by improving steatosis and ballooning, irrespective of diabetes. Sitagliptin has stronger efficacy than that of weight reduction. Keywords: fatty liver, NASH, sitagliptin, NAS, fibrosis, steatosis, ballooning, histological activity

Dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: safety, tolerability, and efficacy

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Mary Elizabeth Cox

2010-01-01

Full Text Available Mary Elizabeth Cox1, Jennifer Rowell1, Leonor Corsino1, Jennifer B Green1,21Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition. Duke University Medical Center, Durham, NC, USA; 2Department of Medicine, Division of Endocrinology, Durham Veterans Affairs Medical Center, Durham, NC, USAAbstract: Although glycemic control is an important and effective way to prevent and minimize the worsening of diabetes-related complications, type 2 diabetes is a progressive disease which often proves difficult to manage. Most affected patients will eventually require therapy with multiple medications in order to reach appropriate glycemic targets. The dipeptidyl peptidase-4 (DPP-4 inhibitors constitute a relatively new class of oral medications for the treatment of type 2 diabetes, which has become widely incorporated into clinical practice. This review summarizes the available data on the efficacy, safety, and tolerability of these medications.Keywords: type 2 diabetes, pharmacotherapy, DPP-4 inhibitor, sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin

The DPP4 Inhibitor Linagliptin Protects from Experimental Diabetic Retinopathy.

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Dietrich, Nadine; Kolibabka, Matthias; Busch, Stephanie; Bugert, Petra; Kaiser, Ulrike; Lin, Jihong; Fleming, Thomas; Morcos, Michael; Klein, Thomas; Schlotterer, Andrea; Hammes, Hans-Peter

2016-01-01

Dipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control in type 2 diabetes, however, their influence on the retinal neurovascular unit remains unclear. Vasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats (diabetes duration of 24 weeks), DPP4 activity (fluorometric assay), GLP-1 (ELISA), methylglyoxal (LC-MS/MS), acellular capillaries and pericytes (quantitative retinal morphometry), SDF-1a and heme oxygenase-1 (ELISA), HMGB-1, Iba1 and Thy1.1 (immunohistochemistry), nuclei in the ganglion cell layer, GFAP (western blot), and IL-1beta, Icam1, Cxcr4, catalase and beta-actin (quantitative RT-PCR) were determined. In C. elegans, neuronal function was determined using worm tracking software. Linagliptin decreased DPP4 activity by 77% and resulted in an 11.5-fold increase in active GLP-1. Blood glucose and HbA1c were reduced by 13% and 14% and retinal methylglyoxal by 66%. The increase in acellular capillaries was diminished by 70% and linagliptin prevented the loss of pericytes and retinal ganglion cells. The rise in Iba-1 positive microglia was reduced by 73% with linagliptin. In addition, the increase in retinal Il1b expression was decreased by 65%. As a functional correlate, impairment of motility (body bending frequency) was significantly prevented in C. elegans. Our data suggest that linagliptin has a protective effect on the microvasculature of the diabetic retina, most likely due to a combination of neuroprotective and antioxidative effects of linagliptin on the neurovascular unit.

The DPP4 Inhibitor Linagliptin Protects from Experimental Diabetic Retinopathy.

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Nadine Dietrich

Full Text Available Dipeptidyl peptidase 4 (DPP4 inhibitors improve glycemic control in type 2 diabetes, however, their influence on the retinal neurovascular unit remains unclear.Vasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats (diabetes duration of 24 weeks, DPP4 activity (fluorometric assay, GLP-1 (ELISA, methylglyoxal (LC-MS/MS, acellular capillaries and pericytes (quantitative retinal morphometry, SDF-1a and heme oxygenase-1 (ELISA, HMGB-1, Iba1 and Thy1.1 (immunohistochemistry, nuclei in the ganglion cell layer, GFAP (western blot, and IL-1beta, Icam1, Cxcr4, catalase and beta-actin (quantitative RT-PCR were determined. In C. elegans, neuronal function was determined using worm tracking software.Linagliptin decreased DPP4 activity by 77% and resulted in an 11.5-fold increase in active GLP-1. Blood glucose and HbA1c were reduced by 13% and 14% and retinal methylglyoxal by 66%. The increase in acellular capillaries was diminished by 70% and linagliptin prevented the loss of pericytes and retinal ganglion cells. The rise in Iba-1 positive microglia was reduced by 73% with linagliptin. In addition, the increase in retinal Il1b expression was decreased by 65%. As a functional correlate, impairment of motility (body bending frequency was significantly prevented in C. elegans.Our data suggest that linagliptin has a protective effect on the microvasculature of the diabetic retina, most likely due to a combination of neuroprotective and antioxidative effects of linagliptin on the neurovascular unit.

Pharmacovigilance Evaluation of the Association Between DPP-4 Inhibitors and Heart Failure: Stimulated Reporting and Moderation by Drug Interactions.

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Fadini, Gian Paolo; Sarangdhar, Mayur; Avogaro, Angelo

2018-04-01

In the SAVOR-TIMI trial, the risk of heart failure (HF) was increased by 27% in T2D patients randomized to the dipeptidyl peptidase-4 inhibitor (DPP4i) saxagliptin. Other studies have provided inconsistent results regarding this association. Herein, we performed a pharmacovigilance analysis of the rate of HF associated with DPP4is, focusing on stimulated reporting and moderation by drug-drug interactions. We mined the FDA adverse event (AE) reporting system (FAERS) from 2004q1 to 2017q3, including a total of 9906,642 AE reports. Rates (/1000 reports) of HF within the reports for DPP4is and reports for other antidiabetic drugs were calculated for the period up to 2013q3 (date of publication of the SAVOR-TIMI trial results) and from 2013q4 to 2017q3. Analyses were refined by filtering according to therapeutic area, concomitant diseases and drugs, and competing AEs. The rate of HF among the AE reports filed for DPP4is significantly increased after 2013q3, especially for saxagliptin. When compared to non-insulin non-glitazone antidiabetic drugs, the proportional reporting ratio (PRR) of HF for DPP4is was 0.62 (95% CI 0.56-0.68) up to 2013q3 and 2.12 (95% CI 1.96-2.28) from 2013q4 to 2017q3. This stimulated reporting was consistent in subanalyses based on the presence/absence of cardiac disorders and after controlling for competing AEs. The rate of HF among AE reports for DPP4is was modestly moderated by the concomitant use of metformin (- 15%) and strongly moderated by the concomitant use of SGLT2 inhibitors (- 63%), even after excluding competing AEs. Within the FAERS, the association between HF and DPP4is was biased by stimulated reporting, implying that the publication of the SAVOR-TIMI trial and the subsequent regulatory warnings primed clinicians to report HF events in DPP4i users as drug-related AEs. The rate of HF associated with DPP4is was moderated when they were used in combination with SGLT2 inhibitors.

Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Prevented Weight Regain in Obese Women with Polycystic Ovary Syndrome Previously Treated with Liraglutide: A Pilot Randomized Study.

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Ferjan, Simona; Janez, Andrej; Jensterle, Mojca

2017-12-01

Weight loss is often nonsustainable after liraglutide cessation. The present study is the first insight into the potential prevention of weight regain in obese subjects who have been withdrawn from liraglutide. We evaluated whether dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in adjunct to metformin prevents body weight regain more effectively than metformin alone in obese polycystic ovary syndrome (PCOS) previously treated with liraglutide. A 12-week prospective randomized open-label study was conducted with 24 obese women with PCOS who had been pretreated with liraglutide 3.0 mg due to antiobesity management (aged 34.3 ± 6.8 years, body mass index [BMI] 36.3 ± 5.2 kg/m 2 , mean ± standard deviation). They were randomized to combined treatment (COMBO) with sitagliptin 100 mg per day (QD) and metformin (MET) 1000 mg twice daily (BID) (n = 12) or MET 1000 mg BID (n = 12). Lifestyle intervention was promoted in both groups. The primary outcome was change in anthropometric measures of obesity. Women treated with MET regain 4.7 ± 2.7 kg (P = 0.002) compared with a 0.9 ± 2.5 kg in COMBO (P = 0.147). BMI increased for 1.7 ± 0.9 kg/m 2 in MET (P = 0.002) compared with 0.3 ± 0.8 kg/m 2 increase in COMBO (P = 0.136). MET group regain 4.5% ± 2.5% of body weight as opposed to 0.8% ± 2.6% in COMBO. The between-treatment differences were significant for weight change (P weight change (P weight regain in obese women with PCOS previously treated with liraglutide.

Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure

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van Gilst Wiek H

2011-09-01

Full Text Available Abstract Background Progressive remodeling after myocardial infarction (MI is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4, an enzyme which inhibits GLP-1 activity. We hypothesized that the DPP-4 inhibitor vildagliptin will increase levels of GLP-1 and may exert protective effects on cardiac function after MI. Methods Sprague-Dawley rats were either subjected to coronary ligation to induce MI and left ventricular (LV remodeling, or sham operation. Parts of the rats with an MI were pre-treated for 2 days with the DPP-4 inhibitor vildagliptin (MI-Vildagliptin immediate, MI-VI, 15 mg/kg/day. The remainder of the rats was, three weeks after coronary artery ligation, subjected to treatment with DPP-4 inhibitor vildagliptin (MI-Vildagliptin Late, MI-VL or control (MI. At 12 weeks, echocardiography and invasive hemodynamics were measured and molecular analysis and immunohistochemistry were performed. Results Vildagliptin inhibited the DPP-4 enzymatic activity by almost 70% and increased active GLP-1 levels by about 3-fold in plasma in both treated groups (p Conclusion Vildagliptin increases the active GLP-1 level via inhibition of DPP-4, but it has no substantial protective effects on cardiac function in this well established long-term post-MI cardiac remodeling model.

First Russian DPP-4 inhibitor Gosogliptin comparing to Vildagliptin in type 2 diabetes mellitus patients

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Karina Oganesovna Galstyan

2015-01-01

The results showed that gosogliptin is an effective hypoglycaemic agent from the group of DPP-4 inhibitors and can be recommended for use in patients with T2DM both as monotherapy and in combination with metformin.

Dgroup: DG00118 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available gliptin phosphate (USAN); Sitagliptin phosphate hydrate (JAN) ... Antidiabetic agent ... DG01601 ... DPP-4 inhibito...PP-4 inhibitor ATC code: A10BH01 DPP4 inhibitor, antidiabetics DPP4 [HSA:1803] [KO:K01278] Transporter: ABCB1 [HSA:5243], SLC22A8 [HSA:9376] ...

Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors

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Deacon, Carolyn F

2007-01-01

Incretins are gut peptides that potentiate nutrient-stimulated insulin secretion following meal ingestion. Activities of the dominant incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, include glucose-dependent stimulation of insulin secretion and, in preclin...... and liraglutide) and DPP-4 inhibitors that act to increase concentrations of endogenous intact incretins (e.g. sitagliptin and vildagliptin). Clinical trials of these incretin-based therapies have shown them to be effective in improving glycaemic control in patients with T2DM....

Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure

Science.gov (United States)

2011-01-01

Background Progressive remodeling after myocardial infarction (MI) is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), an enzyme which inhibits GLP-1 activity. We hypothesized that the DPP-4 inhibitor vildagliptin will increase levels of GLP-1 and may exert protective effects on cardiac function after MI. Methods Sprague-Dawley rats were either subjected to coronary ligation to induce MI and left ventricular (LV) remodeling, or sham operation. Parts of the rats with an MI were pre-treated for 2 days with the DPP-4 inhibitor vildagliptin (MI-Vildagliptin immediate, MI-VI, 15 mg/kg/day). The remainder of the rats was, three weeks after coronary artery ligation, subjected to treatment with DPP-4 inhibitor vildagliptin (MI-Vildagliptin Late, MI-VL) or control (MI). At 12 weeks, echocardiography and invasive hemodynamics were measured and molecular analysis and immunohistochemistry were performed. Results Vildagliptin inhibited the DPP-4 enzymatic activity by almost 70% and increased active GLP-1 levels by about 3-fold in plasma in both treated groups (p vildagliptin, either early or late, did not reverse cardiac remodeling. ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide) mRNA levels were significantly increased in all 3 MI groups, but no significant reductions were observed in both vildagliptin groups. Vildagliptin also did not change cardiomyocyte size or capillary density after MI. No effects were detected on glucose level and body weight in the post-MI remodeling model. Conclusion Vildagliptin increases the active GLP-1 level via inhibition of DPP-4, but it has no substantial protective effects on cardiac function in this well established long-term post-MI cardiac remodeling model. PMID:21955567

Hemoglobin glycation index as a useful predictor of therapeutic responses to dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes.

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Yu-Wei Chen

Full Text Available A high hemoglobin glycation index (HGI and glycated hemoglobin (HbA1c level are associated with greater inflammatory status, and dipeptidyl peptidase-4 (DPP-4 inhibitors can suppress inflammation. We aimed to evaluate the relationship between HGI and the therapeutic effect of DPP-4 inhibitors.This retrospective cohort study followed 468 patients with type 2 diabetes receiving DPP-4 inhibitor treatment for 1 year. Estimated HbA1c was calculated using a linear regression equation derived from another 2969 randomly extracted patients with type 2 diabetes based on fasting plasma glucose (FPG level. The subjects were divided into two groups based on HGI (HGI = observed HbA1c - estimated HbA1c. Mixed model repeated measures were used to compare the treatment efficacy after 1 year in patients with a low (HGI<0, n = 199 and high HGI (HGI≧0, n = 269.There were no significant group differences in mean changes of FPG after 1 year (-12.8 and -13.4 mg/dL in the low and high HGI groups, respectively. However, the patients with a high HGI had a significantly greater reduction in HbA1c from baseline compared to those with a low HGI (-1.9 versus -0.3% [-20.8 versus -3.3 mmol/mol]. Improvements in glycemic control were statistically significantly associated with the tested DPP-4 inhibitors in the high HGI group (-2.4, -1.4, -1.2 and -2.2% [-26.2, -15.3, -13.1 and -24.0 mmol/mol] for vildagliptin, linagliptin, saxagliptin and sitagliptin, respectively but not in the low HGI group.The HGI index derived from FPG and HbA1c may be able to identify who will have a better response to DPP-4 inhibitors.

Boro-norleucine as a P1 residue for the design of selective and potent DPP7 inhibitors.

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Shreder, Kevin R; Wong, Melissa S; Corral, Sergio; Yu, Zhizhou; Winn, David T; Wu, Min; Hu, Yi; Nomanbhoy, Tyzoon; Alemayehu, Senaiet; Fuller, Stacy R; Rosenblum, Jonathan S; Kozarich, John W

2005-10-01

Dipeptide-based inhibitors with C-substituted (alkyl or aminoalkyl) alpha-amino acids in the P2 position and boro-norleucine (boro-Nle) in the P1 position were synthesized. Relative to boro-proline, boro-Nle as a P1 residue was shown able to significantly dial out DPP4, FAP, DPP8, and DPP9 activity. Dab-boro-Nle (4g) proved to be the most selective and potent DPP7 inhibitor with a DPP7 IC50 value of 480 pM.

Experience with DPP-4 inhibitors in the management of patients with type 2 diabetes fasting during Ramadan

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Schweizer A

2013-12-01

Full Text Available Anja Schweizer,1 Serge Halimi,2,3 Sylvie Dejager4 1Novartis Pharma AG, Basel, Switzerland; 2Department of Diabetology, Endocrinology and Nutrition, University Hospital of Grenoble, France; 3Joseph Fourier University, Grenoble, France; 4Novartis Pharma SAS, Rueil-Malmaison, France Abstract: A large proportion of Muslim patients with type 2 diabetes mellitus (T2DM elect to fast during the holy month of Ramadan. For these patients hypo- and hyperglycemia constitute two major complications associated with the profound changes in food pattern during the Ramadan fast, and efficacious treatment options with a low risk of hypoglycemia are therefore needed to manage their T2DM as effectively and safely as possible. Dipeptidyl peptidase-4 (DPP-4 inhibitors modulate insulin and glucagon secretion in a glucose-dependent manner, and consequently a low propensity of hypoglycemia has consistently been reported across different patient populations with these agents. Promising data with DPP-4 inhibitors have now also started to emerge in patients with T2DM fasting during Ramadan. The objective of this review is to provide a comprehensive overview of the currently available evidence and potential role of DPP-4 inhibitors in the management of patients with T2DM fasting during Ramadan whose diabetes is treated with oral antidiabetic drugs, and to discuss the mechanistic basis for their beneficial effects in this setting. Keywords: dipeptidyl peptidase-4, incretin, type 2 diabetes mellitus, hypoglycemia

Increased Risk of Hospitalization for Heart Failure with Newly Prescribed Dipeptidyl Peptidase-4 Inhibitors and Pioglitazone Using the Korean Health Insurance Claims Database

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Sunghwan Suh

2015-06-01

Full Text Available BackgroundWe assessed the association of dipeptidyl peptidase 4 inhibitors (DPP4i with hospitalization for heart failure (HF using the Korean Health Insurance claims database.MethodsWe collected data on newly prescribed sitagliptin, vildagliptin, and pioglitazone between January 1, 2009 and December 31, 2012 (mean follow-up of 336.8 days to 935,519 patients with diabetes (518,614 males and 416,905 females aged 40 to 79 years (mean age of 59.4 years.ResultsDuring the study, 998 patients were hospitalized for primary HF (115.7 per 100,000 patient-years. The incidence rate of hospitalization for HF was 117.7 per 100,000 per patient-years among patients on pioglitazone, 105.7 for sitagliptin, and 135.8 for vildagliptin. The hospitalization rate for HF was greatest in the first 30 days after starting the medication, which corresponded to a significantly higher incidence at days 0 to 30 compared with days 31 to 360 for all three drugs. The hazard ratios were 1.85 (pioglitazone, 2.00 (sitagliptin, and 1.79 (vildagliptin. The incidence of hospitalization for HF did not differ between the drugs for any time period.ConclusionThis study showed an increase in hospitalization for HF in the initial 30 days of the DPP4i and pioglitazone compared with the subsequent follow-up period. However, the differences between the drugs were not significant.

Effects of vildagliptin versus sitagliptin, on cardiac function, heart rate variability and mitochondrial function in obese insulin-resistant rats

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Apaijai, Nattayaporn; Pintana, Hiranya; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2013-01-01

Background and Purpose Long-term high-fat diet (HFD) consumption has been shown to cause insulin resistance, which is characterized by hyperinsulinaemia with metabolic inflexibility. Insulin resistance is associated with cardiac sympathovagal imbalance, cardiac dysfunction and cardiac mitochondrial dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors, vildagliptin and sitagliptin, are oral anti-diabetic drugs often prescribed in patients with cardiovascular disease. Therefore, in this study, we sought to determine the effects of vildagliptin and sitagliptin in a murine model of insulin resistance. Experimental Approach Male Wistar rats weighing 180–200 g, were fed either a normal diet (20% energy from fat) or a HFD (59% energy from fat) for 12 weeks. These rats were then divided into three subgroups to receive vildagliptin (3 mg·kg−1·day−1), sitagliptin (30 mg·kg−1·day−1) or vehicle for another 21 days. Metabolic parameters, oxidative stress, heart rate variability (HRV), cardiac function and cardiac mitochondrial function were determined. Key Results Rats that received HFD developed insulin resistance characterized by increased body weight, plasma insulin, total cholesterol and oxidative stress levels along with a decreased high-density lipoprotein (HDL) level. Moreover, cardiac dysfunction, depressed HRV, cardiac mitochondrial dysfunction and cardiac mitochondrial morphology changes were observed in HFD rats. Both vildagliptin and sitagliptin decreased plasma insulin, total cholesterol and oxidative stress as well as increased HDL level. Furthermore, vildagliptin and sitagliptin attenuated cardiac dysfunction, prevented cardiac mitochondrial dysfunction and completely restored HRV. Conclusions and Implications Both vildagliptin and sitagliptin share similar efficacy in cardioprotection in obese insulin-resistant rats. PMID:23488656

Quantitative Evaluation of Compliance with Recommendation for Sulfonylurea Dose Co-Administered with DPP-4 Inhibitors in Japan

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Motonobu Sakaguchi

2012-09-01

Full Text Available After the launch of dipeptidyl peptidase-4 (DPP-4, a new oral hypoglycemic drug (OHD, in December 2009, severe hypoglycemia cases were reported in Japan. Although the definite cause was unknown, co-administration with sulfonylureas (SU was suspected as one of the potential risk factors. The Japan Association for Diabetes Education and Care (JADEC released a recommendation in April 2010 to lower the dose of three major SUs (glimepiride, glibenclamide, and gliclazide when adding a DPP-4 inhibitor. To evaluate the effectiveness of this risk minimization action along with labeling changes, dispensing records for 114,263 patients prescribed OHDs between December 2008 and December 2010 were identified in the Nihon-Chouzai pharmacy claims database. The adherence to the recommended dosing of SU co-prescribed with DPP-4 inhibitors increased from 46.3% before to 63.8% after the JADEC recommendation (p < 0.01 by time-series analysis, while no change was found in those for SU monotherapy and SU with other OHD co-prescriptions. The adherence was significantly worse for those receiving a glibenclamide prescription. The JADEC recommendation, along with labeling changes, appeared to have a favorable effect on the risk minimization action in Japan. In these instances, a pharmacy claims database can be a useful tool to evaluate risk minimization actions.

Weight neutrality with the DPP-4 inhibitor, vildagliptin: Mechanistic basis and clinical experience

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Foley, James E; Jordan, Jens

2010-01-01

Various factors may confound how diabetes medications affect a patient’s weight. Agents that induce hypoglycemia may promote weight gain through “defensive eating”. Conversely, patients whose hyperglycemia exceeds the renal glucose threshold may overeat to compensate for calories lost in urine and so gain weight when drug therapy ablates glycosuria. Some drugs, such as thiazolidinediones, may promote weight gain via increased lipid storage. Glucagon-like peptide-1 receptor agonists increase satiety, delay gastric emptying, and generally produce weight loss. Dipeptidyl peptidase (DPP)-4 inhibitors are generally weight-neutral, although modest weight loss has been observed with the DPP-4 inhibitor, vildagliptin, in patients with relatively low baseline glycemia. The weight neutrality of vildagliptin likely results in part from its intrinsically low risk for hypoglycemia. Recent studies point to additional potential mechanisms. One study found that drug-naïve patients randomized to vildagliptin exhibited significantly lower chylomicron lipid and apolipoprotein levels than placebo patients, suggesting that vildagliptin may inhibit intestinal fat extraction. Another trial found that patients randomized to vildagliptin versus placebo experienced paradoxical postprandial increases in markers of fatty acid mobilization and oxidation, in conjunction with increased sympathetic stimulation. Elaboration of these and other pathways could further clarify the origins of the favorable weight profile of vildagriptin. PMID:20730070

The Nonglycemic Actions of Dipeptidyl Peptidase-4 Inhibitors

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Na-Hyung Kim

2014-01-01

Full Text Available A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4, cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic peptide (GIP, enhance meal-stimulated insulin secretion from pancreatic β-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

Feedback suppression of meal-induced glucagon-like peptide-1 (GLP-1) secretion mediated through elevations in intact GLP-1 caused by dipeptidyl peptidase-4 inhibition

DEFF Research Database (Denmark)

Baranov, Oleg; Kahle, Melanie; Deacon, Carolyn F

2016-01-01

AIM: To compare directly the clinical effects of vildagliptin and sitagliptin in patients with type 2 diabetes, with a special emphasis on incretin hormones and L-cell feedback inhibition induced by dipeptidyl peptidase (DPP-4) inhibition. METHODS: A total of 24 patients (12 on a diet/exercise re......AIM: To compare directly the clinical effects of vildagliptin and sitagliptin in patients with type 2 diabetes, with a special emphasis on incretin hormones and L-cell feedback inhibition induced by dipeptidyl peptidase (DPP-4) inhibition. METHODS: A total of 24 patients (12 on a diet....../exercise regimen, 12 on metformin) were treated, in randomized order, for 7-9 days, with either vildagliptin (50 mg twice daily = 100 mg/d), sitagliptin (100 mg once daily in those on diet, 50 mg twice daily in those on metformin treatment = 100 mg/d) or placebo (twice daily). A mixed-meal test was performed....... RESULTS: Intact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide concentrations were doubled by both DPP-4 inhibitors. Meal-related total GLP-1 responses were reduced by vildagliptin and sitagliptin treatment alike in the majority of patients (vildagliptin: p = 0...

Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy – focus on alogliptin

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Capuano A

2013-09-01

Full Text Available Annalisa Capuano,1 Liberata Sportiello,1 Maria Ida Maiorino,2 Francesco Rossi,1 Dario Giugliano,2 Katherine Esposito3 1Department of Experimental Medicine, 2Department of Medical, Surgical, Neurological, Metabolic Sciences, and Geriatrics, 3Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy Abstract: Type 2 diabetes mellitus is a complex and progressive disease that is showing an apparently unstoppable increase worldwide. Although there is general agreement on the first-line use of metformin in most patients with type 2 diabetes, the ideal drug sequence after metformin failure is an area of increasing uncertainty. New treatment strategies target pancreatic islet dysfunction, in particular gut-derived incretin hormones. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4 slows degradation of endogenous glucagon-like peptide-1 (GLP-1 and thereby enhances and prolongs the action of the endogenous incretin hormones. The five available DPP-4 inhibitors, also known as 'gliptins' (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with type 2 diabetes. The main differences between the five gliptins on the market include: potency, target selectivity, oral bioavailability, long or short half-life, high or low binding to plasma proteins, metabolism, presence of active or inactive metabolites, excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug–drug interactions. On average, treatment with gliptins is expected to produce a mean glycated hemoglobin (HbA1c decrease of 0.5%–0.8%, with about 40% of diabetic subjects at target for the HbA1c goal <7%. There are very few studies comparing DPP-4 inhibitors. Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycemic control

The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice.

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Olivares, Marta; Neyrinck, Audrey M; Pötgens, Sarah A; Beaumont, Martin; Salazar, Nuria; Cani, Patrice D; Bindels, Laure B; Delzenne, Nathalie M

2018-05-25

Dipeptidyl peptidase 4 (DPP-4) inhibitors are agents designed to increase the half-life of incretins. Although they are administered orally, little is known about their effects on the gut microbiota and functions, despite the fact that some bacteria present in the gut microbiota exhibit DPP-4-like activity. Our objective was to study the impact of the DPP-4 inhibitor vildagliptin on gut functions and the intestinal ecosystem in a murine model of obesity induced by a Western diet (WD). Twenty seven male C57BL/6J mice were randomised to receive a control diet, a WD (45% kJ from fat and 17% kJ from sucrose) or a WD + vildagliptin (0.6 mg/ml in drinking water) for 8 weeks. Vildagliptin significantly reduced DPP-4 activity in the caecal content and faeces. Vildagliptin impacted on the composition of the gut microbiota and its metabolic activity. It mainly decreased Oscillibacter spp. (a direct effect independent of DPP-4 activity was shown on cultured O. valericigenes), increased Lactobacillus spp. and propionate, and reduced the ligands of Toll-like receptors 2 and 4. Vildagliptin protected against the reductions in crypt depth and ileal expression of antimicrobial peptides induced by the WD. In the liver, the expression of immune cell populations (Cd3g and Cd11c [also known as Itgax]) and cytokines was decreased in the WD + vildagliptin-fed mice compared with the WD-fed group. Ex vivo exposure of precision-cut liver slices to vildagliptin showed that this response was not related to a direct effect of the drug on the liver tissue. Our study is the first to consider the DPP-4-like activity of the gut microbiota as a target of DPP-4 inhibition. We propose that vildagliptin exerts beneficial effects at the intestinal level in association with modulation of gut microbiota, with consequences for hepatic immunity. If relevant in humans, this could open new therapeutic uses of DPP-4 inhibition to tackle gut dysfunctions in different pathophysiological contexts. The

The efficacy of therapy with DPP-4 inhibitors combined with insulin in patients with type 2 diabetes mellitus

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Alexander Sergeevich Ametov

2011-12-01

Full Text Available Recently, researchers started to pay increasingly more attention to the role of gastrointestinal hormones in regulation of insulin secretion, i.e. glucosehomeostasis. To-day, there are two approaches to the treatment of DM based on the use of GLP-1 effects. One takes advantage of DPP-4 inhibitorsthe other is combination of these agents with various drugs necessitated by heterogeneity of pathophysiological factors responsible for the developmentof DM2. The latter approach ensures multiple therapeutic effects on DM2 and its complications. Many on-going studies are focused on the use ofcombination of DPP-4 inhibitors and insulin. Vildagliptin (Galvus, Novartis Pharma, Switzerland is presently the sole DPP-4 inhibitor approvedfor application with insulin in Russia.Aim. To estimate the efficacy and safety of DPP-4 inhibitor combined with long-acting insulin in the treatment of DM2. Materials and methods. The study group included 18 patients (2 men and 16 women with DM2 treated with long-acting insulin (glargine, humulinNPH for at least 3 months at a mean daily dose of 31.96?4.95 U. The age of the patients averaged 59.9?2.84 years (46-75, DM2 duration8.9?1.18 years (2-15. Parameters of comprehensive glycemic control (FG, PPG, HbA1c, LMWH - low-molecular weight heparins CGM-continuousglucose monitoring were measured using a CGMS system in the beginning and end of the study. Functional activity of pancreatic betbeta-cells and insulinresistance (HOMA-IR, lipid metabolism, and anthropometric characteristics were estimated. Results. Combined therapy resulted in positive dynamics of carbohydrate metabolism within 12 weeks after onset. The functional activity of pancreaticbetbeta-cells significantly (by 157.96 U improved by the end of the study. Changes of HOMA-IR were insignificant. CGM showed that prescription ofvildagliptin to the patients who failed to reach compensation of DM2 with long-acting insulin alone significantly improved glycemic control

Effects of Inhibiting Dipeptidyl Peptidase-4 (DPP4 in Cows with Subclinical Ketosis.

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Kirsten Schulz

Full Text Available The inhibition of dipeptidyl peptidase-4 (DPP4 via specific inhibitors is known to result in improved glucose tolerance and insulin sensitivity and decreased accumulation of hepatic fat in type II diabetic human patients. The metabolic situation of dairy cows can easily be compared to the status of human diabetes and non-alcoholic fatty liver. For both, insulin sensitivity is reduced, while hepatic fat accumulation increases, characterized by high levels of non-esterified fatty acids (NEFA and ketone bodies.Therefore, in the present study, a DPP4 inhibitor was employed (BI 14332 for the first time in cows. In a first investigation BI 14332 treatment (intravenous injection at dosages of up to 3 mg/kg body weight was well tolerated in healthy lactating pluriparous cows (n = 6 with a significant inhibition of DPP4 in plasma and liver. Further testing included primi- and pluriparous lactating cows suffering from subclinical ketosis (β-hydroxybutyrate concentrations in serum > 1.2 mM; n = 12. The intension was to offer effects of DPP4 inhibition during comprehensive lipomobilisation and hepatosteatosis. The cows of subclinical ketosis were evenly allocated to either the treatment group (daily injections, 0.3 mg BI 14332/kg body weight, 7 days or the control group. Under condition of subclinical ketosis, the impact of DPP4 inhibition via BI 14332 was less, as in particular β-hydroxybutyrate and the hepatic lipid content remained unaffected, but NEFA and triglyceride concentrations were decreased after treatment. Owing to lower NEFA, the revised quantitative insulin sensitivity check index (surrogate marker for insulin sensitivity increased. Therefore, a positive influence on energy metabolism might be quite possible. Minor impacts on immune-modulating variables were limited to the lymphocyte CD4+/CD8+ ratio for which a trend to decreased values in treated versus control animals was noted. In sum, the DPP4 inhibition in cows did not affect glycaemic

Effects of Inhibiting Dipeptidyl Peptidase-4 (DPP4) in Cows with Subclinical Ketosis

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Schulz, Kirsten; Frahm, Jana; Kersten, Susanne; Meyer, Ulrich; Rehage, Jürgen; Piechotta, Marion; Meyerholz, Maria; Breves, Gerhard; Reiche, Dania; Sauerwein, Helga; Dänicke, Sven

2015-01-01

The inhibition of dipeptidyl peptidase-4 (DPP4) via specific inhibitors is known to result in improved glucose tolerance and insulin sensitivity and decreased accumulation of hepatic fat in type II diabetic human patients. The metabolic situation of dairy cows can easily be compared to the status of human diabetes and non-alcoholic fatty liver. For both, insulin sensitivity is reduced, while hepatic fat accumulation increases, characterized by high levels of non-esterified fatty acids (NEFA) and ketone bodies.Therefore, in the present study, a DPP4 inhibitor was employed (BI 14332) for the first time in cows. In a first investigation BI 14332 treatment (intravenous injection at dosages of up to 3 mg/kg body weight) was well tolerated in healthy lactating pluriparous cows (n = 6) with a significant inhibition of DPP4 in plasma and liver. Further testing included primi- and pluriparous lactating cows suffering from subclinical ketosis (β-hydroxybutyrate concentrations in serum > 1.2 mM; n = 12). The intension was to offer effects of DPP4 inhibition during comprehensive lipomobilisation and hepatosteatosis. The cows of subclinical ketosis were evenly allocated to either the treatment group (daily injections, 0.3 mg BI 14332/kg body weight, 7 days) or the control group. Under condition of subclinical ketosis, the impact of DPP4 inhibition via BI 14332 was less, as in particular β-hydroxybutyrate and the hepatic lipid content remained unaffected, but NEFA and triglyceride concentrations were decreased after treatment. Owing to lower NEFA, the revised quantitative insulin sensitivity check index (surrogate marker for insulin sensitivity) increased. Therefore, a positive influence on energy metabolism might be quite possible. Minor impacts on immune-modulating variables were limited to the lymphocyte CD4+/CD8+ ratio for which a trend to decreased values in treated versus control animals was noted. In sum, the DPP4 inhibition in cows did not affect glycaemic control like

Effects of Inhibiting Dipeptidyl Peptidase-4 (DPP4) in Cows with Subclinical Ketosis.

Science.gov (United States)

Schulz, Kirsten; Frahm, Jana; Kersten, Susanne; Meyer, Ulrich; Rehage, Jürgen; Piechotta, Marion; Meyerholz, Maria; Breves, Gerhard; Reiche, Dania; Sauerwein, Helga; Dänicke, Sven

2015-01-01

The inhibition of dipeptidyl peptidase-4 (DPP4) via specific inhibitors is known to result in improved glucose tolerance and insulin sensitivity and decreased accumulation of hepatic fat in type II diabetic human patients. The metabolic situation of dairy cows can easily be compared to the status of human diabetes and non-alcoholic fatty liver. For both, insulin sensitivity is reduced, while hepatic fat accumulation increases, characterized by high levels of non-esterified fatty acids (NEFA) and ketone bodies.Therefore, in the present study, a DPP4 inhibitor was employed (BI 14332) for the first time in cows. In a first investigation BI 14332 treatment (intravenous injection at dosages of up to 3 mg/kg body weight) was well tolerated in healthy lactating pluriparous cows (n = 6) with a significant inhibition of DPP4 in plasma and liver. Further testing included primi- and pluriparous lactating cows suffering from subclinical ketosis (β-hydroxybutyrate concentrations in serum > 1.2 mM; n = 12). The intension was to offer effects of DPP4 inhibition during comprehensive lipomobilisation and hepatosteatosis. The cows of subclinical ketosis were evenly allocated to either the treatment group (daily injections, 0.3 mg BI 14332/kg body weight, 7 days) or the control group. Under condition of subclinical ketosis, the impact of DPP4 inhibition via BI 14332 was less, as in particular β-hydroxybutyrate and the hepatic lipid content remained unaffected, but NEFA and triglyceride concentrations were decreased after treatment. Owing to lower NEFA, the revised quantitative insulin sensitivity check index (surrogate marker for insulin sensitivity) increased. Therefore, a positive influence on energy metabolism might be quite possible. Minor impacts on immune-modulating variables were limited to the lymphocyte CD4+/CD8+ ratio for which a trend to decreased values in treated versus control animals was noted. In sum, the DPP4 inhibition in cows did not affect glycaemic control like

Sitagliptin, An Anti-diabetic Drug, Suppresses Estrogen Deficiency-Induced OsteoporosisIn Vivo and Inhibits RANKL-Induced Osteoclast Formation and Bone Resorption In Vitro

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Chuandong Wang

2017-06-01

Full Text Available Postmenopausal osteoporosis is a disease characterized by excessive osteoclastic bone resorption. Some anti-diabetic drugs were demonstrated for anti-osteoclastic bone-loss effects. The present study investigated the skeletal effects of chronic administration of sitagliptin, a dipeptidyl peptidase IV (DPP IV inhibitor that is increasingly used for type 2 diabetes treatments, in an estrogen deficiency-induced osteoporosis and elucidated the associated mechanisms. This study indicated that sitagliptin effectively prevented ovariectomy-induced bone loss and reduced osteoclast numbers in vivo. It was also indicated that sitagliptin suppressed receptor activator of nuclear factor-κB ligand (RANKL-mediated osteoclast differentiation, bone resorption, and F-actin ring formation in a manner of dose-dependence. In addition, sitagliptin significantly reduced the expression of osteoclast-specific markers in mouse bone-marrow-derived macrophages, including calcitonin receptor (Calcr, dendrite cell-specific transmembrane protein (Dc-stamp, c-Fos, and nuclear factor of activated T-cells cytoplasmic 1 (Nfatc1. Further study indicated that sitagliptin inhibited osteoclastogenesis by suppressing AKT and ERK signaling pathways, scavenging ROS activity, and suppressing the Ca2+ oscillation that consequently affects the expression and/or activity of the osteoclast-specific transcription factors, c-Fos and NFATc1. Collectively, these findings suggest that sitagliptin possesses beneficial effects on bone and the suppression of osteoclast number implies that the effect is exerted directly on osteoclastogenesis.

Dapagliflozin Compared to DPP-4 inhibitors is Associated with Lower Risk of Cardiovascular Events and All-cause Mortality in Type 2 Diabetes Patients (CVD-REAL Nordic)

DEFF Research Database (Denmark)

Persson, F; Nyström, Thomas; Jørgensen, Marit Eika

2018-01-01

AIMS: To compare the sodium glucose-cotransporter-2-inhibitor (SGLT-2i) dapagliflozin versus dipeptidyl peptidase-4 inhibitors (DPP-4i) regarding risk associations of MACE (nonfatal myocardial infarction, nonfatal stroke or cardiovascular [CV] mortality), hospital events for heart failure (HHF), ...

Soluble DPP-4 up-regulates toll-like receptors and augments inflammatory reactions, which are ameliorated by vildagliptin or mannose-6-phosphate.

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Lee, Dong-Sung; Lee, Eun-Sol; Alam, Md Morshedul; Jang, Jun-Hyeog; Lee, Ho-Sub; Oh, Hyuncheol; Kim, Youn-Chul; Manzoor, Zahid; Koh, Young-Sang; Kang, Dae-Gil; Lee, Dae Ho

2016-02-01

Studies have shown that dipeptidyl peptidase-4 (DPP-4) inhibitors have anti-inflammatory effects. Soluble DPP-4 (sDPP-4) has been considered as an adipokine of which actions need to be further characterized. We investigated the pro-inflammatory actions of sDPP-4 and the anti-inflammatory effects of DPP-4 inhibition, using vildagliptin, as an enzymatic inhibitor, and mannose-6-phosphate (M6P) as a competitive binding inhibitor. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, vildagliptin suppressed the increased expression of inducible nitric oxide synthase (iNOS) and phosphorylated JNK (pJNK), activation of the NF-κB pathway, and the resultant NO and proinflammatory cytokine production. Although sDPP-4 alone did not affect the protein level of iNOS or pJNK or the production of NO in RAW264.7 cells, it did amplify iNOS expression, NO responses, and proinflammatory cytokine production in LPS-stimulated RAW264 cells. As a probable mechanism, we found that sDPP-4 caused dose-dependent increases in the expression levels of toll-like receptor 4 (TLR4) and TLR2 in RAW264.7 cells, and that these alterations were inhibited by vildagliptin, M6P, or bisindolylmaleimide II, a protein kinase C inhibitor. Either vildagliptin or M6P suppressed iNOS expression and NO and cytokine production in LPS+DPP-4-co-stimulated macrophages, while combined treatment of the co-stimulated cells with both agents had increased anti-inflammatory effects compared with either treatment alone. Intravenous injection of sDPP-4 to C57BL/6J mice increased the expression of both TLRs in kidney and white adipose tissues. Our findings suggest that sDPP-4 enhances inflammatory actions via TLR pathway, while DPP-4 inhibition with either an enzymatic or binding inhibitor has anti-inflammatory effects. Copyright © 2015 Elsevier Inc. All rights reserved.

The dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin functions as antioxidant on human endothelial cells exposed to chronic hyperglycemia and metabolic high-glucose memory.

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Pujadas, Gemma; De Nigris, Valeria; Prattichizzo, Francesco; La Sala, Lucia; Testa, Roberto; Ceriello, Antonio

2017-06-01

Dipeptidyl peptidase-4 inhibitors are widely used in type 2 diabetes. Endothelium plays a crucial role maintaining vascular integrity and function. Chronic exposure to high glucose drives to endothelial dysfunction generating oxidative stress. Teneligliptin is a novel dipeptidyl peptidase-4 inhibitor with antioxidant properties. This study is aimed to verify a potential protective action of teneligliptin in endothelial cells exposed to high glucose. Human umbilical vein endothelial cells were cultured under normal (5 mmol/L) or high glucose (25 mmol/L) during 21 days, or at high glucose during 14 days followed by 7 days at normal glucose, to reproduce the high-metabolic memory state. During this period, different concentrations of teneligliptin (0.1, 1.0 and 3.0 µmol/L) or sitagliptin (0.5 µmol/L) were added to cells. Ribonucleic acid and protein expression were assessed for antioxidant response, proliferation, apoptosis and endoplasmic reticulum stress markers. Teneligliptin promotes the antioxidant response in human umbilical vein endothelial cells, reducing ROS levels and inducing Nrf2-target genes messenger ribonucleic acid expression. Teneligliptin, but not sitagliptin, reduces the expression of the nicotine amide adenine dinucleotide phosphate oxidase regulatory subunit P22 -phox , however, both blunt the high glucose-induced increase of TXNIP. Teneligliptin improves proliferation rates in human umbilical vein endothelial cells exposed to high glucose, regulating the expression of cell-cycle inhibitors markers (P53, P21 and P27), and reducing proapoptotic genes (BAX and CASP3), while promotes BCL2 expression. Teneligliptin ameliorates high glucose-induced endoplasmic reticulum stress reducing the expression of several markers (BIP, PERK, ATF4, CHOP, IRE1a and ATF6). Teneligliptin has antioxidant properties, ameliorates oxidative stress and apoptotic phenotype and it can overcome the metabolic memory effect, induced by chronic exposure to high

DPP4 deficiency exerts protective effect against H2O2 induced oxidative stress in isolated cardiomyocytes.

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Hui-Chun Ku

Full Text Available Apart from the antihyperglycemic effects, DPP4 inhibitors and GLP-1 molecules are involved in the preservation of cardiac functions. We have demonstrated that DPP4-deficient rats possess resistance to endotoxemia and ischemia/reperfusion stress. However, whether the decrease of DPP4 activity simply augmented the GLP-1 signaling or that such decrease resulted in a change of cellular function remain unclear. Accordingly, we investigated the responses of H(2O(2-induced oxidative stress in adult wild-type and DPP4-deficient rats isolated cardiomyocytes. The coadministration of GLP-1 or DPP4 inhibitor was also performed to define the mechanisms. Cell viability, ROS concentration, catalase activity, glucose uptake, prosurvival, proapoptotic signaling, and contractile function were examined after cells exposed to H(2O(2. DPP4-deficient cardiomyocytes were found to be resistant to H(2O(2-induced cell death via activating AKT signaling, enhancing glucose uptake, preserving catalase activity, diminishing ROS level and proapoptotic signaling. GLP-1 concentration-dependently improved cell viability in wild-type cardiomyocyte against ROS stress, and the ceiling response concentration (200 nM was chosen for studies. GLP-1 was shown to decrease H(2O(2-induced cell death by its receptor-dependent AKT pathway in wild-type cardiomyocytes, but failed to cause further activation of AKT in DPP4-deficient cardiomyocytes. Acute treatment of DPP4 inhibitor only augmented the protective effect of low dose GLP-1, but failed to alter fuel utilization or ameliorate cell viability in wild-type cardiomyocytes after H(2O(2 exposure. The improvement of cell viability after H(2O(2 exposure was correlated with the alleviation of cellular contractile dysfunction in both DPP4-deficient and GLP-1 treated wild-type cardiomyocytes. These findings demonstrated that GLP-1 receptor-dependent pathway is important and exert protective effect in wild-type cardiomyocyte. Long term loss of

Network meta-analysis of liraglutide versus dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes in Japanese patients.

Science.gov (United States)

Ayers, Dieter; Kanters, Steve; Goldgrub, Rachel; Hughes, Monica; Kato, Ryo; Kragh, Nana

2017-09-01

To determine the comparative efficacy and safety of liraglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors as antidiabetics for Japanese patients with uncontrolled type 2 diabetes (T2DM). We searched for randomized controlled trials (RCTs) evaluating outcomes among Japanese adults with uncontrolled T2DM and including liraglutide or DPP-4 inhibitors up to August 2016. We extracted data on trial and patient characteristics, and the following outcomes: HbA1c, weight, patients meeting HbA1c <7%, patients experiencing hypoglycemic events, microalbuminuria, estimated glomerular filtration rate (eGFR) and creatinine. We synthesized data using network meta-analyses (NMA) using a Bayesian framework. Continuous outcomes were modeled using normal likelihoods and an identity link, while dichotomous outcomes were modeled using a binomial likelihood and a logit link. The systematic literature review yielded 39 publications pertaining to 38 trials. A total of 27 trials (5032 patients) reported change in HbA1c at 12 weeks and at 24 weeks 9 trials (2091 patients). All treatments showed statistically significant reductions in HbA1c relative to placebo at 12 and 24 weeks. Liraglutide 0.9 mg was statistically superior to all DPP-4 interventions (vildagliptin, sitagliptin, linagliptin, alogliptin, teneligliptin, trelagliptin and omarigliptin) at 12 weeks and 24 weeks among those reporting. Treatments were not statistically differentiable with respect to weight change and risk of hypoglycemia. Finally, no comparisons of eGFR and microalbuminuria were conducted, as this data was reported in too few trials to conduct analyses. Some important outcomes were limited by poor reporting (eGFR and microalbuminuria) or low event rates (hypoglycemia). The follow-up time was relatively short. Clinically, the 24 week time point is more important as it demonstrates more sustained results. Our research suggests that liraglutide 0.9 mg offers a more efficacious treatment option for T2DM than the

Synthesis and structure-activity relationship of N-alkyl Gly-boro-Pro inhibitors of DPP4, FAP, and DPP7.

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Hu, Yi; Ma, Lifu; Wu, Min; Wong, Melissa S; Li, Bei; Corral, Sergio; Yu, Zhizhou; Nomanbhoy, Tyzoon; Alemayehu, Senaiet; Fuller, Stacy R; Rosenblum, Jonathan S; Rozenkrants, Natasha; Minimo, Lauro C; Ripka, William C; Szardenings, Anna K; Kozarich, John W; Shreder, Kevin R

2005-10-01

The structure-activity relationship of various N-alkyl Gly-boro-Pro derivatives against three dipeptidyl peptidases (DPPs) was studied. In a series of N-cycloalkyl analogs, DPP4 and fibroblast activation protein-alpha (FAP) optimally preferred N-cycloheptyl whereas DPP7 tolerated even larger cycloalkyl rings. Gly alpha-carbon derivatization of N-cyclohexyl or N-(2-adamantyl) Gly-boro-Pro resulted in a significant decrease in potency against all the three DPPs.

The effects of dipeptidyl peptidase-4 inhibitors on bone fracture among patients with type 2 diabetes mellitus: A network meta-analysis of randomized controlled trials.

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Jun Yang

Full Text Available The association between dipeptidyl peptidase-4 inhibitors (DPP-4is, a class of anti-diabetes, and bone fracture in patients with type 2 diabetes mellitus (T2DM is unknown. This meta-analysis aimed to systematically evaluate the effects of DPP-4is on bone fracture in T2DM patients.We searched the Cochrane Library, Embase, Medline and ClinicalTrials.gov from inception through April 28th, 2016 to identify randomized controlled trials (RCTs that compared DPP-4is with placebo or other anti-diabetes in T2DM patients. RCTs lasting more than 12 weeks and having data on bone fracture were included. We conducted random-effects meta-analysis to estimate odds ratios (ORs and their 95% confidence intervals (CIs, and network meta-analysis (NMA to supplement direct comparisons. Predictive interval plot and node-splitting method were used to evaluate the heterogeneity and inconsistency for NMA, while the funnel plot was applied to explore publication bias. Besides, study quality was assessed according to Cochrane risk of bias tool.We identified 75 RCTs with a total of 70,207 patients and 11 treatments: interventions included 5 DPP-4is (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin, while controls included placebo and 5 other anti-diabetes (sulfonylureas, glucagon-like peptide-1 receptor agonists, metformin, thiazolidinediones, sodium-glucose co-transporter 2 inhibitors. In the NMA, the risk of fracture for alogliptin tended to decrease when versus placebo (OR, 0.51; 95% CI, 0.29 to 0.88. Besides, aloglitpin had a lower risk compared with linagliptin (OR, 0.45; 95% CI, 0.20 to 0.99 and saxagliption (OR, 0.46; 95%CI, 0.25 to 0.84; the risk was higher with saxagliptin when versus sitagliptin (OR, 1.90; 95% CI, 1.04 to 3.47 and sulfonylureas (OR, 1.98; 95% CI, 1.06 to 3.71. In the direct pairwise meta-analysis, alogliptin was associated with a non-significant tendency to reduction of bone fracture compared with placebo (OR, 0.54; 95% CI, 0.29 to 1

Dipeptidyl peptidase-4 inhibition and narrow-band ultraviolet-B light in psoriasis (DINUP): study protocol for a randomised controlled trial.

LENUS (Irish Health Repository)

Lynch, Maeve

2016-01-15

Moderate to severe psoriasis is a systemic inflammatory disease associated with insulin resistance, obesity and type 2 diabetes (T2DM). Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that improves glycaemia and has a marketing authorisation for the treatment of T2DM. Non-immunosuppressive therapies that are effective for psoriasis and its associated comorbidities would be a significant advance in the treatment of this chronic disease.

Comparison of vildagliptin twice daily vs. sitagliptin once daily using continuous glucose monitoring (CGM: Crossover pilot study (J-VICTORIA study

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Sakamoto Masaya

2012-08-01

Full Text Available Abstract Background No previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood glucose levels using continuous glucose monitoring (CGM and cardiovascular parameters. Methods Twenty patients with type 2 diabetes mellitus were randomly allocated to groups who received vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM was used to determine: 1 mean (± standard deviation 24-hour blood glucose level, 2 mean amplitude of glycemic excursions (MAGE, 3 fasting blood glucose level, 4 highest postprandial blood glucose level and time, 5 increase in blood glucose level after each meal, 6 area under the curve (AUC for blood glucose level ≥180 mg/dL within 3 hours after each meal, and 7 area over the curve (AOC for daily blood glucose level Results The mean 24-hour blood glucose level was significantly lower in patients taking vildagliptin than sitagliptin (142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012. In patients taking vildagliptin, MAGE was significantly lower (110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040, the highest blood glucose level after supper was significantly lower (206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015, the AUC (≥180 mg/dL within 3 h was significantly lower after breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025, and urinary CPR level was significantly higher (97.0 ± 41.6 vs. 85.2 ± 39.9 μg/day; p = 0.008 than in patients taking sitagliptin. There were no significant differences in plasma HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin. Conclusions CGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin than those taking sitagliptin. There

Comparison of vildagliptin twice daily vs. sitagliptin once daily using continuous glucose monitoring (CGM): Crossover pilot study (J-VICTORIA study)

Science.gov (United States)

2012-01-01

Background No previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood glucose levels using continuous glucose monitoring (CGM) and cardiovascular parameters. Methods Twenty patients with type 2 diabetes mellitus were randomly allocated to groups who received vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM was used to determine: 1) mean (± standard deviation) 24-hour blood glucose level, 2) mean amplitude of glycemic excursions (MAGE), 3) fasting blood glucose level, 4) highest postprandial blood glucose level and time, 5) increase in blood glucose level after each meal, 6) area under the curve (AUC) for blood glucose level ≥180 mg/dL within 3 hours after each meal, and 7) area over the curve (AOC) for daily blood glucose level vildagliptin than sitagliptin (142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012). In patients taking vildagliptin, MAGE was significantly lower (110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040), the highest blood glucose level after supper was significantly lower (206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015), the AUC (≥180 mg/dL) within 3 h was significantly lower after breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025), and urinary CPR level was significantly higher (97.0 ± 41.6 vs. 85.2 ± 39.9 μg/day; p = 0.008) than in patients taking sitagliptin. There were no significant differences in plasma HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin. Conclusions CGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin than those taking sitagliptin. There were no significant differences in BNP and PAI-1 levels between patients taking vildagliptin and

[Research progress of dipeptidyl peptidase 4 inhibitors on healing of chronic diabetic foot ulcers].

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Gao, Yunyi; Liang, Yujie; Ran, Xingwu

2018-05-01

To review the effect of dipeptidyl peptidase 4 (DPP-4) inhibitors on the wound healing and its mechanisms in chronic diabetic foot ulcers. The latest literature concerning DPP-4 inhibitors for chronic diabetic foot ulcers was extensively reviewed, as well as the potential benefit and mechanism of DPP-4 inhibitors on wound healing of diabetic foot ulcers was analyzed thoroughly. DPP-4 inhibitors can accelerated the ulcer healing. The mechanisms probably include inhibiting the expression of the matrix metalloproteinase (MMP) and restoring the balance of the wound MMP and the tissue inhibitors of MMP; promoting recruitment of endothelial progenitor cells and augmenting angiogenesis; optimizing extracellular matrix construction and the immune response to persistent hypoxia in chronic diabetes wounds, and so on. At present, clinical researches show that DPP-4 inhibitors may be considered as an adjuvant treatment for chronic diabetic foot ulcers. DPP-4 inhibitors show promise in the local wound healing of chronic diabetic foot ulcers. However, more strictly designed, adequately powered, long-term follow-up, and high-quality randomized control trials are needed to further verify their efficacy and safety for chronic diabetic foot ulcers.

Changes in Adenosine Deaminase Activity in Patients with Type 2 Diabetes Mellitus and Effect of DPP-4 Inhibitor Treatment on ADA Activity

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Lee, Jae-Geun; Kang, Dong Gu; Yu, Jung Re; Kim, Youngree; Kim, Jinsoek; Koh, Gwanpyo

2011-01-01

Background Dipeptidyl peptidase 4 (DPP-4, also known as CD26) binds with adenosine deaminase (ADA) to activate T lymphocytes. Here, we investigated whether ADA activity is specifically affected by treatment with DPP-4 inhibitor (DPP4I) compared with other anti-diabetic agents. Methods Fasting ADA activity, in addition to various metabolic and biochemical parameters, were measured in 262 type 2 diabetes mellitus (T2DM) patients taking various anti-diabetic agents and in 46 non-diabetic control subjects. Results ADA activity was increased in T2DM patients compared with that in non-diabetic control subjects (mean±standard error, 23.1±0.6 U/L vs. 18.6±0.8 U/L; PADA activity was correlated with fasting plasma glucose (r=0.258, P9%) showed significantly increased ADA activity (21.1±0.8 U/L vs. 25.4±1.6 U/L; PADA activity in T2DM patients did not differ from those of other oral anti-diabetic agents or insulin. T2DM patients on metformin monotherapy showed a lower ADA activity (20.9±1.0 U/L vs. 28.1±2.8 U/L; PADA activity is increased in T2DM patients compared to that in non-diabetic patients, is positively correlated with blood glucose level, and that DPP4I has no additional specific effect on ADA activity, except for a glycemic control- or HbA1c-dependent effect. PMID:21738897

Changes in Adenosine Deaminase Activity in Patients with Type 2 Diabetes Mellitus and Effect of DPP-4 Inhibitor Treatment on ADA Activity.

Science.gov (United States)

Lee, Jae-Geun; Kang, Dong Gu; Yu, Jung Re; Kim, Youngree; Kim, Jinsoek; Koh, Gwanpyo; Lee, Daeho

2011-04-01

Dipeptidyl peptidase 4 (DPP-4, also known as CD26) binds with adenosine deaminase (ADA) to activate T lymphocytes. Here, we investigated whether ADA activity is specifically affected by treatment with DPP-4 inhibitor (DPP4I) compared with other anti-diabetic agents. Fasting ADA activity, in addition to various metabolic and biochemical parameters, were measured in 262 type 2 diabetes mellitus (T2DM) patients taking various anti-diabetic agents and in 46 non-diabetic control subjects. ADA activity was increased in T2DM patients compared with that in non-diabetic control subjects (mean±standard error, 23.1±0.6 U/L vs. 18.6±0.8 U/L; PADA activity was correlated with fasting plasma glucose (r=0.258, P9%) showed significantly increased ADA activity (21.1±0.8 U/L vs. 25.4±1.6 U/L; PADA activity in T2DM patients did not differ from those of other oral anti-diabetic agents or insulin. T2DM patients on metformin monotherapy showed a lower ADA activity (20.9±1.0 U/L vs. 28.1±2.8 U/L; PADA activity is increased in T2DM patients compared to that in non-diabetic patients, is positively correlated with blood glucose level, and that DPP4I has no additional specific effect on ADA activity, except for a glycemic control- or HbA1c-dependent effect.

Factors Associated with Treatment Response to Antidiabetic Agents ...

African Journals Online (AJOL)

(sitagliptin and metformin) were the only thiazolidinedione, α-glucosidase inhibitor, DPP-4 inhibitor, and combination agents used, respectively, among the study subjects. Use of Concurrent Medications. Statins were the most commonly prescribed concurrent medication, with 70.0% of subjects receiving statins. This was ...

Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes

DEFF Research Database (Denmark)

Deacon, Carolyn F; Holst, Jens Juul

2013-01-01

INTRODUCTION: Dipeptidyl peptidase (DPP)-4 inhibitors belong to one class of drugs that have been approved for treatment of type 2 diabetes (T2D) based on the glucose-lowering actions of the gastrointestinal hormone glucagon-like peptide (GLP)-1. Several different compounds are now available...... of the different DPP-4 inhibitors, all are small orally active compounds with broadly similar HbA1c-lowering efficacy. They improve glycaemic control in T2D, without increasing the risk of hypoglycaemia or causing weight gain. They can be used as monotherapy or in combination with other anti-diabetic therapies......, and although their mechanism of action (inhibition of the catalytic activity of DPP-4) is the same, there are fundamental differences between them. AREAS COVERED: The authors discuss the differences between different DPP-4 inhibitors and review their therapeutic efficacy and key safety data. The literature...

The Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Protects against Dyslipidemia-Related Kidney Injury in Apolipoprotein E Knockout Mice

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Jingjing Li

2014-06-01

Full Text Available The goal of this study was to investigate the possible protective effects of sitagliptin against dyslipidemia-related kidney injury in apolipoprotein E knockout (apoE−/− mice. Eight-week-old male apoE−/− mice were randomized to receive either a high fat diet (HFD, apoE−/− group or HFD mixed with sitagliptin (sita + apoE−/− group for 16 weeks. A control group of age- and gender-matched C57BL/6J mice were fed a HFD. The apoE−/− group exhibited increases in body weight and serum lipid levels in addition to high-density lipoprotein, and increases in 24-h urinary 8-hydroxy-2-deoxyguanosine and albuminuria excretion. Decreased insulin sensitivity was also observed in the apoE−/− group. These mice additionally contained enlargements of the glomerular mesangial matrix area, lipid deposition area, and renal interstitium collagen area. The apoE−/− group also demonstrated down-regulation of phosphorylated AMP-activated protein kinase (AMPK, increases in renal mRNA expression of transforming growth factor-beta 1 (TGF-β1 and fibronectin (FN, and increased protein expression of Akt, TGF-β1, FN and p38/ERK mitogen-activated protein kinase (MAPK. Sitagliptin treatment successfully ameliorated all the deleterious effects of dyslipidemia tested. To our knowledge, this is the first time that sitagliptin has been shown to reverse the renal dysfunction and structural damage induced by dyslipidemia in apoE−/− mice. Our results suggest that the renoprotective mechanism of sitagliptin may be due to a reduction in Akt levels, a restoration of AMPK activity, and inhibition of TGF-β1, FN, and p38/ERK MAPK signaling pathways.

SVMDLF: A novel R-based Web application for prediction of dipeptidyl peptidase 4 inhibitors.

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Chandra, Sharat; Pandey, Jyotsana; Tamrakar, Akhilesh K; Siddiqi, Mohammad Imran

2017-12-01

Dipeptidyl peptidase 4 (DPP4) is a well-known target for the antidiabetic drugs. However, currently available DPP4 inhibitor screening assays are costly and labor-intensive. It is important to create a robust in silico method to predict the activity of DPP4 inhibitor for the new lead finding. Here, we introduce an R-based Web application SVMDLF (SVM-based DPP4 Lead Finder) to predict the inhibitor of DPP4, based on support vector machine (SVM) model, predictions of which are confirmed by in vitro biological evaluation. The best model generated by MACCS structure fingerprint gave the Matthews correlation coefficient of 0.87 for the test set and 0.883 for the external test set. We screened Maybridge database consisting approximately 53,000 compounds. For further bioactivity assay, six compounds were shortlisted, and of six hits, three compounds showed significant DPP4 inhibitory activities with IC 50 values ranging from 8.01 to 10.73 μm. This application is an OpenCPU server app which is a novel single-page R-based Web application for the DPP4 inhibitor prediction. The SVMDLF is freely available and open to all users at http://svmdlf.net/ocpu/library/dlfsvm/www/ and http://www.cdri.res.in/svmdlf/. © 2017 John Wiley & Sons A/S.

Wound healing effects of dipeptidyl peptidase-4 inhibitors: An emerging concept in management of diabetic foot ulcer-A review.

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Saboo, Apoorva; Rathnayake, Ayeshmanthe; Vangaveti, Venkat N; Malabu, Usman H

2016-01-01

Dipeptidyl peptidase-4 (DPP-4) inhibitors have a well-known effect on glycaemic control in patients with diabetes but little is known on their wound healing role in this group of population. This paper reviews the effects of DPP-4 inhibitors on wound healing of diabetic foot ulcers. Published data on effects and mechanism of DDP-4 inhibitors on wound healing were derived from Medline, PubMed and Google Scholar search of English language literature from 1994 to 2014 using the key words such as "DPP-4 inhibitors", "endothelial healing" "diabetes" and "chronic ulcers". DPP-4 inhibitors show a potential benefit in processes of wound healing in diabetic chronic foot ulcers. The enzyme inhibitors promote recruitment of endothelial progenitor cells and allow the final scaffolding of wounds. Furthermore DPP-4 inhibitors augment angiogenesis and have widespread effects on optimising the immune response to persistent hypoxia in chronic diabetes wounds. DPP-4 inhibitors show promise in the local wound healing of diabetic foot ulcers in addition to its already established glycaemic control. In the light of high rate of amputations due to non-healing ulcers with profound psychological and economical liability, more investigations on the usefulness of DPP-4 inhibitors in the high risk diabetes population are needed. Copyright © 2015 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Managing diabetic patients with moderate or severe renal impairment using DPP-4 inhibitors: focus on vildagliptin

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Russo E

2013-04-01

Full Text Available Eleonora Russo, Giuseppe Penno, Stefano Del Prato Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Disease, Azienda Ospedaliero Universitaria di Pisa, and University of Pisa, Pisa, Italy Background: Dipeptidyl peptidase-4 (DPP-4 inhibitors are novel classified oral anti-diabetic drugs for the treatment of type 2 diabetes mellitus (T2DM that provide important reduction in glycated hemoglobin, with a low risk for hypoglycemia and no weight gain. In T2DM patients with reduced renal function, adequate glycemic control is essential to delay the progress of kidney dysfunction, but they are at a greater risk of experiencing hypoglycemic events, especially with longer-acting sulfonylureas and meglitinides. Objective: To evaluate vildagliptin as an option to achieve glycemic control in T2DM patients with moderate or severe chronic kidney disease (CKD. Methods: A comprehensive search in the literature was performed using the term "vildagliptin." Original articles and reviews exploring our topic were carefully selected. Results: Vildagliptin provides effective glycemic control in patients with T2DM and CKD. Dose reductions are required for vildagliptin and other DPP-4 inhibitors, except linagliptin, in T2DM patients with moderate-to-severe CKD. Dose of vildagliptin had to be reduced by half (to 50 mg/day both for moderate (estimated glomerular filtration rate [eGFR] ≥30 to ≤50 mL/min and severe CKD (eGFR < 30 mL/min. Available results support a favorable efficacy, safety, and tolerability profile for vildagliptin in T2DM with moderate or severe renal failure. Preliminary data may suggest additional benefits beyond improvement of glycemic control. Conclusion: Vildagliptin can be safely used in T2DM patients with varying degrees of renal impairment. Dose adjustments for renal impairment are required. Potential long-term renal benefit of vildagliptin needs to be further explored. Keywords: type 2 diabetes mellitus, renal

Type 2 diabetes impairs odour detection, olfactory memory and olfactory neuroplasticity; effects partly reversed by the DPP-4 inhibitor Linagliptin.

Science.gov (United States)

Lietzau, Grazyna; Davidsson, William; Östenson, Claes-Göran; Chiazza, Fausto; Nathanson, David; Pintana, Hiranya; Skogsberg, Josefin; Klein, Thomas; Nyström, Thomas; Darsalia, Vladimer; Patrone, Cesare

2018-02-23

Recent data suggest that olfactory deficits could represent an early marker and a pathogenic mechanism at the basis of cognitive decline in type 2 diabetes (T2D). However, research is needed to further characterize olfactory deficits in diabetes, their relation to cognitive decline and underlying mechanisms.The aim of this study was to determine whether T2D impairs odour detection, olfactory memory as well as neuroplasticity in two major brain areas responsible for olfaction and odour coding: the main olfactory bulb (MOB) and the piriform cortex (PC), respectively. Dipeptidyl peptidase-4 inhibitors (DPP-4i) are clinically used T2D drugs exerting also beneficial effects in the brain. Therefore, we aimed to determine whether DPP-4i could reverse the potentially detrimental effects of T2D on the olfactory system.Non-diabetic Wistar and T2D Goto-Kakizaki rats, untreated or treated for 16 weeks with the DPP-4i linagliptin, were employed. Odour detection and olfactory memory were assessed by using the block, the habituation-dishabituation and the buried pellet tests. We assessed neuroplasticity in the MOB by quantifying adult neurogenesis and GABAergic inhibitory interneurons positive for calbindin, parvalbumin and carletinin. In the PC, neuroplasticity was assessed by quantifying the same populations of interneurons and a newly identified form of olfactory neuroplasticity mediated by post-mitotic doublecortin (DCX) + immature neurons.We show that T2D dramatically reduced odour detection and olfactory memory. Moreover, T2D decreased neurogenesis in the MOB, impaired the differentiation of DCX+ immature neurons in the PC and altered GABAergic interneurons protein expression in both olfactory areas. DPP-4i did not improve odour detection and olfactory memory. However, it normalized T2D-induced effects on neuroplasticity.The results provide new knowledge on the detrimental effects of T2D on the olfactory system. This knowledge could constitute essentials for

Discovery of DPP IV inhibitors by pharmacophore modeling and QSAR analysis followed by in silico screening.

Science.gov (United States)

Al-Masri, Ihab M; Mohammad, Mohammad K; Taha, Mutasem O

2008-11-01

Dipeptidyl peptidase IV (DPP IV) deactivates the natural hypoglycemic incretin hormones. Inhibition of this enzyme should restore glucose homeostasis in diabetic patients making it an attractive target for the development of new antidiabetic drugs. With this in mind, the pharmacophoric space of DPP IV was explored using a set of 358 known inhibitors. Thereafter, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and physicochemical descriptors that yield selfconsistent and predictive quantitative structure-activity relationships (QSAR) (r(2) (287)=0.74, F-statistic=44.5, r(2) (BS)=0.74, r(2) (LOO)=0.69, r(2) (PRESS) against 71 external testing inhibitors=0.51). Two orthogonal pharmacophores (of cross-correlation r(2)=0.23) emerged in the QSAR equation suggesting the existence of at least two distinct binding modes accessible to ligands within the DPP IV binding pocket. Docking experiments supported the binding modes suggested by QSAR/pharmacophore analyses. The validity of the QSAR equation and the associated pharmacophore models were established by the identification of new low-micromolar anti-DPP IV leads retrieved by in silico screening. One of our interesting potent anti-DPP IV hits is the fluoroquinolone gemifloxacin (IC(50)=1.12 muM). The fact that gemifloxacin was recently reported to potently inhibit the prodiabetic target glycogen synthase kinase 3beta (GSK-3beta) suggests that gemifloxacin is an excellent lead for the development of novel dual antidiabetic inhibitors against DPP IV and GSK-3beta.

Predictive Factors for Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus

Directory of Open Access Journals (Sweden)

Shusuke Yagi

2015-08-01

Full Text Available BackgroundPredictive factors for the efficacy of dipeptidyl peptidase-4 (DPP-4 inhibitors for lowering glycosylated hemoglobin (HbA1c remain unclear in patients with type 2 diabetes mellitus. The aim of this study is therefore to clarify predictive factors of the efficacy of DPP-4 inhibitors for lowering HbA1c after 12 months of treatment.MethodsA total of 191 consecutive type 2 diabetic patients (male sex 55%, mean age, 68.3±35.8 years, who had been treated with DPP-4 inhibitors for 12 months, were enrolled in this study and evaluated retrospectively.ResultsAfter 12 months of DPP-4 inhibitor treatment, random blood glucose level, and HbA1c level, decreased from 167±63 to 151±49 mg/dL (P<0.01, and from 7.5%±1.3% to 6.9%±0.9% (P<0.01 respectively, without severe side effects. Multiple regression analysis showed that predictors of DPP-4 inhibitor treatment efficacy in lowering HbA1c level after 12 months were a decrease in HbA1c level after 3 months of treatment, a high baseline HbA1c level, a low baseline body mass index, and the absence of coronary artery disease.ConclusionMost suitable candidates for treatment with DPP-4 inhibitors are diabetics who are not obese and do not have coronary artery disease. In addition, long-term efficacy of DPP-4 inhibitors can be predicted by decrement of HbA1c after 3 months of treatment.

Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes

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Kodera, Ryo, E-mail: kodera@cc.okayama-u.ac.jp [Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Shikata, Kenichi [Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Takatsuka, Tetsuharu; Oda, Kaori; Miyamoto, Satoshi; Kajitani, Nobuo; Hirota, Daisho; Ono, Tetsuichiro [Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Usui, Hitomi Kataoka [Department of Primary Care and Medical Education, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Makino, Hirofumi [Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan)

2014-01-17

Highlights: •DPP-4 inhibitor decreased urinary albumin excretion in a rat of type 1 diabetes. •DPP-4 inhibitor ameliorated histlogical changes of diabetic nephropathy. •DPP-4 inhibitor has reno-protective effects through anti-inflammatory action. •DPP-4 inhibitor is beneficial on diabetic nephropathy besides lowering blood glucose. -- Abstract: Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. Materials and methods: Five-week-old male Sprague–Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks. Results: PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney. Conclusions: These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose.

Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes

International Nuclear Information System (INIS)

Kodera, Ryo; Shikata, Kenichi; Takatsuka, Tetsuharu; Oda, Kaori; Miyamoto, Satoshi; Kajitani, Nobuo; Hirota, Daisho; Ono, Tetsuichiro; Usui, Hitomi Kataoka; Makino, Hirofumi

2014-01-01

Highlights: •DPP-4 inhibitor decreased urinary albumin excretion in a rat of type 1 diabetes. •DPP-4 inhibitor ameliorated histlogical changes of diabetic nephropathy. •DPP-4 inhibitor has reno-protective effects through anti-inflammatory action. •DPP-4 inhibitor is beneficial on diabetic nephropathy besides lowering blood glucose. -- Abstract: Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. Materials and methods: Five-week-old male Sprague–Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks. Results: PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney. Conclusions: These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose

Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes

DEFF Research Database (Denmark)

Muscelli, Elza; Casolaro, Arturo; Gastaldelli, Amalia

2012-01-01

Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known.......Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known....

Pharmacokinetic drug interaction between gemfibrozil and sitagliptin in healthy Indian male volunteers.

Science.gov (United States)

K P, Arun; Meda, Venkata Subbaiah; Kucherlapati, V S P Raj; Dubala, Anil; M, Deepalakshmi; P R, Anand VijayaKumar; K, Elango; B, Suresh

2012-05-01

To study the impact of gemfibrozil co-administration on the pharmacokinetics of sitagliptin in healthy Indian male volunteers. A randomized open label two-period crossover study involving 12 healthy Indian male volunteers was conducted at a single center. In each phase, the volunteers were administered sitagliptin as 100 mg tablets, either alone or co-administered with gemfibrozil as 600 mg tablets twice daily for 3 days. There was a 2-week washout period between phases. The venous blood samples were serially collected at 0-12 h post-dose, and plasma concentrations of the study drugs were estimated by a validated high-performance liquid chromatography-ultraviolet method. Relative to the administration of sitagliptin alone, co-administration with gemfibrozil increased the AUC₀₋₁₂ (2,167 ± 82.9 vs. 2,970 ± 76.4 ng h/ml; p gemfibrozil, this interaction may not have any clinical significance as sitagliptin has a wide therapeutic index. Hence, in clinical practice, sitagliptin as 100 mg tablets and gemfibrozil as 600 mg tablets may be co-prescribed without much threat of sitagliptin toxicity. However, these results may not hold if the dose of sitagliptin is increased or if is co-prescribed with other antidiabetic drugs and/or cytochrome P450 2C8/human organic anion transporter-3 inhibitors. Further studies are needed to confirm these results in patients.

Inadequate Triglyceride Management Worsens the Durability of Dipeptidyl Peptidase-4 Inhibitor in Subjects with Type 2 Diabetes Mellitus

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Masashi Shimoda

2017-01-01

Full Text Available Dipeptidyl peptidase-4 (DPP-4 inhibitors are often used all over the world and exert various beneficial effects including glucose-lowering effect in many subjects with type 2 diabetes. It is poorly understood, however, which factors are closely related with the durability of glucose-lowering effect by DPP-4 inhibitor. In this study, we examined retrospectively which factors could mainly influence the durability of DPP-4 inhibitor. We enrolled 212 participants with type 2 diabetes to whom DPP-4 inhibitor was administered for over 1 year without an addition or increase of other hypoglycemic agents. Age and baseline HbA1c level were significantly higher in the effective group than those in the ineffective group. The effective group had a tendency of smaller amounts of weight change, average total cholesterol, and average triglyceride compared with the ineffective group. Multiple logistic regression analysis showed that average triglyceride and baseline HbA1c were independent predictors associated with the durability of DPP-4 inhibitor. Moreover, an average triglyceride level contributed to the durability of DPP-4 inhibitor in the obese group (BMI ≥ 25 kg/m2 but not in the nonobese group (BMI < 25 kg/m2. These results suggest the importance of strict triglyceride management to maintain the durability of glucose-lowering effect by DPP-4 inhibitor, especially in obese subjects with type 2 diabetes.

Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type 2 diabetes

DEFF Research Database (Denmark)

Deacon, Carolyn F; Holst, Jens Juul

2010-01-01

data presented at Scientific Meetings and peer-reviewed studies published since 2007. WHAT THE READER WILL GAIN: This article reviews pharmacokinetic and pharmacodynamic characteristics of linagliptin. Linagliptin belongs to a new chemical class of dipeptidyl pepidase-4 (DPP-4) inhibitors, which...... comprise xanthine-based compounds. It is a potent, long-acting inhibitor with high selectivity for DPP-4 versus the related enzymes DPP-8 and DPP-9. The drug has modest oral availability in humans, but is absorbed rapidly to inhibit plasma DPP-4 activity by > 80% over 24 h. It is not metabolized...

Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas

DEFF Research Database (Denmark)

Deacon, Carolyn F.; Lebovitz, HE

2016-01-01

compound being launched in 2006, but the class now globally encompasses at least 11 different compounds. DPP-4 inhibitors improve glycaemic control with similar efficacy to SUs, but do not usually provoke hypoglycaemia or weight gain, are relatively free from adverse side effects, and have recently been...... drugs (DPP-4 inhibitors and SUs), highlighting differences and similarities between members of the same class, as well as discussing the potential advantages and disadvantages of the two drug classes. While both classes have their merits, the choice of which to use depends on the characteristics of each...

Treatment progression in sulfonylurea and dipeptidyl peptidase-4-inhibitor cohorts of type 2 diabetes patients on metformin

Directory of Open Access Journals (Sweden)

Peng X

2016-08-01

Full Text Available Xiaomei Peng, Dingfeng Jiang, Dongju Liu, Oralee J Varnado, Jay P Bae Eli Lilly and Company, Global Patient Outcomes and Real World Evidence, Indianapolis, IN, USA Background: Metformin is an oral antidiabetic drug (OAD widely used as first-line therapy in type 2 diabetes (T2D treatments. Numerous treatment pathways after metformin failure exist. It is important to understand how treatment choices influence subsequent therapy progressions. This retrospective study compares adherence to, persistence with, and treatment progression in sulfonylurea (SU and dipeptidyl peptidase-4 (DPP-4 inhibitor patient cohorts with T2D on metformin. Methods: Using health insurance claims data, matched patient cohorts were created and OAD use was compared in patients with T2D initiating SU or DPP-4 inhibitors (index drugs since January 1, 2010, to December 31, 2010, with background metformin therapy. Propensity score matching adjusted for possible selection bias. Persistence was measured via Cox regression as days to a ≥60-day gap in index drug possession; adherence was defined as proportion of days covered (PDC ≥80%. Evolving treatment patterns were traced at 6-month intervals for 24 months following index drug discontinuation. Results: From among 19,621 and 7,484 patients in the SU and DPP-4 inhibitor cohorts, respectively, 6,758 patient pairs were matched. Persistence at 12 months in the SU cohort was 48.0% compared to 52.5% for the DPP-4 inhibitor cohort. PDC adherence (mean [SD] during the 12-month follow-up period was 63.3 (29.7 for the SU cohort and 65.5 (28.7 for the DPP-4 inhibitor cohort. PDC ≥80% was 40.5% and 43.4% in the SU and DPP-4 inhibitor cohorts, respectively. A higher percentage of patients in the SU cohort remained untreated. Following index drug discontinuation, monotherapy was more common in the SU cohort, while use of two or three OADs was more common in the DPP-4 inhibitor cohort. Insulin therapy initiation was higher in the SU

Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes

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Vardarli, Irfan; Nauck, Michael A; Köthe, Lars D

2011-01-01

Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P...

DPP-4 inhibitor treatment: β-cell response but not HbA1c reduction is dependent on the duration of diabetes

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Kozlovski P

2017-03-01

Full Text Available Plamen Kozlovski,1 Vaishali Bhosekar,2 James E Foley3 1Novartis Pharma AG, Basel, Switzerland; 2Novartis Healthcare Private Limited, Hyderabad, India; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Introduction: Dipeptidyl peptidase-4 (DPP-4 inhibitors reduce hyperglycemia in patients with type 2 diabetes mellitus (T2DM by enhancing insulin and suppressing glucagon secretion. Since T2DM is associated with progressive loss of β-cell function, we hypothesized that the DPP-4 inhibitor action to improve β-cell function would be attenuated with longer duration of T2DM.Methods: Data from six randomized, placebo-controlled trials of 24 weeks duration, where β-cell response to vildagliptin 50 mg twice daily was assessed, were pooled. In each study, the insulin secretory rate relative to glucose (ISR/G 0–2h during glucose load (standard meal or oral glucose tolerance test was assessed at baseline and end of study. The mean placebo-subtracted difference (PSD in the change in ISR/G 0–2h from baseline for each study was evaluated as a function of age, duration of T2DM, baseline ISR/G 0–2h, glycated hemoglobin (HbA1c, fasting plasma glucose, body mass index, and mean PSD in the change in HbA1c from baseline, using univariate model.Results: There was a strong negative association between the PSD in the change from baseline in ISR/G 0–2h and duration of T2DM (r= −0.89, p<0.02. However, there was no association between the PSD in the change from baseline in ISR/G 0–2h and the PSD in the change from baseline in HbA1c (r=0.33, p=0.52. None of the other characteristics were significantly associated with mean PSD change in ISR/G 0–2h.Conclusion: These findings indicate that the response of the β-cell, but not the HbA1c reduction, with vildagliptin is dependent on duration of T2DM. Further, it can be speculated that glucagon suppression may become the predominant mechanism via which glycemic control is improved when treatment with a

In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

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Araújo, F.; Shrestha, N.; Gomes, M. J.; Herranz-Blanco, B.; Liu, D.; Hirvonen, J. J.; Granja, P. L.; Santos, H. A.; Sarmento, B.

2016-05-01

Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.

Lansoprazole enhances the antidiabetic effect of sitagliptin in mice with diet-induced obesity and healthy human subjects.

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Hao, ShaoJun; Sun, JianHua; Tian, XiKui; Sun, Xu; Zhang, ZhenXing; Gao, Yuan

2014-08-01

Proton pump inhibitors as adjunctive therapy would improve diabetes control and could enhance the hypoglycaemic activity of DPP-4 inhibitors. The aim of the study was to investigate the short-term effects of lansoprazole (LPZ), sitagliptin (SITA) and their combination therapy on glucose regulation and gut peptide secretion. Glucose and gut peptide were determined and compared after short-term administration of LPZ or SITA, or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects (n = 16) in a 75 g oral glucose tolerance test (OGTT) by a crossover design. In DIO mice, LPZ significantly improve glucose metabolism, increase plasma C-peptide and insulin compared with vehicle treatment. Furthermore, the combination of LPZ and SITA improved glucose tolerance additively, with higher plasma insulin and C-peptide levels compared with SITA-treated mice. Similarly, in human in the OGTT, the combination showed significant improvement in glucose-lowering and insulin increase vs SITA-treated group. However, no significant differences in area under curve (AUC) of insulin, glucose and C-peptide between the LPZ-treated group and baseline, except that mean AUCgastrin was significantly increased by LPZ. LPZ and SITA combination therapy appears to have complementary mechanisms of action and additive antidiabetic effect. © 2014 Royal Pharmaceutical Society.

Effect of Sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes

DEFF Research Database (Denmark)

Tremblay, AJ; Lamarche, B; Deacon, Carolyn F.

2011-01-01

as glucose homeostasis in patients with type 2 diabetes. Methods: Thirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1 ± 6.4 years and a body mass index of 30.7 ± 4.9 kg/m2) were recruited in this double-blind cross-over study using sitagliptin 100 mg/day or placebo......Aim: Recent studies indicate that type 2 diabetes is associated with an increased secretion of both hepatic and intestinal lipoproteins, leading to the accumulation of atherogenic triglyceride (TG)-rich lipoproteins. Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 that has been shown...... to reduce fasting and postprandial glucose levels in patients with type 2 diabetes presumably through incretin hormone-mediated improvements in islet function. The objective of the present study is to examine the effects of treatment with sitagliptin on postprandial lipid and incretin hormone levels as well...

A review of dipeptidyl peptidase-4 inhibitors. Hot topics from randomized controlled trials

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Deacon, Carolyn F

2018-01-01

The first clinical study to investigate effects of dipeptidyl peptidase-4 (DPP-4) inhibition was published in 2002, and since then, numerous randomized controlled trials (RCTs) have shown that DPP-4 inhibitors are efficacious, safe and well-tolerated. This review will focus upon RCTs which have i...

Efficacious and safe management of type 2 diabetes mellitus using DPP-4 inhibitors

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Alexander Sergeevich Ametov

2010-06-01

Full Text Available Diabetes mellitus (DM is believed to be the third most frequent direct cause of death after cardiovascular and oncological diseases. Therefore, solutionof DM-related problems is a major challenge facing health authorities in many countries. No doubt, strict control of glycemia is an indispensablecondition for the reduction of the frequency of diabetic complications. Indeed, many strategies developed in the recent years allowed metabolic controlin DM patients to be significantly improved. Basic and clinical research of the last decade provided a basis for the development of highly promisingtrends in the treatment of CD2, such as the use of incretins. Inhibitors of dipeptylpeptidase-4 (DPP-4 including Galvus (vildagliptin and GalvusMet (vildagliptin + metformin have been available in this country for the last 2 years. International studies showed high efficiency and safety of bothagents. They help to achieve adequate glycemic control in the absence of side effects and complications. Galvus significantly reduces daily variabilityof glycemia that is known to be a risk factor of severe vascular complications of DM. Another advantage of these drugs is they can be used by agedpatients at risk of cardiovascular disorders suffering hypertension. An example of combined therapy using Galvus Met in a DM2 patient is presenteddemonstrating markedly improved glycemic control, blood glucose dynamics, and quality of life. Galvus and Galvus Met can be prescribed as aninitial treatment in combination with all traditional oral hypoglycemic agents and insulin.

Sarcoid-like lung granulomas in a hemodialysis patient treated with a dipeptidyl peptidase-4 inhibitor.

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Sada, Ken-Ei; Wada, Jun; Morinaga, Hiroshi; Tuchimochi, Shigeyuki; Uka, Mayu; Makino, Hirofumi

2014-04-01

It has been reported that the inhibition of dipeptidyl peptidase-4 (DPP-4)/CD26 on T-cells by DPP-4 enzymatic inhibitors suppresses lymphocyte proliferation and reduces the production of various cytokines, including tumor necrosis factor (TNF)-α. A 72-year-old female with diabetic nephropathy on hemodialysis developed multiple lung nodules following the administration of vildagliptin. A biopsy demonstrated the histology of granulomas without caseous necrosis. The discontinuation of vildagliptin resulted in the disappearance of the granulomas within 4 months. As granulomatosis often develops in patients under anti-TNF-α therapy, the accumulation of DPP-4 inhibitors or its metabolites is possibly linked to unrecognized complications, such as sarcoid-like lung granulomas.

Sitagliptin down-regulates retinol-binding protein 4 and reduces insulin resistance in gestational diabetes mellitus: a randomized and double-blind trial.

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Sun, Xia; Zhang, Zhendong; Ning, Hui; Sun, Hong; Ji, Xianghong

2017-06-01

Gestational diabetes mellitus (GDM) is a condition that affects increasing number of pregnant women worldwide. Sitagliptin was reported to alleviate symptoms of type 2 diabetes mellitus by reducing serum levels of retinol-binding protein 4 (RBP-4). We investigated the effectiveness of sitagliptin on insulin sensitivity parameters in GDM patients. Pregnant GDM women in the 2nd trimester were recruited for this study. Participants were then assigned randomly to sitagliptin treatment group or placebo treatment group, and administered sitagliptin or placebo daily for 16 weeks. Glucose and insulin profiles, as well as serum RBP-4 level, were measured at both baseline and end of the study. After 16 weeks of treatment, participants in the STL group exhibited significantly improved levels of fasting plasma glucose and serum insulin, homeostasis model of assessment of β cell function (HOMA-β) and insulin resistance (HOMA-IR), compared with those in the placebo group. Serum levels of RBP-4 were also markedly decreased in the sitagliptin treatment group, and more importantly it was positively correlated with improved insulin resistance parameters. Our study supports a potentially promising role of sitagliptin in improving insulin resistance by decreasing RBP-4 in GDM-affected women.

Sitagliptin reduces urinary microalbumin in experimental model of diabetic nephropathy.

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Tsavdaridis, Ioannis; Papadimitriou, Dimochristos; Karanikola, Dora; Kalousis, Kostas; Katsouda, Areti; Mironidou-Tzouveleki, Maria

2015-01-01

The term Diabetic kidney disease (DKD) refers to any disease of the kidney that is a result of long-term hyperglycemia caused either by diabetes mellitus type 1 (DT1) or type 2 (DT2). When DKD coexists with macro albuminuria or proteinuria the condition is called diabetic nephropathy. DKD is the primary cause of renal failure since it is responsible for the 44% of new cases presented in the U.S.A. in 2008. Sitagliptin is an inhibitor of the enzyme dipeptidyl peptidase and is used as a treatment for diabetes since 2006. Through the inhibition of the enzyme's action sitagliptin prevents the degradation of GLP-1 which is an endogenous peptide with significant hypoglycemic actions, particularly postprandial. The proven hypoglycemic actions of sitagliptin led the researchers to further study the possible effects sitagliptin may have on the complications of diabetes mellitus such as diabetic nephropathy. The purpose of the study is to examine the effect of sitagliptin on diabetic nephropathy using biochemical parameters for assessment. 27db/db mice were used in total. They were about 4 weeks old. The mice were randomly divided into 3 groups each one consisting of 9 mice, the first 2 groups received sitagliptin treatment over a period of 32 weeks while the third did not receive any treatment. In the first group the mice received 200mg sitagliptin per Kg of body weight and in the second 10mg per Kg. At the end of the 32 weeks period the serum glucose, urea, creatinine, cholesterol, LDL, HDL, hsCRP and triglycerides as well as the urinary creatinine and microalbumin were measured in all 3 groups. The first group (received 200mg/kg) in comparison to the third group (control group) exhibited a reduction in the biochemical parameters measured: glucose -12.35% (P=0.16), urea -17.18% (P=0.61), creatinine -0.81% (P=0.95 ), cholesterol -19.28% (P=0,09), HDL -12,25% (P=0.26), LDL -31.2% (P=0.25), triglycerides -13,9% (P=0.37), hsCRP -49.8% (P=0.06), microalbumin -37.8% (P<0

Effect of Sitagliptin on Glycemic Control, Body Weight, Blood Pressure and Serum Lipid Profile in Type 2 Diabetic Hyperlipidemic Patients

International Nuclear Information System (INIS)

Hussain, M.; Atif, M. A.; Akhtar, L.; Ali, B.; Tunio, A. G.; Serwar, G.

2016-01-01

Background: Dyslipidaemia is a global health issue in developed as well as in developing countries. People with type 2 Diabetes mellitus are more susceptible to develop dyslipidaemia and its related complications. The objective of the study was to assess the effect of sitagliptin a (DPP-4 inhibitor) oral antidiabetic drug on blood sugar, body weight, blood pressure and dyslipidaemia in type 2 diabetic patients. Methods: This 12 weeks open label observational study was conducted at outdoor of diabetic clinic of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan in which newly diagnosed type 2 diabetic patients (n=78) with poor glycaemic control(HbA1c >7.2 percent) were selected. The patient received sitagliptin 50 mg twice daily for 12 weeks. Results: After 12 weeks treatment with sitagliptin, there was a significant reduction in the value of HbA1c from 8.184 percent±0.467 at baseline to 7.0200 percent±0.459 at 12 weeks (p<0.05). Body weight also decreased significantly from 80.21kg±7.156 at baseline to 71.74 kg±6.567 at 12 weeks (p<0.05).Systolic blood pressure decreased (SBP) decreased significantly from 138.17±6.050 mmHg at baseline to 131.22±6.311 mmHg at 12 weeks (p<0.05). Significant changes were also seen in diastolic blood pressure which decreased from 83.14±6.714 mmHg at baseline to 75.28±6.481 mmHg at 12 weeks (p<0.05). Significant reduction in the serum level of total Cholesterol (TC), triglycerides (TG) and Low density lipoprotein cholesterol (LDL-C) were detected (TC: 222.09±13.538 to 209.41±13.475 mg/dl, p<0.05; TG: 170.99±6.940 to 143.45±8.279 mg/dl, p<0.05; LDL-C 120.00±5.804 to 109.06±6.278 mg/dl, p<0.05). High density lipoprotein cholesterol (HDL-C) increased significantly from 42.99±4.836 mg/dl at baseline to 49.97±3.490 mg/dl at 12 weeks. Conclusion: Sitagliptin not only improves blood glucose control but also body weight, blood pressure and lipid profile in type 2 diabetic hyperlipidaemia patients. (author)

Effectiveness and Safety of Newer Antidiabetic Medications for Ramadan Fasting Diabetic Patients

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Ehab Mudher Mikhael

2016-01-01

Full Text Available Hypoglycemia is the most common side effects for most glucose-lowering therapies. It constitutes a serious risk that faces diabetic patients who fast during Ramadan (the 9th month in the Islamic calendar. New glucose-lowering classes like dipeptidyl peptidase-4 (DPP-4 inhibitors, glucagon-like peptide 1 receptor agonist (GLP-1 RA, and sodium-glucose cotransporter-2 (SGLT-2 inhibitors are efficacious in controlling blood glucose level with less tendency to induce hypoglycemia and thus may constitute a good choice for diabetic patients during Ramadan. This study reviews the safety and efficacy of newer glucose-lowering therapies during Ramadan. This study was accomplished through a careful literature search about studies that assess the benefit and side effects of these new glucose-lowering therapies during Ramadan during September 2015. Vildagliptin, sitagliptin, liraglutide, exenatide, and dapagliflozin were the only studied glucose-lowering therapies. All of the studied newer glucose-lowering therapies except dapagliflozin were associated with reduced risk to induce hypoglycemia. Gastrointestinal upset was common with the usage of liraglutide while increased thirst sensation was common with dapagliflozin. In conclusion DPP-4 inhibitors such as vildagliptin and sitagliptin may form a suitable glucose-lowering therapy option for Ramadan fasting patients.

Multinational Internet-based survey of patient preference for newer oral or injectable Type 2 diabetes medication

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Marco daCosta DiBonaventura

2010-11-01

Full Text Available Marco daCosta DiBonaventura1, Jan-Samuel Wagner1, Cynthia J Girman2, Kimberly Brodovicz2, Qiaoyi Zhang3, Ying Qiu3, Sri-Ram Pentakota3, Larry Radican31Health Sciences Practice, Kantar Health, New York; 2Epidemiology, 3Global Health Outcomes, Merck, Whitehouse Station, New Jersey, USABackground: The prevalence of Type 2 diabetes mellitus continues to rise. Although glucagon-like peptide-1 (GLP-1 analog and dipeptidyl peptidase-4 (DPP-4 inhibitor medications are effective, there are differences between these products, including method of administration (injectable versus oral. The objective of this study was to examine patient preferences (and predictors of preferences for two different medication profiles, one similar to a GLP-1 analog (liraglutide and another similar to a DPP-4 inhibitor (sitagliptin.Methods: Internet survey data were collected in two waves (wave 1, n = 2402; wave 2, n = 1340 using patients from the US and Europe. Patients were presented with two hypothetical medication profiles (“drug A” and “drug B”, resembling sitagliptin and liraglutide, respectively and asked to report their preferences.Results: Most patients in wave 1 and wave 2 reported that overall they would prefer a drug with the sitagliptin-like profile (81.9% and 84.4%, respectively over a drug with the liraglutide-like profile (18.1% and 15.6%, respectively, and >80% of patients reported that they would be able to take a drug with the sitagliptin-like profile as directed by their physician for a longer period. The likelihood of preferring the sitagliptin-like profile significantly increased as age (odds ratio [OR] = 1.02 and importance placed on method of administration (OR = 1.32 increased (P < 0.05. Although the sitagliptin-like profile was preferred by the majority of patients in all subgroups, a lower proportion of patients with obesity, with weight gain, with A1C values above target, and who exercised preferred the sitagliptin-like profile compared with

Dipeptidyl Peptidase-4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation.

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Ikedo, Taichi; Minami, Manabu; Kataoka, Hiroharu; Hayashi, Kosuke; Nagata, Manabu; Fujikawa, Risako; Higuchi, Sei; Yasui, Mika; Aoki, Tomohiro; Fukuda, Miyuki; Yokode, Masayuki; Miyamoto, Susumu

2017-06-19

Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP-4 (dipeptidyl peptidase-4) inhibitors have anti-inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP-4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. IAs were surgically induced in 7-week-old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide-treated RAW264.7 macrophages. In the anagliptin-treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP-1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide-stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP-1, and IL-6 (interleukin 6) independent of GLP-1 (glucagon-like peptide 1), the key mediator in the antidiabetic effects of DPP-4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal-regulated kinase 5), which mediates the anti-inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP-1 and IL-6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. A DPP-4 inhibitor, anagliptin, prevents the growth of IAs via its anti-inflammatory effects on macrophages. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Treatment Discontinuation and Clinical Events in Type 2 Diabetes Patients Treated with Dipeptidyl Peptidase-4 Inhibitors or NPH Insulin as Third-Line Therapy

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Cristiano S. Moura

2018-01-01

Full Text Available Objective. To compare dipeptidyl peptidase-4 (DPP-4 inhibitors with neutral protamine Hagedorn (NPH insulin, in terms of effectiveness and safety for the management of patients with type 2 diabetes mellitus (DM2 not controlled on metformin and sulfonylureas. Methods. A retrospective cohort study of individuals with DM2 newly dispensed with either DPP-4 inhibitors or NPH as third-line therapy, after metformin and sulfonylurea. Treatment discontinuation, macrovascular outcomes, and hypoglycemia were compared using multivariable Cox regression models, adjusted for sex, age, year of cohort entry, place of residence, hypertension, past history of hypoglycemia, diabetic ketoacidosis, comorbidities, and number of visits to emergency departments, outpatient physician, and hospitalizations. Results. Treatment discontinuation and hypoglycemia occurred more frequently with NPH than with DPP-4 inhibitor users. In the adjusted Cox model, the use of NPH compared to that of DPP-4 inhibitors was associated with a higher risk of discontinuation (HR: 1.33; 95% CI 1.27–1.40 and hypoglycemia (HR: 2.98; 95% CI 2.72–3.28. Risk of cardiovascular events was similar across groups. Conclusions. This real-world analysis suggests that DM2 patients initiating third-line therapy with NPH have poorer control of diabetes when compared to DPP-4 inhibitor initiators.

Dipeptidyl peptidase-4 (CD26): knowing the function before inhibiting the enzyme.

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Matteucci, E; Giampietro, O

2009-01-01

Dipeptidyl peptidase-4 (DPP4) or adenosine deaminase complexing protein 2 (ADCP 2) or T-cell activation antigen CD26 (EC 3.4.14.5.) is a serine exopeptidase belonging to the S9B protein family that cleaves X-proline dipeptides from the N-terminus of polypeptides, such as chemokines, neuropeptides, and peptide hormones. The enzyme is a type II transmembrane glycoprotein, expressed on the surface of many cell types, whose physiological functions are largely unknown. Protein dimerisation should be required for catalytic activity and glycosylation of the enzyme could impact on its physiological functions. The dimeric glycoprotein ADCP has been found linked to adenosine deaminase (ADA) whose relationship with lymphocyte maturation-differentiation is well-established. Since implicated in the regulation of the biological activity of hormones and chemokines, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, DPP4 inhibition offers a new potential therapeutic approach for type 2 diabetes mellitus, as monotherapy and adjunct therapy to other oral agents. The clinical use of presently available orally active inhibitors of DPP4, however, has been associated with side effects that have been in part attributed to the inhibition of related serine proteases, such as DPP8 and DPP9. Indeed, it is noteworthy that CD26 has a key role in immune regulation as a T cell activation molecule and in immune-mediated disorder. All-cause infections were increased after sitagliptin treatment. It is noteworthy that the effects of DPP4 inhibition on the immune system have not been extensively investigated. So far, only routine laboratory safety variables have been measured in published randomised controlled trials. The review summarises present knowledge in the field and suggests some potential directions of future research.

Microflora Disturbance during Progression of Glucose Intolerance and Effect of Sitagliptin: An Animal Study

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Xinfeng Yan

2016-01-01

Full Text Available Background. Emerging evidences have shown a close interplay between obesity, diabetes, and intestinal flora disturbance. Dipeptidyl peptidase-4 inhibitor, exemplified by sitagliptin, is highly efficacious in treating type 2 diabetes (T2DM, yet little is known if sitagliptin exerts beneficial effects on microbiota associated with obesity and T2DM. We evaluated changes of gut microbiota following the induction of obesity and T2DM in a streptozotocin treated high fat/high carbohydrate fed (HF/HC-STZ rat model and explored the effect of sitagliptin on gut microbiota for HF/HC-STZ rats. Methods. Sitagliptin was administered via oral gavage to diabetic rats. Fecal DNA extraction and 454 pyrosequencing based on analysis of 16S rRNA genes was utilized to determine the overall structure of microbiota in fecal DNA samples. Results. Results showed that, at the level of phylum, there was higher abundance of Firmicutes and Tenericutes and less abundance of Bacteroidetes in obese rats compared to their lean counterparts. At the level of genus, short-chain fatty acid- (SCFA- producing bacteria, Blautia, Roseburia, and Clostridium, and probiotics Lactobacillus, Bifidobacterium, and so forth were identified significantly different from each other among conditions. Conclusion. Marked shifts of the gut microbiota structure were observed in the rats during development of glucose intolerance. Intestinal flora changed in the process of glucose intolerance, and treatment of sitagliptin moderately corrected the dysbiosis of microbiota in T2DM.

Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors

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Holst, Jens Juul

2004-01-01

in the treatment of Type 2 diabetes, causing marked improvements in glycaemic profile, insulin sensitivity and beta-cell performance, as well as weight reduction. The hormone is metabolised rapidly by the enzyme dipeptidyl peptidase IV (DPP-IV) and, therefore, cannot be easily used clinically. Instead, resistant...... with exendin have been carried out for > 6 months and have indicated efficacy in patients inadequately treated with oral antidiabetic agents. Orally active DPP-IV inhibitors, suitable for once-daily administration, have demonstrated similar efficacy. Diabetes therapy, based on GLP-1 receptor activation...

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Lynch, Maeve

2016-01-15

Moderate to severe psoriasis is a systemic inflammatory disease associated with insulin resistance, obesity and type 2 diabetes (T2DM). Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that improves glycaemia and has a marketing authorisation for the treatment of T2DM. Non-immunosuppressive therapies that are effective for psoriasis and its associated comorbidities would be a significant advance in the treatment of this chronic disease.

Treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes.

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D'Alessio, David A; Denney, Amanda M; Hermiller, Linda M; Prigeon, Ronald L; Martin, Julie M; Tharp, William G; Saylan, Monica Liqueros; He, Yanling; Dunning, Beth E; Foley, James E; Pratley, Richard E

2009-01-01

Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state. The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function. We conducted a randomized, double-blind, placebo-controlled trial. The study was performed in General Clinical Research Centers at two University Hospitals. Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2-7.5%. Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout. Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout. There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.

Association of DPP4 Gene Polymorphisms with Type 2 Diabetes Mellitus in Malaysian Subjects.

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Radwan H Ahmed

Full Text Available Genetic polymorphisms of the Dipeptidyl Peptidase 4 (DPP4 gene may play a role in the etiology of type 2 diabetes mellitus (T2DM. This study aimed to investigate the possible association of single nucleotide polymorphisms (SNPs of the DPP4 gene in Malaysian subjects with T2DM and evaluated whether they had an effect on the serum levels of soluble dipeptidyl peptidase 4 (sDPP-IV.Ten DPP4 SNPs were genotyped by TaqMan genotyping assays in 314 subjects with T2DM and 235 controls. Of these, 71 metabolic syndrome (MetS subjects were excluded from subsequent analysis. The odds ratios (ORs and their 95% confidence interval (CIs were calculated using multiple logistic regression for the association between the SNPs of DPP4 and T2DM. In addition, the serum levels of sDPP-IV were investigated to evaluate the association of the SNPs of DPP4 with the sDPP-IV levels.Dominant, recessive, and additive genetic models were employed to test the association of DPP4 polymorphisms with T2DM, after adjusting for age, race, gender and BMI. The rs12617656 was associated with T2DM in Malaysian subjects in the recessive genetic model (OR = 1.98, p = 0.006, dominant model (OR = 1.95, p = 0.008, and additive model (OR = 1.63, p = 0.001. This association was more pronounced among Malaysian Indians, recessive (OR = 3.21, p = 0.019, dominant OR = 3.72, p = 0.003 and additive model (OR = 2.29, p = 0.0009. The additive genetic model showed that DPP4 rs4664443 and rs7633162 polymorphisms were associated with T2DM (OR = 1.53, p = 0.039, and (OR = 1.42, p = 0.020, respectively. In addition, the rs4664443 G>A polymorphism was associated with increased sDPP-IV levels (p = 0.042 in T2DM subjects.DPP4 polymorphisms were associated with T2DM in Malaysian subjects, and linked to variations in sDPP-IV levels. In addition, these associations were more pronounced among Malaysian Indian subjects.

Identification of residues on human receptor DPP4 critical for MERS-CoV binding and entry

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Song, Wenfei [Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084 (China); Wang, Ying [Comprehensive AIDS Research Center, Research Center for Public Health, School of Medicine, Tsinghua University, Beijing 100084 (China); Wang, Nianshuang; Wang, Dongli [Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084 (China); Guo, Jianying; Fu, Lili [Comprehensive AIDS Research Center, Research Center for Public Health, School of Medicine, Tsinghua University, Beijing 100084 (China); Shi, Xuanling, E-mail: shixuanlingsk@tsinghua.edu.cn [Comprehensive AIDS Research Center, Research Center for Public Health, School of Medicine, Tsinghua University, Beijing 100084 (China)

2014-12-15

Middle East respiratory syndrome coronavirus (MERS-CoV) infects host cells through binding the receptor binding domain (RBD) on its spike glycoprotein to human receptor dipeptidyl peptidase 4 (hDPP4). Here, we report identification of critical residues on hDPP4 for RBD binding and virus entry through analysis of a panel of hDPP4 mutants. Based on the RBD–hDPP4 crystal structure we reported, the mutated residues were located at the interface between RBD and hDPP4, which potentially changed the polarity, hydrophobic or hydrophilic properties of hDPP4, thereby interfering or disrupting their interaction with RBD. Using surface plasmon resonance (SPR) binding analysis and pseudovirus infection assay, we showed that several residues in hDPP4–RBD binding interface were important on hDPP4–RBD binding and viral entry. These results provide atomic insights into the features of interactions between hDPP4 and MERS-CoV RBD, and also provide potential explanation for cellular and species tropism of MERS-CoV infection. - Highlights: • It has been demonstrated that MERS-CoV infects host cells through binding its envelope spike (S) glycoprotein to the host cellular receptor dipeptidyl peptidase 4 (DPP4). • To identify the critical residues on hDPP4 for RBD binding and virus entry, we constructed a panel of hDPP4 mutants based on structure-guided mutagenesis. • Using surface plasmon resonance (SPR) binding analysis and pseudovirus infection assay, we showed that several residues on hDPP4 had significant impacts on virus/receptor interactions and viral entry. • Our study has provided new insights into the features of interactions between hDPP4 and MERS-CoV RBD, and provides potential explanation for cellular and species tropism of MERS-CoV infection.

Description of anti-diabetic drug utilization pre- and post-formulary restriction of sitagliptin: findings from a national health plan.

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Huang, Xingyue; Liu, Zhiwen; Shankar, Ravi R; Rajpathak, Swapnil

2015-08-01

Multi-tiered formularies are commonly used for controlling costs of prescription medications. Focused on type 2 diabetes mellitus (T2DM), this database study assessed drug utilization before and after a formulary restriction (2nd-3rd tier), and compared demographic and clinical characteristics of patients affected vs not by the restriction. Formulary restriction of sitagliptin (SITA) occurred July 1, 2012. The 'pre-period' was defined from January 1-June 30, 2012, the 'grace period' from July 1-September 30, 2012, and the 'post-period' from October 1, 2012-March 31, 2013. Patients from the OptumInsight database were included if diagnosed with T2DM, ≥18 years, had continuous enrollment, and had ≥2 prescriptions of SITA in the pre-period. Those who died or were aged ≥65 years in the post-period were excluded. Patients were grouped into SITA continuer and discontinuer cohorts based on SITA use in the post-period. Descriptive analyses assessed baseline patient characteristics and anti-hyperglycemic drug utilization in the pre- and post-periods. In total, 23,477 patients met inclusion criteria. In the post-period, 36.1% (n = 8480) of patients discontinued SITA. Among SITA discontinuers, 44.1% switched to a preferred DPP-4 inhibitor, 9.2% switched to glucagon-like peptides-1 (GLP-1) or insulin, and 2.4% switched to metformin or sulfonylurea. Of the SITA discontinuers, 21.6% dropped SITA without replacement and 8.4% discontinued all diabetes medications. In the post-period, a greater proportion of SITA discontinuers used GLP-1 (12.6% vs 5.8%) and insulin (29.1% vs 20.9%) than continuers, or had some change in anti-hyperglycemic treatment (67.5% vs 22.1%). Baseline demographic and clinical characteristics were similar between SITA continuers and discontinuers, indicating a lack of an association with SITA discontinuation. This descriptive study used a non-controlled observational approach. Following formulary change, 1/3 of patients discontinued SITA and 30% of

Dipeptidyl Peptidase-4 Inhibitor Development and Post-authorisation Programme for Vildagliptin - Clinical Evidence for Optimised Management of Chronic Diseases Beyond Type 2 Diabetes.

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Strain, William David; Paldánius, Päivi M

2017-08-01

The last decade has witnessed the role of dipeptidyl peptidase-4 (DPP-4) inhibitors in producing a conceptual change in early management of type 2 diabetes mellitus (T2DM) by shifting emphasis from a gluco-centric approach to holistically treating underlying pathophysiological processes. DPP-4 inhibitors highlighted the importance of acknowledging hypoglycaemia and weight gain as barriers to optimised care in T2DM. These complications were an integral part of diabetes management before the introduction of DPP-4 inhibitors. During the development of DPP-4 inhibitors, regulatory requirements for introducing new agents underwent substantial changes, with increased emphasis on safety. This led to the systematic collection of adjudicated cardiovascular (CV) safety data, and, where 95% confidence of a lack of harm could not be demonstrated, the standardised CV safety studies. Furthermore, the growing awareness of the worldwide extent of T2DM demanded a more diverse approach to recruitment and participation in clinical trials. Finally, the global financial crisis placed a new awareness on the health economics of diabetes, which rapidly became the most expensive disease in the world. This review encompasses unique developments in the global landscape, and the role DPP-4 inhibitors, specifically vildagliptin, have played in research advancement and optimisation of diabetes care in a diverse population with T2DM worldwide.

Association of DPP4 Gene Polymorphisms with Type 2 Diabetes Mellitus in Malaysian Subjects

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Ahmed, Radwan H.; Huri, Hasniza Zaman; Al-Hamodi, Zaid; Salem, Sameer D.; Al-absi, Boshra; Muniandy, Sekaran

2016-01-01

Background Genetic polymorphisms of the Dipeptidyl Peptidase 4 (DPP4) gene may play a role in the etiology of type 2 diabetes mellitus (T2DM). This study aimed to investigate the possible association of single nucleotide polymorphisms (SNPs) of the DPP4 gene in Malaysian subjects with T2DM and evaluated whether they had an effect on the serum levels of soluble dipeptidyl peptidase 4 (sDPP-IV). Method Ten DPP4 SNPs were genotyped by TaqMan genotyping assays in 314 subjects with T2DM and 235 co...

Synthetic (+)-antroquinonol exhibits dual actions against insulin resistance by triggering AMP kinase and inhibiting dipeptidyl peptidase IV activities.

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Hsu, C Y; Sulake, R S; Huang, P-K; Shih, H-Y; Sie, H-W; Lai, Y-K; Chen, C; Weng, C F

2015-01-01

The fungal product (+)-antroquinonol activates AMP kinase (AMPK) activity in cancer cell lines. The present study was conducted to examine whether chemically synthesized (+)-antroquinonol exhibited beneficial metabolic effects in insulin-resistant states by activating AMPK and inhibiting dipeptidyl peptidase IV (DPP IV) activity. Effects of (+)-antroquinonol on DPP IV activity were measured with a DPPIV Assay Kit and effects on GLP-1-induced PKA were measured in AR42J cells. Translocation of the glucose transporter 4, GLUT4, induced either by insulin-dependent PI3K/AKT signalling or by insulin-independent AMPK activation, was assayed in differentiated myotubes. Glucose uptake and GLUT4 translocation were assayed in L6 myocytes. Mice with diet-induced obesity were used to assess effects of acute and chronic treatment with (+)-antroquinonol on glycaemic control in vivo. The results showed that of (+)-antroquinonol (100 μM ) inhibited the DPP IV activity as effectively as the clinically used inhibitor, sitagliptin. The phosphorylation of AMPK Thr(172) in differentiated myotubes was significantly increased by (+)-antroquinonol. In cells simultaneously treated with S961 (insulin receptor antagonist), insulin and (+)-antroquinonol, the combination of (+)-antroquinonol plus insulin still increased both GLUT4 translocation and glucose uptake. Further, (+)-antroquinonol and sitagliptin reduced blood glucose, when given acutely or chronically to DIO mice. Chemically synthesized (+)-antroquinonol exhibits dual effects to ameliorate insulin resistance, by increasing AMPK activity and GLUT4 translocation, along with inhibiting DPP IV activity. © 2014 The British Pharmacological Society.

Ursodeoxycholic acid potentiates dipeptidyl peptidase-4 inhibitor sitagliptin by enhancing glucagon-like peptide-1 secretion in patients with type 2 diabetes and chronic liver disease: a pilot randomized controlled and add-on study

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Ota, Tsuguhito; Kato, Ken-ichiro; Takeshita, Yumie; Misu, Hirofumi; Kaneko, Shuichi

2018-01-01

Objective We evaluated the effects of ursodeoxycholic acid (UDCA) on glucagon-like peptide-1 (GLP-1) secretion and glucose tolerance in patients with type 2 diabetes with chronic liver disease. Research design and methods Japanese patients with type 2 diabetes (glycated hemoglobin (HbA1c) levels ≥7.0%) and chronic liver disease were included in this study. Sixteen patients (HbA1c level, 7.2%±0.6%(55.2 mmol/mol)) were randomized to receive 900 mg UDCA for 12 weeks followed by 50 mg sitagliptin add-on therapy for 12 weeks (UDCA-first group; n=8) or 50 mg sitagliptin for 12 weeks followed by 900 mg UDCA add-on therapy for 12 weeks (sitagliptin-first group; n=8). All patients underwent a liquid high-fat meal test before and after 12 or 24 weeks of treatment. Results The baseline characteristics were similar between the UDCA-first and sitagliptin-first groups. There was a decrease in body weight (72.5±8.4 to 70.6±8.6 kg; P=0.04) and the HbA1c level (7.0%±0.3% to 6.4%±0.5%(53.0 to 46.4 mmol/mol); P=0.01) in the UDCA-first group. The HbA1c level decreased further after sitagliptin administration (6.4%±0.5% to 6.0%±0.4%(46.4 to 42.1 mmol/mol); P<0.01). Although there were no initial changes in the weight and HbA1c level in the sitagliptin-first group, the HbA1c level decreased after UDCA addition (7.1%±1.1% to 6.6%±0.9%(54.1 to 48.6 mmol/mol); P=0.04). UDCA alone increased the area under the curve0–30 for GLP-1 response (115.4±47.2 to 221.9±48.9 pmol·min/L; P<0.01), but not the glucose-dependent insulinotropic polypeptide response, in the UDCA-first group. Conclusions UDCA treatment resulted in a greater reduction in HbA1c levels, and an increased early phase GLP-1 secretion. Trial registration number NCT01337440. PMID:29607050

Short-term and long-term effects of dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus patients with renal impairment: a meta-analysis of randomized controlled trials.

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Li, Ruifei; Wang, Rui; Li, Haixia; Sun, Sihao; Zou, Meijuan; Cheng, Gang

2016-09-01

To assess the short-term and long-term effects of dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes mellitus patients with renal impairment, a meta-analysis of randomized clinical trials of DPP-4 inhibitor interventions in type 2 diabetes mellitus patients with renal impairment was performed. PubMed, Embase, Cochrane Library and ClinicalTrials.gov were searched through the end of March 2015. Randomized clinical trials were selected if (1) DPP-4 inhibitors were compared with a placebo or other active-comparators, (2) the treatment duration was ≥12 weeks and (3) data regarding changes in haemoglobin A1c (HbA1c ), changes in fasting plasma glucose or hypoglycaemia and other adverse events were reported. Of 790 studies, ten studies on eight randomized clinical trials were included. Compared with the control group, DPP-4 inhibitors were associated with a greater HbA1c reduction in both the short-term [mean differences (MD) = -0.45, 95% confidence intervals (-0.57, -0.33), p 1] and long-term [MD = -0.33, 95% confidence intervals (-0.63, -0.03), p = 0.03] treatments. However, the long-term greater reduction in HbA1c with DPP-4 inhibitor treatment was only significant when the control treatment comprised placebo plus stable background treatment, but not glipizide plus stable background treatment. DPP-4 inhibitors were associated with a greater fasting plasma glucose reduction [MD = -12.59, 95% confidence intervals (-22.01, -3.17), p = 0.009] over the short-term; however, this effect was not present over the long-term. Regarding the hypoglycaemia adverse events assessment, the long-term treatment data indicated there was no increased risk of hypoglycaemia compared with placebo or active-controlled anti-diabetic drugs. The present meta-analysis confirms that DPP-4 inhibitors are effective and equivalent to other agents in type 2 diabetes mellitus patients with renal impairment. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015

Effectiveness and safety of dipeptidyl peptidase 4 inhibitors in the management of type 2 diabetes in older adults: a systematic review and development of recommendations to reduce inappropriate prescribing.

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Schott, Gisela; Martinez, Yolanda V; Ediriweera de Silva, R Erandie; Renom-Guiteras, Anna; Vögele, Anna; Reeves, David; Kunnamo, Ilkka; Marttila-Vaara, Minna; Sönnichsen, Andreas

2017-10-16

Preventable drug-related hospital admissions can be associated with drugs used in diabetes and the benefits of strict diabetes control may not outweigh the risks, especially in older populations. The aim of this study was to look for evidence on risks and benefits of DPP-4 inhibitors in older adults and to use this evidence to develop recommendations for the electronic decision support tool of the PRIMA-eDS project. Systematic review using a staged approach which searches for systematic reviews and meta-analyses first, then individual studies only if prior searches were inconclusive. The target population were older people (≥65 years old) with type 2 diabetes. We included studies reporting on the efficacy and/or safety of DPP-4 inhibitors for the management of type 2 diabetes. Studies were included irrespective of DPP-4 inhibitors prescribed as monotherapy or in combination with any other drug for the treatment of type 2 diabetes. The target intervention was DPP-4 inhibitors compared to placebo, no treatment, other drugs to treat type 2 diabetes or a non-pharmacological intervention. Thirty studies (reported in 33 publications) were included: 1 meta-analysis, 17 intervention studies and 12 observational studies. Sixteen studies were focused on older adults and 14 studies reported subgroup analyses in participants ≥65, ≥70, or ≥75 years. Comorbidities were reported by 26 studies and frailty or functional status by one study. There were conflicting findings regarding the effectiveness of DPP-4 inhibitors in older adults. In general, DPP-4 inhibitors showed similar or better safety than placebo and other antidiabetic drugs. However, these safety data are mainly based on short-term outcomes like hypoglycaemia in studies with HbA1c control levels recommended for younger people. One recommendation was developed advising clinicians to reconsider the use of DPP-4 inhibitors for the management of type 2 diabetes in older adults with HbA1c companies and authored or

Treatment choices for the glycaemic management of patients with type 2 diabetes and chronic kidney disease: Analysis of the SAIL patient linked dataset.

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Min, Thinzar; Davies, Gareth I; Rice, Sam; Chess, James; Stephens, Jeffrey W

Chronic kidney disease (CKD) is common in type 2 diabetes and limits the treatment choices for glycaemic control. Our aim was to examine real-world prescribing for managing hyperglycaemia in the presence of CKD. The SAIL (Secure Anonymised Information Linkage) databank was used to examine prescribing during the period from the 1st of January to 30th December 2014. CKD was defined as:- none or mild CKD, eGFR ≥60mL/min/1.73m 2 ; moderate CKD eGFR <60mL/min/1.73m 2 ; and severe CKD eGFR <30mL/min/1.73m 2 or requiring dialysis. We identified 9585 subjects who received any form of glucose lowering therapy (8363 had no/mild CKD; 1137 moderate CKD; 85 severe CKD). There was a linear association between insulin use and CKD severity with approximately 54% of those with severe CKD receiving insulin. Sulphonylureas use did not differ among the CKD groups and was approximately 40%. Metformin showed a linear decrease across the groups, however approximately 21% in the severe CKD group received metformin. The use of dipeptidyl peptidase 4 inhibitors (DPP-4i) was approximately 20% and did not differ among groups. The DPP-4 inhibitor choice was:- 1% vildagliptin, 9% saxagliptin, 58% sitagliptin, and 32% linaglitpin. With respect to sitagliptin and saxagliptin, 72% and 62% received an inappropriately high dose in the setting of CKD. We observed that a considerable proportion of patients with type 2 diabetes and CKD were receiving metformin and non dose-adjusted DPP-4 inhibitors. Careful consideration of medication use and dosaging is required in the setting of CKD and type 2 diabetes. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Implementation of GLP-1 based therapy of type 2 diabetes mellitus using DPP-IV inhibitors

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Holst, Jens Juul

2003-01-01

GLP-1 is a peptide hormone from the intestinal mucosa. It is secreted in response to meal ingestion and normally functions in the so-called ileal brake i. e. inhibition of upper gastrointestinal motility and secretion when nutrients are present in the distal small intestine. It also induces satiety...... of the peptide is necessary because of an exceptionally rapid rate of degradation catalyzed the enzyme dipeptidyl peptidase IV. With inhibitors of this enzyme, it is possible to protect the endogenous hormone and thereby elevate both fasting and postprandial levels of the active hormone. This leads to enhanced...... insulin secretion and glucose turnover. But will DPP-IV inhibition enhance all effects of the endogenous peptide? The mode of action of GLP-1 is complex involving also interactions with sensory neurons and the central nervous system, where a DPP-IV mediated degradation does not seem to occur. Therefore...

KLK5 induces shedding of DPP4 from circulatory Th17 cells in type 2 diabetes

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Titli Nargis

2017-11-01

Conclusions: Our study provides mechanistic insights into the molecular interaction between KLK5 and DPP4 as well as CD4+ T cell derived KLK5 mediated enzymatic cleavage of DPP4 from cell surface. Thus, our study uncovers a hitherto unknown cellular source and mechanism behind enhanced plasma DPP4 activity in T2DM.

Dipeptidyl peptidase-4 inhibition in chronic kidney disease and potential for protection against diabetes-related renal injury.

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Penno, G; Garofolo, M; Del Prato, S

2016-05-01

Type 2 diabetes mellitus (T2DM) is associated with a high risk of chronic kidney disease (CKD). About 20% of patients with T2DM have CKD of stage ≥ 3; up to 40% have some degree of CKD. Beyond targeting all renal risk factors together, renin-angiotensin-aldosterone system blockers are to date the only effective mainstay for the treatment of diabetic kidney disease (DKD). Indeed, several potentially nephroprotective agents have been in use, which have been unsuccessful. Some glucose-lowering agents, including dipeptidyl peptidase-4 inhibitors (DPP-4i), have shown promising results. Here, we discuss the evidence that glucose lowering with DPP-4i may be an option for protecting against diabetes-related renal injury. A comprehensive search was performed of the literature using the terms "alogliptin," "linagliptin," "saxagliptin," "sitagliptin," and "vildagliptin" for original articles and reviews addressing this topic. DPP-4i are an effective, well-tolerated treatment option for T2DM with any degree of renal impairment. Preclinical observations and clinical studies suggest that DPP-4i might also be a promising strategy for the treatment of DKD. The available data are in favor of saxagliptin and linagliptin, but the consistency of results points to the possible nephroprotective effect of DPP-4i. This property appears to be independent of glucose lowering and can potentially complement other therapies that preserve renal function. Larger prospective clinical trials are ongoing, which might strengthen these hypothesis-generating findings. The improvement in albuminuria associated with DPP-4i suggests that these agents may provide renal benefits beyond their glucose-lowering effects, thus offering direct protection from DKD. These promising results must be interpreted with caution and need to be confirmed in forthcoming studies. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human

Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials

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Madsbad, Sten; Krarup, Thure; Deacon, Carolyn F

2008-01-01

-acting glucagon-like peptide-1 receptor agonists liraglutide and exenatide long-acting release reduce haemoglobin A1c by about 1.0-2.0% and have fewer gastrointestinal side-effects. The orally available dipeptidyl peptidase-4 inhibitors, that is sitagliptin and vildagliptin reduce haemoglobin A1c by 0...

An Effective Delivery System of Sitagliptin Using Optimized Mucoadhesive Nanoparticles

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Afzal Haq Asif

2018-05-01

Full Text Available Sitagliptin (MK-0431, is a potent oral hypoglycemic drug that is used for treating type 2 diabetes mellitus. However, the short half-life of sitagliptin requires patients to take a high dose of 50 mg twice per day, and the fraction of sitagliptin reversibly bound to plasma proteins is as low as 38%. In addition, it was reported that approximately 79% of sitagliptin is excreted unchanged in the urine for elimination without metabolism. Thus, a better delivery system is needed to improve the benefits of sitagliptin in patients. The drug content and percentage yield were found to be 73 ± 2% and 92 ± 2%, respectively. The optimized sitagliptin nanoparticle sizes were between 350–950 nm, and the surfaces were smooth and nearly spherical in shape. In addition, the optimized sitagliptin nanoparticles have an indicated excellent bioadhesion property of (6.1 ± 0.5 h. The swelling of the nanoparticles is 168 ± 15%. The pattern of sitagliptin release from the mucoadhesive nanoparticles follows the Korsmeyer-Peppas model. More importantly, the extended sitagliptin retention time, of up to 12 h in the gastrointestinal tract, suggests that the optimized mucoadhesive nanoparticle formulation is more efficient, and has a greater potential to be used for oral delivery compared to the conventional sitagliptin administration in the drug solution. This is the first developed delivery system using the optimized mucoadhesive nanoparticles to enhance the effectiveness of sitagliptin.

Efficacy and safety of autoinjected exenatide once-weekly suspension versus sitagliptin or placebo with metformin in patients with type 2 diabetes: The DURATION-NEO-2 randomized clinical study.

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Gadde, Kishore M; Vetter, Marion L; Iqbal, Nayyar; Hardy, Elise; Öhman, Peter

2017-07-01

Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors treat type 2 diabetes through incretin-signaling pathways. This study compared the efficacy and safety of the glucagon-like peptide-1 receptor agonist exenatide once-weekly (Miglyol) suspension for autoinjection (QWS-AI) with the dipeptidyl peptidase-4 inhibitor sitagliptin or placebo. In this open-label, multicentre study of patients with type 2 diabetes who had suboptimal glycaemic control on metformin monotherapy, 365 patients were randomized to receive exenatide 2.0 mg QWS-AI, sitagliptin 100 mg once daily or oral placebo (3:2:1 ratio). The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to 28 weeks. At 28 weeks, exenatide QWS-AI significantly reduced HbA1c from baseline compared to sitagliptin (-1.13% vs -0.75% [baseline values, 8.42% and 8.50%, respectively]; P  = .02) and placebo (-0.40% [baseline value, 8.50%]; P = .001). More exenatide QWS-AI-treated patients achieved HbA1c <7.0% than did sitagliptin- or placebo-treated patients (43.1% vs 32.0% and 24.6%; both P  < .05). Exenatide QWS-AI and sitagliptin reduced fasting plasma glucose from baseline to 28 weeks (-21.3 and -11.3 mg/dL) vs placebo (+9.6 mg/dL), with no significant difference between the 2 active treatments. Body weight decreased with both active treatments (-1.12 and -1.19 kg), but not with placebo (+0.15 kg). No improvement in blood pressure was observed in any group. The most common adverse events with exenatide QWS-AI were gastrointestinal events and injection-site reactions. This study demonstrated that exenatide QWS-AI reduced HbA1c more than sitagliptin or placebo and was well tolerated. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Dipeptidyl Peptidase-4 Inhibitors as a Third-Line Oral Antihyperglycaemic Agent in Patients with Type 2 Diabetes Mellitus: The Impact of Ethnicity

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X. Zhang

2014-01-01

Full Text Available Aims. The aim of this study is to examine the efficacy of adding a dipeptidyl peptidase-4 (DPP-4 inhibitor to patients with type 2 diabetes inadequately controlled by metformin and sulphonylurea combination treatment. The response of Asian and non-Asian patients to this regimen was also examined. Methods. The medical and computerized records of 80 patients were examined. These patients had baseline HbA1c levels ranging from 7.0 to 12.5% and had a DPP-4 inhibitor add-on therapy for a minimum period of 12 weeks. The primary endpoint was the change in HbA1c level before and after DPP-4 inhibitor treatment. Results. During oral triple therapy, there was a reduction of HbA1c from 8.3% (7.7–8.9 to 7.2% (6.8–7.6 and 26 patients (32.5% achieved an HbA1c <7%. Poor baseline glycaemic control, lower BMI, and younger age were associated with a better response, but duration of diabetes and gender did not affect outcome. The HbA1c reduction was not different between Asians and non-Asians group [−1.00% (0.6–1.3 vs −0.90% (0.4–1.6]. Conclusions. DPP-4 inhibitor as a third-line add-on therapy can achieve significant glycaemic improvement in patients with type 2 diabetes inadequately controlled on the combination of metformin and sulphonylurea. The improvement in HbA1c was similar between Asian and non-Asian patients.

Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes

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Deacon, Carolyn F

2018-01-01

-1 is an intestinal hormone with potent insulinotropic and glucagonostatic effects and can normalise blood glucose levels in patients with type 2 diabetes, but the native peptide is not therapeutically useful because of its inherent metabolic instability. Using the GLP-1/DPP-4 system and type 2...... diabetes as an example, this review summarises how knowledge of a peptide's biological effects coupled with an understanding of the pathways involved in its metabolic clearance can be exploited in a rational, step-by-step manner to develop a therapeutic agent, which is effective and well tolerated, and any...

Gastrointestinal Adverse Events of Dipeptidyl Peptidase 4 Inhibitors in Type 2 Diabetes: A Systematic Review and Network Meta-analysis.

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Wu, Shanshan; Chai, Sanbao; Yang, Jun; Cai, Ting; Xu, Yang; Yang, Zhirong; Zhang, Yuan; Ji, Linong; Sun, Feng; Zhan, Siyan

2017-09-01

The purpose of this study was to systematically evaluate the effect of dipeptidyl peptidase 4 inhibitors on gastrointestinal adverse events in patients with type 2 diabetes. MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from inception through April 28, 2016. Randomized controlled trials that compared dipeptidyl peptidase 4 inhibitor-based therapies with placebo and other hypoglycemic agents in type 2 diabetes were included. The duration of studies was at least 4 weeks. A total of 165 randomized controlled trials and 122,072 patients were included in the study. Dipeptidyl peptidase 4 inhibitors did not increase the incidence of gastrointestinal adverse events after the treatment with alogliptin (odds ratio [OR] = 0.83; 95% CI, 0.59-1.15), linagliptin (OR = 1.11; 95% CI, 0.92-1.35), saxagliptin (OR = 0.96; 95% CI, 0.80-1.15), sitagliptin (OR = 0.95; 95% CI, 0.64-1.14), teneligliptin (OR = 1.50; 95% CI, 0.81-2.77), and vildagliptin (OR = 0.80; 95% CI, 0.63-1.01) compared with placebo. Compared with glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors significantly decreased the incidence of gastrointestinal adverse events with alogliptin (OR = 0.26; 95% CI, 0.15-0.44), linagliptin (OR = 0.43; 95% CI, 0.25-0.74), saxagliptin (OR = 0.28; 95% CI, 0.17-0.46), sitagliptin (OR = 0.24; 95% CI, 0.17-0.35), and vildagliptin (OR = 0.27; 95% CI, 0.18-0.41). Dipeptidyl peptidase 4 inhibitors were not associated with an increased risk of gastrointestinal adverse events relative to metformin and α-glucosidase inhibitors, respectively. The network meta-analysis found that compared with glucagon-like peptide 1 receptor agonists, metformin, and α-glucosidase inhibitor, dipeptidyl peptidase 4 inhibitors are associated with a lower incidence of gastrointestinal adverse events. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Sarcopenia in Elderly Diabetic Patients: Role of Dipeptidyl Peptidase 4 Inhibitors.

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Rizzo, Maria Rosaria; Barbieri, Michelangela; Fava, Ilaria; Desiderio, Manuela; Coppola, Carla; Marfella, Raffaele; Paolisso, Giuseppe

2016-10-01

Our study aimed to investigate the effect of dipeptidyl peptidase 4 inhibitors (DPP4-I) on sarcopenic parameters in elderly type 2 diabetic patients. All elderly diabetic patients were invited to present themselves at our outpatient Geriatric Centre to undergo to evaluation of glycemic, inflammatory, and sarcopenic parameters and to perform a meal test for glucagon-like peptide-1 analogue (GLP-1) activity evaluation. According to European Working Group on Sarcopenia in Older People (EWGSOP) criteria, sarcopenic parameters were assessed by bioelectrical impedance analysis (BIA) and Kern dynamometer and 4-m gait speed tests. All patients received standardized meals for the assessment of postprandial levels of GLP-1 activity. Data of 80 elderly diabetic patients treated with oral glucose-lowering drugs (DPP4-I or Sulfonylureas Group) for at least 24 months before enrollment were analyzed. The DPP4-I Group showed appropriate glycemic control, lower levels of inflammatory parameters, a significant and greater increase, during interprandial periods, of GLP-1 activity, and better sarcopenic parameters (fat-free mass, skeletal muscle mass, and related indices, muscle strength, and gait speed) compared with the Sulfonylureas Group. Univariate analysis showed that sarcopenic parameters correlated with glycemic control and with GLP-1 area under the curve values. Multivariate analysis confirms these relationships. The results are consistent with the hypothesis that DPP4-I use might have a positive effect on the loss of muscle mass and its function. Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

Macrocarpal C isolated from Eucalyptus globulus inhibits dipeptidyl peptidase 4 in an aggregated form.

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Kato, Eisuke; Kawakami, Kazuhiro; Kawabata, Jun

2018-12-01

Dipeptidyl peptidase 4 (DPP-4) inhibitors are used for the treatment of type-2 diabetes mellitus. Various synthetic inhibitors have been developed to date, and plants containing natural DPP-4 inhibitors have also been identified. Here, 13 plant samples were tested for their DPP-4 inhibitory activity. Macrocarpals A-C were isolated from Eucalyptus globulus through activity-guided fractionation and shown to be DPP-4 inhibitors. Of these, macrocarpal C showed the highest inhibitory activity, demonstrating an inhibition curve characterised by a pronounced increase in activity within a narrow concentration range. Evaluation of macrocarpal C solution by turbidity, nuclear magnetic resonance spectroscopy and mass spectrometry indicated its aggregation, which may explain the characteristics of the inhibition curve. These findings will be valuable for further study of potential small molecule DPP-4 inhibitors.

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins [v2; ref status: indexed, http://f1000r.es/4wz

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Sandeep Chakraborty

2015-01-01

Full Text Available The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4 inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237 and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff with known structures using serine protease (SPASE motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of

Attenuation of renovascular damage in Zucker diabetic fatty rat by NWT-03, an egg protein hydrolysate with ACE- and DPP4-inhibitory Activity.

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Yumei Wang

Full Text Available BACKGROUND: Dipeptidyl peptidase 4 (DPP4 and angiotensin-converting enzyme (ACE are important target enzymes in glycemic control and renovascular protection. Here, we studied the effect of NWT-03, an egg protein hydrolysate with DPP4- and ACE-inhibitory activity, on renovascular damage in Zucker diabetic fatty (ZDF rats. Comparisons were made to rats treated with vildagliptin (VIL, included as a positive control for the effect of DPP4 inhibition. METHODS: ZDF rats received NWT-03 (1 g/kg/day or VIL (3 mg/kg/day from 10 to 25 weeks of age. Metabolic and renal functions were assessed; the kidney was removed for histological analysis of glomerulosclerosis and expression of pro-inflammatory/fibrotic markers (RT-PCR and Western blotting; and the aorta was removed for studies of endothelium-dependent relaxation (EDR. FINDINGS: Hyperinsulinemic ZDF rats typically developed signs of type-2 diabetes and renovascular damage, as evidenced by albuminuria, glomerulosclerosis, and impaired EDR. Neither NWT-03 nor VIL improved metabolic parameters; for VIL, this was despite a 5-fold increase in glucagon-like peptide (GLP-1 levels. NWT-03 and VIL both reduced renal interleukin (Il-1β/Il-13 mRNA expression and glomerulosclerosis. However, only NWT-03 additionally decreased renal tumor necrosis factor (TNF-α mRNA and P22(phox protein expression, reduced albuminuria, and restored aortic EDR. Indomethacin added to the organ bath instantly improved aortic EDR, indicating a role for cyclooxygenase (COX-derived contractile prostanoids in opposing relaxation in ZDF rats. This indomethacin effect was reduced by NWT-03, but not by VIL, and coincided with decreased renal COX-1/2 protein expression. CONCLUSION AND INTERPRETATION: Long-term supplementation with the egg protein hydrolysate NWT-03 attenuated renovascular damage in this preclinical rat model of type 2 diabetes. A comparison to the DPP4-inhibitor VIL suggests that the effects of NWT-03 were related to both

Identification of Dipeptidyl-Peptidase (DPP5 and DPP7 in Porphyromonas endodontalis, Distinct from Those in Porphyromonas gingivalis.

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Haruka Nishimata

Full Text Available Dipeptidyl peptidases (DPPs that liberate dipeptides from the N-terminal end of oligopeptides are crucial for the growth of Porphyromonas species, anaerobic asaccharolytic gram negative rods that utilize amino acids as energy sources. Porphyromonas endodontalis is a causative agent of periapical lesions with acute symptoms and Asp/Glu-specific DPP11 has been solely characterized in this organism. In this study, we identified and characterized two P. endodontalis DPPs, DPP5 and DPP7. Cell-associated DPP activity toward Lys-Ala-4-methylcoumaryl-7-amide (MCA was prominent in P. endodontalis ATCC 35406 as compared with the Porphyromonas gingivalis strains ATCC 33277, 16-1, HW24D1, ATCC 49417, W83, W50, and HNA99. The level of hydrolysis of Leu-Asp-MCA by DPP11, Gly-Pro-MCA by DPP4, and Met-Leu-MCA was also higher than in the P. gingivalis strains. MER236725 and MER278904 are P. endodontalis proteins belong to the S9- and S46-family peptidases, respectively. Recombinant MER236725 exhibited enzymatic properties including substrate specificity, and salt- and pH-dependence similar to P. gingivalis DPP5 belonging to the S9 family. However, the kcat/Km figure (194 µM-1·sec-1 for the most potent substrate (Lys-Ala-MCA was 18.4-fold higher as compared to the P. gingivalis entity (10.5 µM-1·sec-1. In addition, P. endodontalis DPP5 mRNA and protein contents were increased several fold as compared with those in P. gingivalis. Recombinant MER278904 preferentially hydrolyzed Met-Leu-MCA and exhibited a substrate specificity similar to P. gingivalis DPP7 belonging to the S46 family. In accord with the deduced molecular mass of 818 amino acids, a 105-kDa band was immunologically detected, indicating that P. endodontalis DPP7 is an exceptionally large molecule in the DPP7/DPP11/S46 peptidase family. The enhancement of four DPP activities was conclusively demonstrated in P. endodontalis, and remarkable Lys-Ala-MCA-hydrolysis was achieved by qualitative and

Identification of Dipeptidyl-Peptidase (DPP)5 and DPP7 in Porphyromonas endodontalis, Distinct from Those in Porphyromonas gingivalis.

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Nishimata, Haruka; Ohara-Nemoto, Yuko; Baba, Tomomi T; Hoshino, Tomonori; Fujiwara, Taku; Shimoyama, Yu; Kimura, Shigenobu; Nemoto, Takayuki K

2014-01-01

Dipeptidyl peptidases (DPPs) that liberate dipeptides from the N-terminal end of oligopeptides are crucial for the growth of Porphyromonas species, anaerobic asaccharolytic gram negative rods that utilize amino acids as energy sources. Porphyromonas endodontalis is a causative agent of periapical lesions with acute symptoms and Asp/Glu-specific DPP11 has been solely characterized in this organism. In this study, we identified and characterized two P. endodontalis DPPs, DPP5 and DPP7. Cell-associated DPP activity toward Lys-Ala-4-methylcoumaryl-7-amide (MCA) was prominent in P. endodontalis ATCC 35406 as compared with the Porphyromonas gingivalis strains ATCC 33277, 16-1, HW24D1, ATCC 49417, W83, W50, and HNA99. The level of hydrolysis of Leu-Asp-MCA by DPP11, Gly-Pro-MCA by DPP4, and Met-Leu-MCA was also higher than in the P. gingivalis strains. MER236725 and MER278904 are P. endodontalis proteins belong to the S9- and S46-family peptidases, respectively. Recombinant MER236725 exhibited enzymatic properties including substrate specificity, and salt- and pH-dependence similar to P. gingivalis DPP5 belonging to the S9 family. However, the kcat/Km figure (194 µM-1·sec-1) for the most potent substrate (Lys-Ala-MCA) was 18.4-fold higher as compared to the P. gingivalis entity (10.5 µM-1·sec-1). In addition, P. endodontalis DPP5 mRNA and protein contents were increased several fold as compared with those in P. gingivalis. Recombinant MER278904 preferentially hydrolyzed Met-Leu-MCA and exhibited a substrate specificity similar to P. gingivalis DPP7 belonging to the S46 family. In accord with the deduced molecular mass of 818 amino acids, a 105-kDa band was immunologically detected, indicating that P. endodontalis DPP7 is an exceptionally large molecule in the DPP7/DPP11/S46 peptidase family. The enhancement of four DPP activities was conclusively demonstrated in P. endodontalis, and remarkable Lys-Ala-MCA-hydrolysis was achieved by qualitative and quantitative

Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors

DEFF Research Database (Denmark)

Hansotia, Tanya; Baggio, Laurie L; Delmeire, Dominique

2004-01-01

with GIPR(-/-) or GLP-1R(-/-) mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-IV (DPP-IV) inhibitors valine pyrrolidide (Val-Pyr) and SYR106124 lowered glucose and increased plasma insulin...

4-Substituted boro-proline dipeptides: synthesis, characterization, and dipeptidyl peptidase IV, 8, and 9 activities.

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Wu, Wengen; Liu, Yuxin; Milo, Lawrence J; Shu, Ying; Zhao, Peng; Li, Youhua; Woznica, Iwona; Yu, Gengli; Sanford, David G; Zhou, Yuhong; Poplawski, Sarah E; Connolly, Beth A; Sudmeier, James L; Bachovchin, William W; Lai, Jack H

2012-09-01

The boroProline-based dipeptidyl boronic acids were among the first DPP-IV inhibitors identified, and remain the most potent known. We introduced various substitutions at the 4-position of the boroProline ring regioselectively and stereoselectively, and incorporated these aminoboronic acids into a series of 4-substituted boroPro-based dipeptides. Among these dipeptidyl boronic acids, Arg-(4S)-boroHyp (4q) was the most potent inhibitor of DPP-IV, DPP8 and DPP9, while (4S)-Hyp-(4R)-boroHyp (4o) exhibited the most selectivity for DPP-IV over DPP8 and DPP9. Copyright © 2012 Elsevier Ltd. All rights reserved.

Canagliflozin provides greater attainment of both HbA1c and body weight reduction versus sitagliptin in patients with type 2 diabetes.

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Schernthaner, Guntram; Lavalle-González, Fernando J; Davidson, Jaime A; Jodon, Holly; Vijapurkar, Ujjwala; Qiu, Rong; Canovatchel, William

2016-11-01

To evaluate the proportion of patients with type 2 diabetes mellitus (T2DM) achieving reductions in both glycated hemoglobin (HbA1c) and body weight with canagliflozin, a sodium glucose co-transporter 2 inhibitor, versus sitagliptin over 52 weeks. Data were pooled from two, randomized, Phase 3 studies of canagliflozin 100 and 300 mg versus sitagliptin 100 mg as add-on to metformin, and canagliflozin 300 mg versus sitagliptin 100 mg as add-on to metformin plus sulfonylurea (N = 1856). The composite end points of change from baseline in both HbA1c HbA1c HbA1c and body weight over 52 weeks versus sitagliptin. A greater proportion of patients had both HbA1c and body weight reductions with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (67.7%, 72.6%, and 44.1%, respectively). Among patients with HbA1c and body weight reductions, more patients achieved the composite end point of HbA1c HbA1c and body weight, and more patients with HbA1c and body weight reductions achieved HbA1c <7.0% and body weight reduction ≥5% with canagliflozin versus sitagliptin over 52 weeks. www.ClinicalTrials.gov identifiers are NCT01106677; NCT01137812.

Vildagliptin and its metabolite M20.7 induce the expression of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells.

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Asakura, Mitsutoshi; Karaki, Fumika; Fujii, Hideaki; Atsuda, Koichiro; Itoh, Tomoo; Fujiwara, Ryoichi

2016-10-19

Vildagliptin is a potent, orally active inhibitor of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes mellitus. It has been reported that vildagliptin can cause hepatic dysfunction in patients. However, the molecular-mechanism of vildagliptin-induced liver dysfunction has not been elucidated. In this study, we employed an expression microarray to determine hepatic genes that were highly regulated by vildagliptin in mice. We found that pro-inflammatory S100 calcium-binding protein (S100) a8 and S100a9 were induced more than 5-fold by vildagliptin in the mouse liver. We further examined the effects of vildagliptin and its major metabolite M20.7 on the mRNA expression levels of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells. In HepG2 cells, vildagliptin, M20.7, and sitagliptin - another DPP-4 inhibitor - induced S100A9 mRNA. In HL-60 cells, in contrast, S100A8 and S100A9 mRNAs were significantly induced by vildagliptin and M20.7, but not by sitagliptin. The release of S100A8/A9 complex in the cell culturing medium was observed in the HL-60 cells treated with vildagliptin and M20.7. Therefore, the parental vildagliptin- and M20.7-induced release of S100A8/A9 complex from immune cells, such as neutrophils, might be a contributing factor of vildagliptin-associated liver dysfunction in humans.

Dipeptidyl peptidase 4 - An important digestive peptidase in Tenebrio molitor larvae.

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Tereshchenkova, Valeriia F; Goptar, Irina A; Kulemzina, Irina A; Zhuzhikov, Dmitry P; Serebryakova, Marina V; Belozersky, Mikhail A; Dunaevsky, Yakov E; Oppert, Brenda; Filippova, Irina Yu; Elpidina, Elena N

2016-09-01

Dipeptidyl peptidase 4 (DPP 4) is a proline specific serine peptidase that plays an important role in different regulatory processes in mammals. In this report, we isolated and characterized a unique secreted digestive DPP 4 from the anterior midgut of a stored product pest, Tenebrio molitor larvae (TmDPP 4), with a biological function different than that of the well-studied mammalian DPP 4. The sequence of the purified enzyme was confirmed by mass-spectrometry, and was identical to the translated RNA sequence found in a gut EST database. The purified peptidase was characterized according to its localization in the midgut, and substrate specificity and inhibitor sensitivity were compared with those of human recombinant DPP 4 (rhDPP 4). The T. molitor enzyme was localized mainly in the anterior midgut of the larvae, and 81% of the activity was found in the fraction of soluble gut contents, while human DPP 4 is a membrane enzyme. TmDPP 4 was stable in the pH range 5.0-9.0, with an optimum activity at pH 7.9, similar to human DPP 4. Only specific inhibitors of serine peptidases, diisopropyl fluorophosphate and phenylmethylsulfonyl fluoride, suppressed TmDPP 4 activity, and the specific dipeptidyl peptidase inhibitor vildagliptin was most potent. The highest rate of TmDPP 4 hydrolysis was found for the synthetic substrate Arg-Pro-pNA, while Ala-Pro-pNA was a better substrate for rhDPP 4. Related to its function in the insect midgut, TmDPP 4 efficiently hydrolyzed the wheat storage proteins gliadins, which are major dietary proteins of T. molitor. Published by Elsevier Ltd.

Prediction of the effect on antihyperglycaemic action of sitagliptin by plasma active form glucagon-like peptide-1.

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Kushiyama, Akifumi; Kikuchi, Takako; Tanaka, Kentaro; Tahara, Tazu; Takao, Toshiko; Onishi, Yukiko; Yoshida, Yoko; Kawazu, Shoji; Iwamoto, Yasuhiko

2016-06-10

To investigate whether active glucagon-like peptide-1 (GLP-1) is a prediction Factor of Effect of sitagliptin on patients with type 2 diabetes mellitus (GLP-1 FEST:UMIN000010645). Seventy-six patients with type 2 diabetes, who had insufficient glycemic control [Hemoglobin A1c (HbA1c) ≥ 7%] in spite of treatment with metformin and/or sulfonylurea, were included in the investigation. Patients were divided into three groups by tertiles of fasting plasma active GLP-1 level, before the administration of 50 mg sitagliptin. At baseline, body mass index, serum UA, insulin and HOMA-IR were higher in the high active GLP-1 group than in the other two groups. The high active GLP-1 group did not show any decline of HbA1c (7.6% ± 1.4% to 7.5% ± 1.5%), whereas the middle and low groups indicated significant decline of HbA1c (7.4 ± 0.7 to 6.8 ± 0.6 and 7.4 ± 1.2 to 6.9 ± 1.3, respectively) during six months. Only the low and middle groups showed a significant increment of active GLP-1, C-peptide level, a decreased log and proinsulin/insulin ratio after administration. In logistic analysis, the low or middle group is a significant explanatory variable for an HbA1c decrease of ≥ 0.5%, and its odds ratio is 4.5 (1.40-17.6) (P = 0.01) against the high active GLP-1 group. This remains independent when adjusted for HbA1c level before administration, patients' medical history, medications, insulin secretion and insulin resistance. Plasma fasting active GLP-1 is an independent predictive marker for the efficacy of dipeptidyl peptidase 4 inhibitor sitagliptin.

The Dipeptidyl Peptidases 4, 8, and 9 in Mouse Monocytes and Macrophages: DPP8/9 Inhibition Attenuates M1 Macrophage Activation in Mice.

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Waumans, Yannick; Vliegen, Gwendolyn; Maes, Lynn; Rombouts, Miche; Declerck, Ken; Van Der Veken, Pieter; Vanden Berghe, Wim; De Meyer, Guido R Y; Schrijvers, Dorien; De Meester, Ingrid

2016-02-01

Atherosclerosis remains the leading cause of death in Western countries. Dipeptidyl peptidase (DPP) 4 has emerged as a novel target for the prevention and treatment of atherosclerosis. Family members DPP8 and 9 are abundantly present in macrophage-rich regions of atherosclerotic plaques, and DPP9 inhibition attenuates activation of human M1 macrophages in vitro. Studying this family in a mouse model for atherosclerosis would greatly advance our knowledge regarding their potential as therapeutic targets. We found that DPP4 is downregulated during mouse monocyte-to-macrophage differentiation. DPP8 and 9 expression seems relatively low in mouse monocytes and macrophages. Viability of primary mouse macrophages is unaffected by DPP4 or DPP8/9 inhibition. Importantly, DPP8/9 inhibition attenuates macrophage activation as IL-6 secretion is significantly decreased. Mouse macrophages respond similarly to DPP inhibition, compared to human macrophages. This shows that the mouse could become a valid model species for the study of DPPs as therapeutic targets in atherosclerosis.

ROLE OF DPP-IV INHIBITORS IN TREATMENT OF TYPE II DIABETES

OpenAIRE

Patel Kishan D; Patel Grishma M.

2010-01-01

Emerging as an epidemic of the 21st century type II diabetes has become a major health problem throughout the globe. Known treatments of type II diabetes mellitus have limitations such as weight gain and hypoglycaemias. A new perspective is the use of incretin hormones and incretin enhancers. Incretin mimetics are a new class of pharmacological agents with multiple antihyperglycemic actions that mimic the actions of incretin hormones such as glucagon-like peptide (GLP)-1. DPP-4, a protease th...

Neuroprotective effect of selective DPP-4 inhibitor in experimental vascular dementia.

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Jain, Swati; Sharma, Bhupesh

2015-12-01

Vascular risk factors are associated with a higher incidence of dementia. Diabetes mellitus is considered as a main risk factor for Alzheimer's disease and vascular dementia. Both forms of dementia are posing greater risk to the world population and are increasing at a faster rate. In the past we have reported the induction of vascular dementia by experimental diabetes. This study investigates the role of vildagliptin, a dipeptidyl peptidase-4 inhibitor in the pharmacological interdiction of pancreatectomy diabetes induced vascular endothelial dysfunction and subsequent vascular dementia in rats. Attentional set shifting and Morris water-maze test were used for assessment of learning and memory. Vascular endothelial function, blood brain barrier permeability, serum glucose, serum nitrite/nitrate, oxidative stress (viz. aortic superoxide anion, brain thiobarbituric acid reactive species and brain glutathione), brain calcium and inflammation (myeloperoxidase) were also estimated. Pancreatectomy diabetes rats have shown impairment of endothelial function, blood brain barrier permeability, learning and memory along with increase in brain inflammation, oxidative stress and calcium. Administration of vildagliptin has significantly attenuated pancreatectomy induced impairment of learning, memory, endothelial function, blood brain barrier permeability and biochemical parameters. It may be concluded that vildagliptin, a dipeptidyl peptidase-4 inhibitor may be considered as potential pharmacological agents for the management of pancreatectomy induced endothelial dysfunction and subsequent vascular dementia. The selective modulators of dipeptidyl peptidase-4 may further be explored for their possible benefits in vascular dementia. Copyright © 2015 Elsevier Inc. All rights reserved.

Inhibitory potency of Withania somnifera extracts against DPP-4: an ...

African Journals Online (AJOL)

Materials and Methods: Young and matured fresh roots, leaves, and fruits of WS plant extract were considered and were systematically evaluated for DPP-4 inhibitory activity using in vitro method, enzyme kinetics, phytochemical analysis, RP-HPLC, LCMS and 1H and 13C NMR method and structure-activity relationship ...

Dipeptidyl Peptidase-4 Inhibitors and the Risk of Pancreatitis in Patients with Type 2 Diabetes Mellitus: A Population-Based Cohort Study

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Young-Gun Kim

2018-01-01

Full Text Available Background. Information on the risk of acute pancreatitis in patients receiving dipeptidyl-peptidase IV inhibitors (DPP-4i is limited and controversial. One study suggested that the differences in findings between these meta-analyses were attributed to whether they included large randomized control trials with cardiovascular outcomes or not. The aim of our study was to determine whether the use of DPP-4i increases the risk of acute pancreatitis compared with sulfonylurea (SU and whether the risk is higher in patients with underlying cardiovascular disease (CVD. Methods. A population-based cohort study was performed using Korean National Health Insurance Service-National Sample Cohort data. We included 33,395 new users of SU and DPP-4i from 1 January 2008 to 31 December 2015. SU-treated patients and DPP-4i-treated patients were matched by 1 : 1 propensity score matching. We used Kaplan–Meier curves and Cox proportional hazards regression analysis to calculate the risk of acute pancreatitis. Results. The hazard ratio (HR of hospitalization for acute pancreatitis was 0.642 (95% confidence interval (CI: 0.535–0.771 in DPP-4i-treated patients compared with SU-treated patients. The HR of DPP-4i use was also lower than that of SU use in patients without underlying CVD (HR: 0.591; 95% CI: 0.476–0.735 but not in patients with underlying CVD (HR: 0.727; 95% CI: 0.527–1.003. Conclusion. Our findings suggest that DPP-4i is less likely to cause drug-induced pancreatitis than SU. This finding was not evident in patients with CVD, but DPP-4i was not more likely to induce pancreatitis in these patients than SU was.

Diabetes Prevention Program (DPP)

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... Recruiting Patients & Families Consortia, Networks & Centers Reports & Planning Diabetes Prevention Program (DPP) The NIDDK-sponsored Diabetes Prevention ... Diabetes Prevention Program for those who are eligible. Diabetes Prevention Program (DPP) DPP Goal The DPP looked ...

DPP6 domains responsible for its localization and function.

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Lin, Lin; Long, Laura K; Hatch, Michael M; Hoffman, Dax A

2014-11-14

Dipeptidyl peptidase-like protein 6 (DPP6) is an auxiliary subunit of the Kv4 family of voltage-gated K(+) channels known to enhance channel surface expression and potently accelerate their kinetics. DPP6 is a single transmembrane protein, which is structurally remarkable for its large extracellular domain. Included in this domain is a cysteine-rich motif, the function of which is unknown. Here we show that this cysteine-rich domain of DPP6 is required for its export from the ER and expression on the cell surface. Disulfide bridges formed at C349/C356 and C465/C468 of the cysteine-rich domain are necessary for the enhancement of Kv4.2 channel surface expression but not its interaction with Kv4.2 subunits. The short intracellular N-terminal and transmembrane domains of DPP6 associates with and accelerates the recovery from inactivation of Kv4.2, but the entire extracellular domain is necessary to enhance Kv4.2 surface expression and stabilization. Our findings show that the cysteine-rich domain of DPP6 plays an important role in protein folding of DPP6 that is required for transport of DPP6/Kv4.2 complexes out of the ER. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Possible applications of gliptins (dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus on the various modes of insulin therapy

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Gagik Radikovich Galstyan

2015-10-01

Full Text Available The evidence for DPP-4 inhibitors effectiveness at the late stages of type 2 diabetes mellitus (T2DM are still growing. This is particularly important for those patients who receive insulin without adequately glycemic control. This publication provides the overview of studies which demonstrate high efficacy of Vildagliptin in reducing the blood glucose level in patients with hight duration of T2DM and insulin therapy. DPP-4 inhibitors normalize basal and postprandial glucagon secretion with pancreas α-cells that helps to provide better glycemic control and to reduce a risk of hypoglycemia. Besides, there are very interesting data for Vildagliptin to reduce insulin requirement in T2DM patients in addition to HbA1clevel decrease.

Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study.

Science.gov (United States)

Seong, Jong-Mi; Choi, Nam-Kyong; Shin, Ju-Young; Chang, Yoosoo; Kim, Ye-Jee; Lee, Joongyub; Kim, Ju-Young; Park, Byung-Joo

2015-01-01

Data on the comparative effectiveness of oral antidiabetics on cardiovascular outcomes in a clinical practice setting are limited. This study sought to determine whether a differential risk of cardiovascular disease (CVD) exists for the combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor plus metformin versus a sulfonylurea derivative plus metformin or pioglitazone plus metformin. We conducted a cohort study of 349,476 patients who received treatment with a DPP-4 inhibitor, sulfonylurea, or pioglitazone plus metformin for type 2 diabetes using the Korean national health insurance claims database. The incidence of total CVD and individual outcomes of myocardial infarction (MI), heart failure (HF), and ischemic stroke (IS) were assessed using the hazard ratios (HRs) estimated from a Cox proportional-hazards model weighted for a propensity score. During follow-up, 3,881 patients developed a CVD, including 428 MIs, 212 HFs, and 1,487 ISs. The adjusted HR with 95% confidence interval (CI) for a sulfonylurea derivative plus metformin compared with a DPP-4 inhibitor plus metformin was 1.20 (1.09-1.32) for total CVD; 1.14 (1.04-1.91) for MI; 1.07 (0.71-1.62) for HF; and 1.51 (1.28-1.79) for IS. The HRs with 95% CI for total CVD, MI, HF, and IS for pioglitazone plus metformin were 0.89 (0.81-0.99), 1.05 (0.76-1.46), 4.81 (3.53-6.56), and 0.81 (0.67-0.99), respectively. Compared with a DPP-4 inhibitor plus metformin, treatment with a sulfonylurea drug plus metformin was associated with increased risks of total CVD, MI, and IS, whereas the use of pioglitazone plus metformin was associated with decreased total CVD and IS risks.

Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study.

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Jong-Mi Seong

Full Text Available Data on the comparative effectiveness of oral antidiabetics on cardiovascular outcomes in a clinical practice setting are limited. This study sought to determine whether a differential risk of cardiovascular disease (CVD exists for the combination of a dipeptidyl peptidase-4 (DPP-4 inhibitor plus metformin versus a sulfonylurea derivative plus metformin or pioglitazone plus metformin.We conducted a cohort study of 349,476 patients who received treatment with a DPP-4 inhibitor, sulfonylurea, or pioglitazone plus metformin for type 2 diabetes using the Korean national health insurance claims database. The incidence of total CVD and individual outcomes of myocardial infarction (MI, heart failure (HF, and ischemic stroke (IS were assessed using the hazard ratios (HRs estimated from a Cox proportional-hazards model weighted for a propensity score.During follow-up, 3,881 patients developed a CVD, including 428 MIs, 212 HFs, and 1,487 ISs. The adjusted HR with 95% confidence interval (CI for a sulfonylurea derivative plus metformin compared with a DPP-4 inhibitor plus metformin was 1.20 (1.09-1.32 for total CVD; 1.14 (1.04-1.91 for MI; 1.07 (0.71-1.62 for HF; and 1.51 (1.28-1.79 for IS. The HRs with 95% CI for total CVD, MI, HF, and IS for pioglitazone plus metformin were 0.89 (0.81-0.99, 1.05 (0.76-1.46, 4.81 (3.53-6.56, and 0.81 (0.67-0.99, respectively.Compared with a DPP-4 inhibitor plus metformin, treatment with a sulfonylurea drug plus metformin was associated with increased risks of total CVD, MI, and IS, whereas the use of pioglitazone plus metformin was associated with decreased total CVD and IS risks.

A Randomized Controlled Trial of Vildagliptin Versus Alogliptin: Effective Switch From Sitagliptin in Patients With Type 2 Diabetes.

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Shigematsu, Erina; Yamakawa, Tadashi; Oba, Mari S; Suzuki, Jun; Nagakura, Jo; Kadonosono, Kazuaki; Terauchi, Yasuo

2017-07-01

We investigated the effects of vildagliptin or alogliptin on blood glucose and hemoglobin A1c (HbA1c) in patients with type 2 diabetes inadequately controlled by sitagliptin. In a single-center open-label trial, 35 patients with inadequate glycemic control on sitagliptin therapy (50 mg once daily) were randomly switched to treatment with vildagliptin (50 mg twice daily) or alogliptin (25 mg once daily). After 12 weeks, patients who failed to achieve the target HbA1c level of vildagliptin or alogliptin treatment were switched to high-dose sitagliptin (100 mg once daily) and the effect on glycemic control was assessed. Vildagliptin did not significantly alter the mean plasma glucose level (175.5 ± 54.4 mg/dL vs. 179.1 ± 73.4 mg/dL) or HbA1c (8.01% vs. 8.02%) after 12 weeks. With alogliptin, mean plasma glucose increased from 175.4 ± 50.9 mg/dL to 195.3 ± 55.0 mg/dL after 12 weeks and HbA1c increased significantly from 8.0% to 8.3% (P vildagliptin to high-dose sitagliptin (100 mg daily), HbA1c was increased to 8.3%, but it was significantly (P vildagliptin group than the alogliptin group (P = 0.008), but the response rate (achieving the target HbA1c vildagliptin, alogliptin, and sitagliptin) were different, and the effects of vildagliptin and sitagliptin were stronger than that of alogliptin.

Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV

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Landersdorfer, Cornelia B; He, Yan-Ling; Jusko, William J

2012-01-01

AIMS To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology. METHODS Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling. RESULTS A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h−1 (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%). CONCLUSIONS Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties. PMID:22442826

Identification and characterization of a dipeptidyl peptidase IV inhibitor from aronia juice

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Kozuka, Miyuki [Department of Health and Nutrition, Faculty of Human Science, Hokkaido Bunkyo University, Eniwa 061-1449 (Japan); Yamane, Takuya, E-mail: t-yamane@pharm.hokudai.ac.jp [Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812 (Japan); Nakano, Yoshihisa [Center for Research and Development Bioresources, Research Organization for University-Community Collaborations, Osaka Prefecture University, Sakai, Osaka 599-8570 (Japan); Nakagaki, Takenori [Institute of Food Sciences, Nakagaki Consulting Engineer Co., Ltd, Nishi-ku, Sakai 593-8328 (Japan); Ohkubo, Iwao [Department of Nutrition, School of Nursing and Nutrition, Tenshi College, Higashi-ku, Sapporo 065-0013 (Japan); Ariga, Hiroyoshi [Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812 (Japan)

2015-09-25

Aronia berries have many potential effects on health, including an antioxidant effect, effect for antimutagenesis, hepatoprotection and cardioprotection, an antidiabetic effect and inhibition of cancer cell proliferation. Previous human studies have shown that aronia juice may be useful for treatment of obesity disorders. In this study, we found that aronia juice has an inhibitory effect against dipeptidyl peptidase IV (DPP IV) (EC 3.4.14.5). DPP IV is a peptidase that cleaves the N-terminal region of incretins such as glucagon-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Inactivation of incretins by DPP IV induces reduction of insulin secretion. Furthermore, we identified that cyanidin 3, 5-diglucoside as the DPP IV inhibitor in aronia juice. DPP IV was inhibited more strongly by cyanidin 3, 5-diglucoside than by cyanidin and cyanidin 3-glucoside. The results suggest that DPP IV is inhibited by cyanidin 3, 5-diglucoside present in aronia juice. The antidiabetic effect of aronia juice may be mediated through DPP IV inhibition by cyanidin 3, 5-diglucoside. - Highlights: • DPP IV activity is inhibited by aronia juice. • DPP IV inhibitor is cyanidin 3, 5-diglucoside in aronia juice. • DPP IV is inhibited by cyanidin 3, 5-diglucoside more than cyanidin and cyanidin 3-glucoside.

Cost-consequence analysis of sitagliptin versus sulfonylureas as add-on therapy for the treatment of diabetic patients in Italy

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Lorenzoni V

2017-11-01

Full Text Available Valentina Lorenzoni,1 Fabio Baccetti,2 Stefano Genovese,3 Enrico Torre,4 Giuseppe Turchetti1 1Institute of Management, Scuola Superiore Sant’Anna, Pisa, Italy; 2SD Diabetology, ASL Toscana Nordovest, Massa Carrara, Italy; 3Cardiovascular and Metabolic Department, IRCCS Multimedica Sesto San Giovanni, Milan, Italy; 4SSD Endocrinologia, Diabetologia e Malattie metaboliche, ASL 3 Genovese, Genoa, Italy Objective: Diabetes mellitus is a chronic disease related to a significant impact in both epidemiologic and economic terms. In Italy, around 3.6 million people are affected by diabetes and this number is expected to increase significantly in the next few years. As recommended by current national and international guidelines, metformin (Met is prescribed as first-line pharmacological treatment, and many pharmacological alternatives are available for patients uncontrolled with Met monotherapy. Despite the availability of many innovative oral antidiabetic drugs (OADs, such as dipeptidyl peptidase 4 inhibitors (DPP4-i and its first-in-class sitagliptin (SITA, which entered the Italian market in the last 10 years, their usage is consistently lower than traditional drugs such as sulfonylureas (SUs. In fact, due to higher acquisition costs, the prescription of innovative OADs in Italy is restricted to specialist, resulting in a prominent usage of traditional OAD that can be prescribed also by general practitioners (GPs. A cost consequence analysis (CCA was performed in order to compare SITA with SU, as second-line therapy in add-on to Met, in terms of costs and related clinical events over 36 months.Methods: A CCA was conducted on a hypothetical cohort of 100,000 type 2 diabetes mellitus (T2DM patients uncontrolled with Met monotherapy, from both the Italian National Health Service (INHS and societal perspective. Therefore, both direct (drugs, self-monitoring, hypoglycemia, major cardiovascular events [MACEs], and switch to insulin and indirect costs

Effect of sitagliptin on blood glucose control in patients with type 2 diabetes mellitus who are treatment naive or poorly responsive to existing antidiabetic drugs: the JAMP study.

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Sakura, Hiroshi; Hashimoto, Naotake; Sasamoto, Kazuo; Ohashi, Hiroshi; Hasumi, Sumiko; Ujihara, Noriko; Kasahara, Tadasu; Tomonaga, Osamu; Nunome, Hideo; Honda, Masashi; Iwamoto, Yasuhiko

2016-12-01

To investigate the ameliorating effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood glucose control in patients with type 2 diabetes mellitus who were previously untreated with or who have a poor responsive to existing antidiabetic drugs. Sitagliptin (50 mg/day) was added on to the pre-existing therapy for type 2 diabetes and changes in the glycated hemoglobin (HbA1c) level after 3 months of treatment were compared with the baseline and performed exploratory analysis. HbA1c levels were significantly decreased after 1 month of treatment compared to baseline, with a mean change in HbA1c level from baseline of -0.73% (range, -0.80 to -0.67) in the entire study population at 3 months. Patients who received a medium dose of glimepiride showed the least improvement in HbA1c levels. The percentage of patients who achieved an HbA1c level of blood glucose level of type 2 diabetes mellitus who were previously untreated with, or poorly responsive to, existing antidiabetic drugs. Thus, sitagliptin is expected to be useful in this patient group. However, the additional administration of sitagliptin in patients treated with medium-dose glimepiride only slightly improved blood glucose control when corrected for baseline HbA1c level.

Dipeptidyl peptidase IV inhibitors derived from a mangrove flora Rhizophora mucronata: An in silico approach

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Selvaraj Gurudeeban

2012-08-01

Full Text Available Dipeptidyl peptidase IV (DPP IV is responsible for conversion of glucose tolerance (GLP-1, into inactive form. The inhibition of DPP IV would be beneficial in the treatment of diabetes mellitus. Therefore, the aim of the present study was to isolate and evaluate cystine, phenyl acetic acid, acrylamide, caprylone and oleic acid from Rhizophora mucronata inhibitory action on DPP IV inhibitors using in silico approach. In silico analysis of cystine, phenyl acetic acid, acrylamide, caprylone and oleic acid on human apo DPP IV protein was done by using Autodoc 4.0. Among the five compounds cysteine acts as an inhibitor with binding energy -5.89 kcal/mol, seven hydrogen bond interactions at residues VAL459, VAL 459, GLU408, GLU206, ARG358, GLU205 and SER209 to suppresses the action of DPP IV protein.

Incretin-based therapies for type 2 diabetes mellitus in Asian patients: Analysis of clinical trials

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Melva Louisa

2010-08-01

Full Text Available Aim To review the effi cacy and safety data on incretin-based therapies currently available (exenatide, liraglutide, sitagliptin, vildagliptin for the treatment of type 2 diabetes mellitus in Asian population.Methods We conducted Medline search of all relevant randomized clinical trials of incretin-based therapies for type 2 diabetes mellitus in Asian populations. Data pertinent to the efficacy and safety of GLP-1 mimetics and DPP-4 inhibitors were extracted and used.Results We found 14 randomized controlled trials of incretin based-therapy which included 3567 type 2 diabetes mellitus in Asian population (Japanese, Chinese, Korean, Indian. It was shown that incretin-based therapies improved HbA1c at higher extent (up to -1.42% in exenatide 10 mcg bid, -1.85% for liraglutide 0.9 mg qd, -1.4% for sitagliptin 100 mg and -1.4% for vildagliptin 50 mg bid compared to the effects observed in studies with Caucasian population, with comparable safety profile.Conclusion The efficacy of incretin-based therapies in Asian patients improved glycemic parameters in a higher magnitude on some glycemic parameters compared with those in Caucasian population. These results indicate that incretin-based therapies may be more effective in Asian population than in Caucasian. (Med J Indones 2010; 19: 205-12Key words: exenatide, incretin, liraglutide, sitagliptin, type-2 diabetes, vildagliptin

Association of dipeptidyl peptidase 4 inhibitors with risk of metastases in patients with type 2 diabetes and breast, prostate or digestive system cancer.

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Rathmann, Wolfgang; Kostev, Karel

2017-04-01

Experimental and animal studies have supported the hypothesis that dipeptidyl peptidase-4 inhibitors (DPP-4i) may accelerate tumor metastasis. The aim was to analyze the relationships between DPP-4i therapy with risk of metastases in type 2 diabetes patients with breast, prostate and digestive organ cancers. Type 2 diabetes patients with first diagnoses of breast, prostate or digestive organ cancer were selected in general and internal medicine practices (Disease Analyzer Germany: 01/2008-12/2014). Propensity score matching between DPP-4i users and non-users was carried out for age, sex, diabetes duration, and metformin use. Time-dependent Cox regression models were used to estimate hazard ratios (HR) for metastases further adjusting for HbA1c, body mass index, comorbidity and co-therapy with glucose-lowering drugs (3-4years follow-up). 668 patients with newly diagnosed breast cancer, 906 with prostate cancer and 908 with digestive organ cancer were analyzed. In Cox regression, use of DPP-4i was not associated with an increased risk of metastases in patients with breast (adjusted HR, 95%CI: 1.00, 0.49-2.02), prostate (0.98, 0.54-1.77) or digestive organ cancers (0.97, 0.57-1.66). This first observational study in patients with type 2 diabetes and breast, prostate or digestive organ cancer found no increased risk of metastases in DPP-4i users. Copyright © 2017 Elsevier Inc. All rights reserved.

Hypoglycemia hospitalization frequency in patients with type 2 diabetes mellitus: a comparison of dipeptidyl peptidase 4 inhibitors and insulin secretagogues using the French health insurance database

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Detournay B

2015-07-01

Full Text Available Bruno Detournay,1 Serge Halimi,2,3 Julien Robert,1 Céline Deschaseaux,4 Sylvie Dejager5,6 1Cemka-Eval, Bourg-la Reine, France; 2Department of Diabetology, Endocrinology and Nutrition, Grenoble University Hospital Center, Grenoble, France; 3University Joseph Fourier, Grenoble, France; 4Novartis Pharma SAS, Market Access Department, Rueil-Malmaison, France; 5Novartis Pharma SAS, Medical and Scientific Affairs, Rueil Malmaison, France; 6Department of Diabetology, Metabolism and Endocrinology, Pitié-Salpétrière Hospital, Paris, France Aim: We aimed to compare the frequency of severe hypoglycemia leading to hospitalization (HH and emergency visits (EV for any cause in patients with type 2 diabetes mellitus exposed to dipeptidyl peptidase 4 (DPP4 inhibitors (DPP4-i versus those exposed to insulin secretagogues (IS; sulfonylureas or glinides. Methods: Data were extracted from the EGB (Echantillon Généraliste des Bénéficiaires database, comprising a representative sample of ~1% of patients registered in the French National Health Insurance System (~600,000 patients. Type 2 diabetes mellitus patients exposed to regimens containing either a DPP4-i (excluding treatment with IS, insulin, or glucagon-like peptide 1 analog or IS (excluding treatment with insulin and any incretin therapy between 2009 and 2012 were selected. HH and EV during the exposure periods were identified in both cohorts. A similar analysis was conducted considering vildagliptin alone versus IS. Comparative analyses adjusting for covariates within the model (subjects matched for key characteristics and using multinomial regression models were performed. Results: Overall, 7,152 patients exposed to any DPP4-i and 1,440 patients exposed to vildagliptin were compared to 10,019 patients exposed to IS. Eight patients (0.11% from the DPP4-i cohort and none from the vildagliptin cohort (0.0% were hospitalized for hypoglycemia versus 130 patients (1.30% from the IS cohort (138

Inhibition of dipeptidyl peptidase-4: The mechanisms of action and clinical use of vildagliptin for the management of type 2 diabetes

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Galina Smushkin

2009-06-01

Full Text Available Galina Smushkin, Adrian VellaDivision of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, USAAbstract: Postprandial hyperglycemia in type 2 diabetes is characterized by impaired insulin secretion and action, decreased glucose effectiveness and defective suppression of glucagon secretion. Newly available therapies for type 2 diabetes target the pathway of the incretin hormone glucagon-like peptide-1 (GLP-1. Oral inhibitors of dipeptidyl peptidase-4 (DPP-4 raise the level of endogenous GLP-1 by inhibiting its clearance thereby lowering fasting and postprandial glucose concentrations. Unlike compounds which act as agonists of the GLP-1 receptor, DPP-4 inhibitors are not associated with significant effects on gastrointestinal motility, which led to a controversy around the mechanisms responsible for their glucose-lowering effects. Here we review the evidence in regards to the mechanisms whereby DPP-4 inhibitors lower glucose concentrations. Their effects are most likely mediated by an increase in endogenous GLP-1, although additional mechanisms may be involved. The pharmacology, efficacy and safety of vildagliptin, a novel DPP-4 inhibitor, are also discussed.Keywords: insulin secretion, insulin action, incretin, DPP-4 inhibitor, glucagon-like peptide 1

Attenuation of Renovascular Damage in Zucker Diabetic Fatty Rat by NWT-03, an Egg Protein Hydrolysate with ACE- and DPP4-Inhibitory Activity

NARCIS (Netherlands)

Wang, Yumei; Landheer, S.; Gilst, van W.H.; Amerongen, van A.

2012-01-01

Background Dipeptidyl peptidase 4 (DPP4) and angiotensin-converting enzyme (ACE) are important target enzymes in glycemic control and renovascular protection. Here, we studied the effect of NWT-03, an egg protein hydrolysate with DPP4- and ACE-inhibitory activity, on renovascular damage in Zucker

Attenuation of Renovascular Damage in Zucker Diabetic Fatty Rat by NWT-03, an Egg Protein Hydrolysate with ACE- and DPP4-Inhibitory Activity

NARCIS (Netherlands)

Wang, Yumei; Landheer, Sjoerd; van Gilst, Wiek H.; van Amerongen, Aart; Hammes, Hans-Peter; Henning, Robert H.; Deelman, Leo E.; Buikema, Hendrik

2012-01-01

Background: Dipeptidyl peptidase 4 (DPP4) and angiotensin-converting enzyme (ACE) are important target enzymes in glycemic control and renovascular protection. Here, we studied the effect of NWT-03, an egg protein hydrolysate with DPP4- and ACE-inhibitory activity, on renovascular damage in Zucker

Does the treatment of type 2 diabetes mellitus with the DPP-4 inhibitor vildagliptin reduce HbA1c to a greater extent in Japanese patients than in Caucasian patients?

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Foley JE

2016-01-01

Full Text Available James E Foley,1 Vaishali Bhosekar,2 Ryuzo Kawamori3 1Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 2Novartis Healthcare Pvt Ltd, Hyderabad, Telangana, India; 3Sportology Center, Juntendo University Graduate School of Medicine, Juntendo University, Tokyo, Japan Background: Previous work suggests that Japanese patients with type 2 diabetes mellitus (T2DM may respond more favorably to a DPP-4 (dipeptidyl peptidase-4 inhibitor than Caucasians. We aimed to compare the efficacy of the DPP-4 inhibitor vildagliptin (50 mg twice daily [bid] between Japanese and Caucasian populations. Methods: This analysis pooled data from 19 studies of drug-naïve patients with T2DM who were treated for 12 weeks with vildagliptin 50 mg bid as monotherapy. The pool comprised Japanese patients (n=338 who had been treated in Japan and Caucasian patients (n=1,275 who were treated elsewhere. Change from baseline (Δ in glycated hemoglobin (HbA1c at 12 weeks (in millimoles per mole versus baseline HbA1c (both in percentage National Glycohemoglobin Standardization Program units [NGSP%] and millimoles per mole for each population was reported. Universal HbA1c in millimoles per mole was calculated from either the Japanese Diabetes Society or the NGSP% HbA1c standards. Results: At baseline, mean values for Japanese and Caucasian patients, respectively, were as follows: age, 59 years and 56 years; % male, 69% and 57%. The average HbA1c was reduced from 7.90% to 6.96% (Japanese Diabetes Society and from 8.57% to 7.50% (United States National Glycohemoglobin Standardization Program, while HbA1c was reduced from 63 mmol/mol to 53 mmol/mol and from 70 mmol/mol to 58 mmol/mol in Japanese and Caucasians, respectively. ΔHbA1c increased with increasing baseline in both populations. The slopes were the same (0.41, r2=0.36; and 0.41, r2=0.15, and the intercepts were 15.4 mmol/mol and 17.2 mmol/mol, respectively. In Japanese patients, mean ΔHbA1c was greater by 1.7 mmol

Use of SGLT2 inhibitors for diabetes and risk of infection: Analysis using general practice records from the NPS MedicineWise MedicineInsight program.

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Gadzhanova, Svetla; Pratt, Nicole; Roughead, Elizabet

2017-08-01

To explore the feasibility of MedicineInsight data to support risk management plan evaluation, focusing on sodium glucose co-transporter 2 (SGLT2) inhibitors for type 2 diabetes. A retrospective study using de-identified electronic general practitioner records. Patients who initiated SGLT2 inhibitor between 1 Jan 2012 to 1 Sep 2015 were compared to patients who initiated dipeptidyl peptidase 4 (DPP-4) inhibitors. The two cohorts were followed-up for six months. Risk of urinary-tract (UT) and genital infections was evaluated. The indication for use of SGLT2 inhibitors, recommended prior diabetes therapies and recommended monitoring were investigates. There were 1977 people in the SGLT2 cohort (with 93% initiated on dapagliflozin) and 1964 people in the DPP-4 cohort. Of the SGLT2 initiators, 54% had a documented indication for use as type 2 diabetes; 86% had used metformin and/or a sulfonylurea in the prior 12months. Renal function monitoring was documented for only 25% in the 6months initiation. The frequency of UTI in the 6months post SGLT2 initiation was not significantly increased compared to the DPP-4 cohort (3.6%vs 4.9%; aHR=0.90, 95% CI 0.66-1.24). Genital infection were more frequent in the SGLT2 than in the DPP-4 cohort (2.9% vs 0.9%, aHR=3.50, 95% CI 1.95-5.89). Similar to existing evidence, we found a higher risk of genital infection associated with SGLT2 inhibitors (primarily dapagliflozin) but no increased risk of UTIs compared to DPP-4 use. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

HbA1c Outcomes in Patients Treated With Canagliflozin Versus Sitagliptin in US Health Plans.

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Thayer, Sarah; Aguilar, Richard; Korrer, Stephanie; Chow, Wing

2017-10-01

Clinical trial evidence supports greater glycemic control with canagliflozin than with sitagliptin. The objective of this study was to provide real-world evidence comparing outcomes in routine clinical practice among patients initiating each medication. With the use of a health care administrative database, patients initiating canagliflozin were compared with patients initiating sitagliptin (first prescription fill as index date). Baseline (6 months before index date) demographic and clinical (eg, comorbidities and diabetes-related complications) characteristics were compared, and propensity score matching was used to control for baseline differences between cohorts. Outcomes included change in glycosylated hemoglobin (HbA 1c ) and persistence with medication over a 9-month period after index date. Before matching, the canagliflozin cohort (N = 3993) was younger than the sitagliptin cohort (N = 12,153) and was composed of fewer women and Medicare Advantage enrollees, with lower mean baseline comorbidity scores (all p < 0.001). Before matching, the canagliflozin cohort (valid n = 1482) had a significantly (p < 0.001) higher baseline HbA 1c (8.60) than the sitagliptin cohort (valid n = 3697; HbA 1c , 8.32). After matching (n = 1472 per cohort), patients were well balanced on baseline characteristics, and HbA 1c values were not significantly different (p = 0.634) between the cohorts. Patients initiating canagliflozin had greater reductions in HbA 1c than patients in the sitagliptin cohort (-0.93% versus -0.57%, respectively; p = 0.004), with similar mean (median) time from index date to follow-up HbA 1c of 185.4 (199.0) and 184.3 (190.5) days, respectively (p = 0.802). Only 29.8% of canagliflozin patients discontinued during follow-up compared with 41.5% of sitagliptin patients (p < 0.001); the average days of persistence on index therapy was longer for canagliflozin patients (152 days) than for sitagliptin patients (139 days; p < 0.001). In this observational study

Identification of novel human dipeptidyl peptidase-IV inhibitors of natural origin (Part II: in silico prediction in antidiabetic extracts.

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Laura Guasch

Full Text Available BACKGROUND: Natural extracts play an important role in traditional medicines for the treatment of diabetes mellitus and are also an essential resource for new drug discovery. Dipeptidyl peptidase IV (DPP-IV inhibitors are potential candidates for the treatment of type 2 diabetes mellitus, and the effectiveness of certain antidiabetic extracts of natural origin could be, at least partially, explained by the inhibition of DPP-IV. METHODOLOGY/PRINCIPAL FINDINGS: Using an initial set of 29,779 natural products that are annotated with their natural source and an experimentally validated virtual screening procedure previously developed in our lab (Guasch et al.; 2012 [1], we have predicted 12 potential DPP-IV inhibitors from 12 different plant extracts that are known to have antidiabetic activity. Seven of these molecules are identical or similar to molecules with described antidiabetic activity (although their role as DPP-IV inhibitors has not been suggested as an explanation for their bioactivity. Therefore, it is plausible that these 12 molecules could be responsible, at least in part, for the antidiabetic activity of these extracts through their inhibitory effect on DPP-IV. In addition, we also identified as potential DPP-IV inhibitors 6 molecules from 6 different plants with no described antidiabetic activity but that share the same genus as plants with known antidiabetic properties. Moreover, none of the 18 molecules that we predicted as DPP-IV inhibitors exhibits chemical similarity with a group of 2,342 known DPP-IV inhibitors. CONCLUSIONS/SIGNIFICANCE: Our study identified 18 potential DPP-IV inhibitors in 18 different plant extracts (12 of these plants have known antidiabetic properties, whereas, for the remaining 6, antidiabetic activity has been reported for other plant species from the same genus. Moreover, none of the 18 molecules exhibits chemical similarity with a large group of known DPP-IV inhibitors.

Dipeptidyl peptidase 4 inhibitor attenuates obesity-induced myocardial fibrosis by inhibiting transforming growth factor-βl and Smad2/3 pathways in high-fat diet-induced obesity rat model.

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Hong, Seul-Ki; Choo, Eun-Ho; Ihm, Sang-Hyun; Chang, Kiyuk; Seung, Ki-Bae

2017-11-01

Obesity-induced myocardial fibrosis may lead to diastolic dysfunction and ultimately heart failure. Activation of the transforming growth factor (TGF)-βl and its downstream Smad2/3 pathways may play a pivotal role in the pathogenesis of obesity-induced myocardial fibrosis, and the antidiabetic dipeptidyl peptidase 4 inhibitors (DPP4i) might affect these pathways. We investigated whether DPP4i reduces myocardial fibrosis by inhibiting the TGF-β1 and Smad2/3 pathways in the myocardium of a diet-induced obesity (DIO) rat model. Eight-week-old male spontaneously hypertensive rats (SHRs) were fed either a normal fat diet (chow) or a high-fat diet (HFD) and then the HFD-fed SHRs were randomized to either the DPP4i (MK-0626) or control (distilled water) groups for 12weeks. At 20weeks old, all the rats underwent hemodynamic and metabolic studies and Doppler echocardiography. Compared with the normal fat diet (chow)-fed SHRs, the HFD-fed SHRs developed a more intense degree of hyperglycemia and dyslipidemia and showed a constellation of left ventricular (LV) diastolic dysfunction, and exacerbated myocardial fibrosis, as well as activation of the TGF-β1 and Smad2/3 pathways. DPP4i significantly improved the metabolic and hemodynamic parameters. The echocardiogram showed that DPP4i improved the LV diastolic dysfunction (early to late ventricular filling velocity [E/A] ratio, 1.49±0.21 vs. 1.77±0.09, p<0.05). Furthermore, DPP4i significantly reduced myocardial fibrosis and collagen production by the myocardium and suppressed TGF-β1 and phosphorylation of Smad2/3 in the heart. In addition, DPP4i decreased TGF-β1-induced collagen production and TGF-β1-mediated phosphorylation and nuclear translocation of Smad2/3 in rat cardiac fibroblasts. In conclusion, DPP4 inhibition attenuated myocardial fibrosis and improved LV diastolic dysfunction in a DIO rat model by modulating the TGF-β1 and Smad2/3 pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of sitagliptin and metformin treatment on incretin hormone and insulin secretory responses to oral and "isoglycemic" intravenous glucose

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Vardarli, Irfan; Arndt, Elisabeth; Deacon, Carolyn F

2014-01-01

,000 mg/day), sitagliptin (100 mg/day), or their combination, on GLP-1 responses and on the incretin effect in 20 patients with type 2 diabetes, comparing an oral glucose challenge (75 g, day 5) and an "isoglycemic" intravenous glucose infusion (day 6). Fasting total GLP-1 was significantly increased...... by metformin and not changed by sitagliptin. After oral glucose, metformin increased and sitagliptin significantly decreased (by 53%) total GLP-1. Fasting and postload intact GLP-1 increased with sitagliptin but not with metformin. After oral glucose, only sitagliptin, but not metformin, significantly...... the numerical contribution of the incretin effect. Insulin secretion with sitagliptin treatment was similarly stimulated with oral and "isoglycemic" intravenous glucose. This points to an important contribution of small changes in incretin concentrations within the basal range or to additional insulinotropic...

Efficacy and safety of the glucagon-like peptide-1 receptor agonist lixisenatide versus the dipeptidyl peptidase-4 inhibitor sitagliptin in young (<50 years obese patients with type 2 diabetes mellitus

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Luc Van Gaal

2014-06-01

Conclusion: In obese patients aged <50 years with T2DM, the proportion of patients with an HbA1c <7% with weight loss ≥5% was similar between groups. Lixisenatide, however, resulted in significantly greater reductions in body weight and postprandial plasma glucose excursions than sitagliptin. Tolerability was similar between groups.

Dgroup: DG01284 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available liptin succinate (JAN/USAN) ... Antidiabetic agent ... DG01601 ... DPP-4 inhibitor Cyp inhibitor ... DG01915 ... CYP3A5 i...nhibitor Unclassified ... DG02044 ... Hypoglycemics ... DG01601 ... DPP-4 inhibitor ... DPP4 inhibitor, antidiabetics DPP4 [HSA:1803] [KO:K01278] ...

Clinical utility and patient considerations in the use of the sitagliptin-metformin combination in Chinese patients

Directory of Open Access Journals (Sweden)

Du Q

2015-02-01

Full Text Available Qiang Du, Yan-Jun Wang, Sheng Yang, Ping HanDepartment of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of ChinaAbstract: The prevalence of diabetes mellitus (DM continues to increase each year. However, the efficacy of glucose-lowering therapies remains unsatisfactory. Moreover, the clinical characteristics and manifestations of DM in Chinese patients are different from those in Western patients. Thus, it is imperative to develop an optimal treatment protocol for lowering blood glucose levels in Chinese patients with DM. Sitagliptin has been used in People’s Republic of China, and sitagliptin and metformin combination therapy may not alter their individual pharmacokinetics. To date, several clinical trials undertaken to investigate the efficacy of sitagliptin and metformin combination therapy have revealed that it effectively controlled glycated hemoglobin, fasting plasma glucose, and postprandial plasma glucose levels to a greater extent than sitagliptin or metformin alone. In addition, the combined therapy was well tolerated and induced few side effects, which were largely mild. Furthermore, the combined therapy was easy to administer, and the patients receiving this therapy showed good compliance. Therefore, for Chinese patients with type 2 DM, sitagliptin and metformin combination therapy is preferred.Keywords: type 2 diabetes mellitus, sitagliptin, metformin

Thorium and uranium redox-active ligand complexes; reversible intramolecular electron transfer in U(dpp-BIAN)2/ U(dpp-BIAN)2(THE)

Energy Technology Data Exchange (ETDEWEB)

Schelter, Eric John [Los Alamos National Laboratory; Wu, Ruilian [Los Alamos National Laboratory; Scott, Brian L [Los Alamos National Laboratory; Thompson, Joe D [Los Alamos National Laboratory; Batista, Enrique R [Los Alamos National Laboratory; Morris, David E [Los Alamos National Laboratory; Kiplinger, Jaqueline L [Los Alamos National Laboratory

2008-01-01

Actinide complexes of the redox-active ligand dpp-BIAN{sup 2-} (dpp-BIAN = bis(2,6-diisopropylphenyl)acenaphthylene), An(dpp-BIAN){sub 2}(THF){sub n} (An = Th, n = 1; An = U, n = 0, 1) have been prepared. Solid-state magnetic and single-crystal X-ray data for U(dpp-BIAN){sub 2}(THF){sub n} show when n = 0, the complex exists in an f{sup 2}-{pi}*{sup 4} configuration; whereas an intramolecular electron transfer occurs for n = 1, resulting in an f{sup 3}-{pi}*{sup 3} ground configuration. The magnetic data also indicate that interconversion between the two forms of the complex is possible, limited only by the ability of THF vapor to penetrate the solid on cooling of the sample. Spectroscopic data indicate the complex exists solely in the f{sup 2}-{pi}*{sup 4} form in solution, evidenced by the appearance of only small changes in the electronic absorption spectra of the U(dpp-BIAN){sub 2} complex on titration with THF and by measurement of the solution magnetic moment m d{sub 8}-tetrahydrofuran using Evans method. Electrochemistry of the complexes is reported, with small differences observed in wave potentials between metals and in the presence of THF. These data represent the first example of a well-defined, reversible intramolecular electron transfer in an f-element complex and the second example of oxidation state change through dative interaction with a metal ion.

The GABAA Antagonist DPP-4-PIOL Selectively Antagonises Tonic over Phasic GABAergic Currents in Dentate Gyrus Granule Cells

DEFF Research Database (Denmark)

Boddum, Kim; Frølund, Bente; Kristiansen, Uffe

2014-01-01

that phasic and tonic GABAA receptor currents can be selectively inhibited by the antagonists SR 95531 and the 4-PIOL derivative, 4-(3,3-diphenylpropyl)-5-(4-piperidyl)-3-isoxazolol hydrobromide (DPP-4-PIOL), respectively. In dentate gyrus granule cells, SR 95531 was found approximately 4 times as potent...

Dgroup: DG01283 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available igliptin hydrobromide hydrate (JAN) ... Antidiabetic agent ... DG01601 ... DPP-4 inhibitor Unclassified ... DG02044 ... H...ypoglycemics ... DG01601 ... DPP-4 inhibitor ... DPP4 inhibitor, antidiabetics DPP4 [HSA:1803] [KO:K01278] ...

Efficacy of vildagliptin and sitagliptin in lowering fasting plasma glucose: Results of a randomized controlled trial.

Science.gov (United States)

Göke, R; Eschenbach, P; Dütting, E D

2015-06-01

This study compared the efficacy of vildagliptin and sitagliptin in lowering fasting plasma glucose (FPG) as single-pill combinations (SPCs) with metformin. The randomized crossover, open-label, active-controlled study design assessed the FPG-lowering abilities of a vildagliptin/metformin (50/1000 mg twice daily) SPC compared with a sitagliptin/metformin (50/1000 mg twice daily) SPC after 2 weeks of treatment in 99 type 2 diabetes patients uncontrolled by stable metformin therapy (1000-2000 mg/day). The change in FPG from baseline to day 14 was significantly greater (P vildagliptin [-21.9 mg/dL (SD 27.0)] than with sitagliptin [-14.5 mg/dL (SD 23.0)]. After 14 days of treatment, the mean FPG was 137.8 mg/dL (SD 28.5) with vildagliptin and 140.1mg/dL (SD 26.5) with sitagliptin (P vildagliptin produced a significantly greater reduction in FPG vs baseline compared with sitagliptin, which may translate into clinical relevance. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins [v3; ref status: indexed, http://f1000r.es/51m

Directory of Open Access Journals (Sweden)

Sandeep Chakraborty

2015-01-01

Full Text Available The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4 inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237 and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff with known structures using serine protease (SPASE motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of

An updated systematic review and meta-analysis on the efficacy and tolerability of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes with moderate to severe chronic kidney disease

Directory of Open Access Journals (Sweden)

Devada Singh-Franco

2016-07-01

Full Text Available Objective: This updated meta-analysis determines the effect of dipeptidyl peptidase-4 inhibitors on glycemic and tolerability outcomes in patients with type 2 diabetes mellitus and chronic kidney disease with glomerular filtration rate of ⩽60 mL/min or on dialysis. Methods: In all, 14 citations were identified from multiple databases. Qualitative assessments and quantitative analyses were performed. Results: There were 2261 participants, 49–79 years of age, 49% men and 44% Caucasians. In seven placebo-comparator studies, reduction in hemoglobin A1c at weeks 12–24 was 0.55% (95% confidence interval: −0.68 to −0.43, P < 0.00001. In three sulfonylurea-comparator studies, dipeptidyl peptidase-4 inhibitors did not significantly reduce hemoglobin A1c at weeks 52–54 (−0.15% (95% confidence interval: −0.32 to 0.02. In one sitagliptin versus albiglutide study, albiglutide significantly reduced hemoglobin A1c in patients with moderate renal impairment (−0.51%. A similar reduction in hemoglobin A1c was seen with sitagliptin versus vildagliptin (−0.56% vs −0.54%. Compared with placebo or sulfonylurea, dipeptidyl peptidase-4 inhibitors did not significantly reduce hemoglobin A1c after 12 and 54 weeks in patients on dialysis. Hypoglycemia was reported by ~30% of patients in both dipeptidyl peptidase-4 inhibitors and placebo groups over 24–52 weeks. While hypoglycemia was more common with a sulfonylurea at 52–54 weeks (risk ratio: 0.46 (95% confidence interval: 0.18 to 1.18, there was significant heterogeneity (I2 = 87%. Limitations included high drop-out rate from most studies and small number of active-comparator studies. Conclusions: Dipeptidyl peptidase-4 inhibitors in patients with chronic kidney disease caused a modest reduction in hemoglobin A1c versus placebo, but not when compared with sulfonylureas or albiglutide, or when used in patients on dialysis. Additional active-comparator studies are needed to

Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: A comparative review

DEFF Research Database (Denmark)

Deacon, Carolyn F.

2011-01-01

The dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antihyperglycaemic agents which were developed for the treatment of type 2 diabetes by rational drug design, based on an understanding of the underlying mechanism of action and knowledge of the structure of the target enzyme. Although...... they differ in terms of their chemistry, they are all small molecules which are orally available. There are some differences between them in terms of their absorption, distribution, metabolism and elimination, as well as in their potency and duration of action, but their efficacy, both in terms of inhibiting...

Simultaneous Estimation of Sitagliptin and Metformin in ...

African Journals Online (AJOL)

A rapid, simple, specific and precise high-performance thin-layer chromatography (HPTLC) method was developed for the simultaneous estimation of sitagliptin (STG) and metformin (MET) content in a fixed dose pharmaceutical formulation and also in bulk drug. In the developed method, aluminium backed silica gel 60 ...

Boundary Dpp promotes growth of medial and lateral regions of the Drosophila wing.

Science.gov (United States)

Barrio, Lara; Milán, Marco

2017-07-04

The gradient of Decapentaplegic (Dpp) in the Drosophila wing has served as a paradigm to characterize the role of morphogens in regulating patterning. However, the role of this gradient in regulating tissue size is a topic of intense debate as proliferative growth is homogenous. Here, we combined the Gal4/UAS system and a temperature-sensitive Gal80 molecule to induce RNAi-mediated depletion of dpp and characterise the spatial and temporal requirement of Dpp in promoting growth. We show that Dpp emanating from the AP compartment boundary is required throughout development to promote growth by regulating cell proliferation and tissue size. Dpp regulates growth and proliferation rates equally in central and lateral regions of the developing wing appendage and reduced levels of Dpp affects similarly the width and length of the resulting wing. We also present evidence supporting the proposal that graded activity of Dpp is not an absolute requirement for wing growth.

Synthesis, QSAR, and Molecular Dynamics Simulation of Amidino-substituted Benzimidazoles as Dipeptidyl Peptidase III Inhibitors.

Science.gov (United States)

Rastija, Vesna; Agić, Dejan; Tomiš, Sanja; Nikolič, Sonja; Hranjec, Marijana; Grace, Karminski-Zamola; Abramić, Marija

2015-01-01

A molecular modeling study is performed on series of benzimidazol-based inhibitors of human dipeptidyl peptidase III (DPP III). An eight novel compounds were synthesized in excellent yields using green chemistry approach. This study is aimed to elucidate the structural features of benzimidazole derivatives required for antagonism of human DPP III activity using Quantitative Structure-Activity Relationship (QSAR) analysis, and to understand the mechanism of one of the most potent inhibitor binding into the active site of this enzyme, by molecular dynamics (MD) simulations. The best model obtained includes S3K and RDF045m descriptors which have explained 89.4 % of inhibitory activity. Depicted moiety for strong inhibition activity matches to the structure of most potent compound. MD simulation has revealed importance of imidazolinyl and phenyl groups in the mechanism of binding into the active site of human DPP III.

Dgroup: DG01282 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available 601 ... DPP-4 inhibitor ... DPP4 inhibitor, antidiabetics DPP4 [HSA:1803] [KO:K01278] ... ...tin tartrate (USAN) Antidiabetic agent ... DG01601 ... DPP-4 inhibitor Unclassified ... DG02044 ... Hypoglycemics ... DG01... DG01282 Chemical ... DGroup Dutogliptin ... D09333 ... Dutogliptin (USAN) D09334 ... Dutoglip

DPP6 Loss Impacts Hippocampal Synaptic Development and Induces Behavioral Impairments in Recognition, Learning and Memory

Directory of Open Access Journals (Sweden)

Lin Lin

2018-03-01

Full Text Available DPP6 is well known as an auxiliary subunit of Kv4-containing, A-type K+ channels which regulate dendritic excitability in hippocampal CA1 pyramidal neurons. We have recently reported, however, a novel role for DPP6 in regulating dendritic filopodia formation and stability, affecting synaptic development and function. These results are notable considering recent clinical findings associating DPP6 with neurodevelopmental and intellectual disorders. Here we assessed the behavioral consequences of DPP6 loss. We found that DPP6 knockout (DPP6-KO mice are impaired in hippocampus-dependent learning and memory. Results from the Morris water maze and T-maze tasks showed that DPP6-KO mice exhibit slower learning and reduced memory performance. DPP6 mouse brain weight is reduced throughout development compared with WT, and in vitro imaging results indicated that DPP6 loss affects synaptic structure and motility. Taken together, these results show impaired synaptic development along with spatial learning and memory deficiencies in DPP6-KO mice.

Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade

DEFF Research Database (Denmark)

Aulinger, Benedikt A; Bedorf, Anne; Kutscherauer, Gabriele

2014-01-01

Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibit......Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4...

L’ÉTUDE CLINIQUE DU MOIS TECOS : confirmation de la sécurité cardiovasculaire de la sitagliptine

OpenAIRE

SCHEEN, André; PAQUOT, Nicolas

2015-01-01

Summary : The cardiovascular safety of sitagliptin has been evaluated in TECOS («Trial Evaluating Cardiovascular Outcomes with Sitagliptin»). TECOS recruited patients with type 2 diabetes and a history of cardiovascular disease who received, as add-on to their usual therapy, either sitagliptin (n = 7.257) or placebo (n = 7.266), with a median follow-up of 3 years. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or ho...

Short article: A randomized-controlled study of sitagliptin for treating diabetes mellitus complicated by nonalcoholic fatty liver disease.

Science.gov (United States)

Deng, Xiao-Long; Ma, Rui; Zhu, Hong-Xia; Zhu, Jun

2017-03-01

This study aimed to evaluate the efficacy and safety of sitagliptin for treating Chinese patients with type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD). In total, 72 Chinese T2DM patients with NAFLD were divided randomly into two groups of 36 patients each group. All 72 patients were assigned to receive either sitagliptin or diet and exercise for 52 weeks between January 2013 and December 2015. The outcomes' measurements included serum levels of hemoglobin A1c, fasting plasma glucose, aspartate aminotransferase, and alanine aminotransferase. Seventy patients completed the study. Sitagliptin showed greater efficacy than the diet and exercise in decreasing the hemoglobin A1c and fasting plasma glucose levels at weeks 13, 26, 39, and 52. In addition, no significant changes in the average aspartate aminotransferase and alanine aminotransferase levels were found during the 52-week follow-up in both the sitagliptin and the control groups. The results of this study indicate that sitagliptin is an effective and safe treatment for patients with T2DM and NAFLD.

Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus

DEFF Research Database (Denmark)

Hemmingsen, Bianca; Sonne, David P; Metzendorf, Maria-Inti

2017-01-01

to 160 weeks. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains and did not perform meta-analyses because there were not enough trials.One trial comparing the DPP-4 inhibitor vildagliptin with placebo reported no deaths (very low-quality evidence). The incidence...... of T2DM by means of WHO diagnostic criteria in this trial was 3/90 participants randomised to vildagliptin versus 1/89 participants randomised to placebo (very low-quality evidence). Also, 1/90 participants on vildagliptin versus 2/89 participants on placebo experienced a serious adverse event (very...... low-quality evidence). One out of 90 participants experienced congestive heart failure in the vildagliptin group versus none in the placebo group (very low-quality evidence). There were no data on non-fatal myocardial infarction, stroke, health-related quality of life or socioeconomic effects reported...

Sitagliptin/Simvastatin: a first combination tablet to treat type 2 diabetes and hypercholesterolemia – a review of its characteristics

Directory of Open Access Journals (Sweden)

Ramadan WH

2015-02-01

Full Text Available Wijdan H Ramadan, Wissam K Kabbara Department of Pharmacy Practice, School of Pharmacy, Lebanese American University, Byblos, Lebanon Background: The purpose of this study was to review the current literature and information on the combination product Juvisync™ (sitagliptin + simvastatin, which was approved by the US Food and Drug Administration in October 2011. Methods: PubMed (2001–2014 was searched for primary and review articles on sitagliptin, simvastatin, or the combination product. Drug manufacturing data and product labeling were also used. Studies of simvastatin, sitagliptin, or the combination were screened and analyzed to include relevant and recent papers. Selected English language trials were limited to those with human subjects and included both safety and efficacy outcomes. Results: When compared with glipizide as add-on therapy to metformin, sitagliptin was noninferior but had lower rates of hypoglycemia and weight gain. In addition, when compared with insulin glargine, sitagliptin was less effective in decreasing glycosylated hemoglobin, but was associated with significantly lower rates of hypoglycemia. Further, trials have shown a beneficial effect of using statins in patients with diabetes mellitus with regard to decreasing cardiovascular risk, regardless of baseline lipid levels or the presence of a cardiac disease. Both medications have also demonstrated an acceptable side effect profile. However, caution is needed when coadministering with any drug that may increase simvastatin levels to reduce the risk of myopathy and rhabdomyolysis. Conclusion: Juvisync should be used in patients requiring both sitagliptin and simvastatin. Both agents have shown good efficacy and acceptable safety profiles. Sitagliptin is a good option for diabetic patients to improve glycemic control with a lower risk of hypoglycemia and weight gain. Keywords: simvastatin, sitagliptin, Juvisync™, diabetes mellitus, hypercholesterolemia

The effects of aerobic exercises and 25(OH D supplementation on GLP1 and DPP4 level in Type II diabetic patients

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Naser Rahimi

2017-01-01

Full Text Available Background: The purpose of this study was to investigate the effects of an 8-week aerobic exercise and supplementation of 25(OHD3 on GLP1 and DDP4 levels in men with type II diabetes. Methods: In this semiexperimental research, among 40–60-year-old men with type II diabetes who were referred to the diabetic center of Isabn-E Maryam hospital in Isfahan; of whom, 48 patients were voluntarily accepted and then were randomly divided into 4 groups: aerobic exercise group, aerobic exercise with 25(OH D supplement group, 25(OH D supplement group, and the control group. An aerobic exercise program was conducted for 8 weeks (3 sessions/week, each session 60 to75 min with 60–80% HRmax. The supplement user group received 50,000 units of oral Vitamin D once weekly for 8 weeks. The GLP1, DPP4, and 25(OH D levels were measured before and after the intervention. At last, the data were statistically analyzed using the ANCOVA and post hoc test of least significant difference. Results: The results of ANCOVA showed a significant difference between the GLP1 and DPP4 levels in aerobic exercise with control group while these changes were not statistically significant between the 25(OH D supplement group with control group (P < 0.05. Conclusions: Aerobic exercises have resulted an increase in GLP1 level and a decrease in DPP4 level. However, consumption of Vitamin D supplement alone did not cause any changes in GLP1and DPP4 levels but led to an increase in 25-hydroxy Vitamin D level.

Cost-effectiveness analysis of metformin+dipeptidyl peptidase-4 inhibitors compared to metformin+sulfonylureas for treatment of type 2 diabetes.

Science.gov (United States)

Kwon, Christina S; Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa

2018-02-01

Patients with type 2 diabetes (T2D) typically use several drug treatments during their lifetime. There is a debate about the best second-line therapy after metformin monotherapy failure due to the increasing number of available antidiabetic drugs and the lack of comparative clinical trials of secondary treatment regimens. While prior research compared the cost-effectiveness of two alternative drugs, the literature assessing T2D treatment pathways is scarce. The purpose of this study was to evaluate the long-term cost-effectiveness of dipeptidyl peptidase-4 inhibitors (DPP-4i) compared to sulfonylureas (SU) as second-line therapy in combination with metformin in patients with T2D. A Markov model was developed with four health states, 1 year cycle, and a 25-year time horizon. Clinical and cost data were collected from previous studies and other readily available secondary data sources. The incremental cost-effectiveness ratio (ICER) was estimated from the US third party payer perspective. Both, costs and outcomes, were discounted at a 3% annual discount rate. One way and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainty on the base-case results. The discounted incremental cost of metformin+DPP-4i compared to metformin+SU was $11,849 and the incremental life-years gained were 0.61, resulting in an ICER of $19,420 per life-year gained for patients in the metformin+DPP-4i treatment pathway. The ICER estimated in the probabilistic sensitivity analysis was $19,980 per life-year gained. Sensitivity analyses showed that the results of the study were not sensitive to changes in the parameters used in base-case. The metformin+DPP-4i treatment pathway was cost-effective compared to metformin+SU as a long-term second-line therapy in the treatment of T2D from the US health care payer perspective. Study findings have the potential to provide clinicians and third party payers valuable evidence for the prescription and utilization of cost

In vitro evaluation of mutagenicity and genotoxicity of sitagliptin ...

African Journals Online (AJOL)

Keywords: Sitagliptin, Artificial sweeteners, Comet assay, DNA damage, Ames assay, Genotoxicity,. Mutagenicity. Tropical Journal of Pharmaceutical Research is indexed by Science Citation Index (SciSearch), Scopus,. International Pharmaceutical Abstract, Chemical Abstracts, Embase, Index Copernicus, EBSCO, African.

Sitagliptin/Simvastatin: a first combination tablet to treat type 2 diabetes and hypercholesterolemia – a review of its characteristics

Science.gov (United States)

Ramadan, Wijdan H; Kabbara, Wissam K

2015-01-01

Background The purpose of this study was to review the current literature and information on the combination product Juvisync™ (sitagliptin + simvastatin), which was approved by the US Food and Drug Administration in October 2011. Methods PubMed (2001–2014) was searched for primary and review articles on sitagliptin, simvastatin, or the combination product. Drug manufacturing data and product labeling were also used. Studies of simvastatin, sitagliptin, or the combination were screened and analyzed to include relevant and recent papers. Selected English language trials were limited to those with human subjects and included both safety and efficacy outcomes. Results When compared with glipizide as add-on therapy to metformin, sitagliptin was noninferior but had lower rates of hypoglycemia and weight gain. In addition, when compared with insulin glargine, sitagliptin was less effective in decreasing glycosylated hemoglobin, but was associated with significantly lower rates of hypoglycemia. Further, trials have shown a beneficial effect of using statins in patients with diabetes mellitus with regard to decreasing cardiovascular risk, regardless of baseline lipid levels or the presence of a cardiac disease. Both medications have also demonstrated an acceptable side effect profile. However, caution is needed when coadministering with any drug that may increase simvastatin levels to reduce the risk of myopathy and rhabdomyolysis. Conclusion Juvisync should be used in patients requiring both sitagliptin and simvastatin. Both agents have shown good efficacy and acceptable safety profiles. Sitagliptin is a good option for diabetic patients to improve glycemic control with a lower risk of hypoglycemia and weight gain. PMID:25709467

Comparative Study on Adding Pioglitazone or Sitagliptin to Patients with Type 2 Diabetes Mellitus Insufficiently Controlled With Metformin

Directory of Open Access Journals (Sweden)

Maryam Jameshorani

2017-12-01

CONCLUSION: Sitagliptin and Pioglitazone demonstrated similar improvements in glycemic control in type 2 diabetes mellitus patients whose diabetes had been inadequately controlled with metformin. Nevertheless, sitagliptin was more effective than pioglitazone regarding lipid and body weight change.

Identification of Dipeptidyl-Peptidase (DPP)5 and DPP7 in Porphyromonas endodontalis, Distinct from Those in Porphyromonas gingivalis

OpenAIRE

Nishimata, Haruka; Ohara-Nemoto, Yuko; Baba, Tomomi T.; Hoshino, Tomonori; Fujiwara, Taku; Shimoyama, Yu; Kimura, Shigenobu; Nemoto, Takayuki K.

2014-01-01

Dipeptidyl peptidases (DPPs) that liberate dipeptides from the N-terminal end of oligopeptides are crucial for the growth of Porphyromonas species, anaerobic asaccharolytic gram negative rods that utilize amino acids as energy sources. Porphyromonas endodontalis is a causative agent of periapical lesions with acute symptoms and Asp/Glu-specific DPP11 has been solely characterized in this organism. In this study, we identified and characterized two P. endodontalis DPPs, DPP5 and DPP7. Cell-ass...

Identification of novel human dipeptidyl peptidase-IV inhibitors of natural origin (part I: virtual screening and activity assays.

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Laura Guasch

Full Text Available BACKGROUND: There has been great interest in determining whether natural products show biological activity toward protein targets of pharmacological relevance. One target of particular interest is DPP-IV whose most important substrates are incretins that, among other beneficial effects, stimulates insulin biosynthesis and secretion. Incretins have very short half-lives because of their rapid degradation by DPP-IV and, therefore, inhibiting this enzyme improves glucose homeostasis. As a result, DPP-IV inhibitors are of considerable interest to the pharmaceutical industry. The main goals of this study were (a to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site. METHODOLOGY/PRINCIPAL FINDINGS: We predicted that 446 out of the 89,165 molecules present in the natural products subset of the ZINC database would inhibit DPP-IV with good ADMET properties. Notably, when these 446 molecules were merged with 2,342 known DPP-IV inhibitors and the resulting set was classified into 50 clusters according to chemical similarity, there were 12 clusters that contained only natural products for which no DPP-IV inhibitory activity has been previously reported. Nine molecules from 7 of these 12 clusters were then selected for in vitro activity testing and 7 out of the 9 molecules were shown to inhibit DPP-IV (where the remaining two molecules could not be solubilized, preventing the evaluation of their DPP-IV inhibitory activity. Then, the hit with the highest activity was used as a lead compound in the prediction of more potent derivatives. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that our virtual-screening protocol was successful in identifying novel

EMPAGLIFLOZIN (SGLT2 INHIBITOR IN TYPE 2 DIABETES MELLITUS

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Mohammed Umar Farooque

2017-05-01

Full Text Available BACKGROUND To study the analysis of metabolic parameters in patients with type 2 diabetes mellitus on empagliflozin, which is a SGLT2 inhibitor. MATERIALS AND METHODS This study was a prospective study of 120 patients with uncontrolled type 2 diabetes mellitus who were admitted as outpatients in JLNMCH Hospital, Bhagalpur. This study was conducted from February 2017 to April 2017. Informed consent was taken from each patient who participated in the study and the study protocol was approved by the institutions ethics and review board. Inclusion Criteria- Patients with type 2 diabetes mellitus and HbA1c >8% meeting any one of the criteria- Patients who were on dual therapy (metformin + sulfonylurea/DPP4 inhibitor; patients who were on triple therapy (metformin + sulfonylurea + DPP4 inhibitor; patients who were on insulin and triple oral therapy (metformin + sulfonylurea + DPP4 inhibitor. Exclusion Criteria- Patients who had history of genital mycotic infections, recurrent urinary tract infections, pyelonephritis, acute illness, type 1 diabetes, pregnant or lactating women, those patients who were with an eGFR below 45. RESULTS The mean age, duration of diabetes, weight and HbA1c in the study population was 54.36 ± 0.88 years, 14.2 ± 3.6 years, 76.25 ± 2.11 kgs and 9.66 ± 0.22%, respectively. The changes in weight and HbA1c were statistically significant across all groups. In 5% of the patients, genital pruritus was reported. Mycotic genital infection was seen in none of the patients on examination. All the four groups chose to discontinue the use of empagliflozin as a result of pruritus at follow up. The baseline daily insulin dose was 42 ± 25 units, and at 4 months, it was reduced to 34 ± 20 units. At follow up, the reduction in insulin level was 19.1% when compared to baseline. CONCLUSION This study showed that there was an improvement in glycaemic control and body weight with minimal side effects when SGLT2 inhibitor was added at any

Dgroup: DG00119 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available in hydrate (JAN/USAN) ... D10262 ... Saxagliptin hydrochloride ... Antidiabetic agent ... DG01601 ... DPP-4 inhibitor T...4 inhibitor ATC code: A10BH03 Antidiabetic, Dipeptidyl peptidase-4 (DPP-4) inhibitor DPP4 [HSA:1803] [KO:K01278] Transporter: ABCB1 [HSA:5243] ...

Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Health.

Science.gov (United States)

Egger, Andrea; Kraenzlin, Marius E; Meier, Christian

2016-12-01

Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.

Effect of vildagliptin, a dipeptidyl peptidase 4 inhibitor, on cardiac hypertrophy induced by chronic beta-adrenergic stimulation in rats

Science.gov (United States)

2014-01-01

Background Heart failure with left ventricular (LV) hypertrophy is often associated with insulin resistance and inflammation. Recent studies have shown that dipeptidyl peptidase 4 (DPP4) inhibitors improve glucose metabolism and inflammatory status. We therefore evaluated whether vildagliptin, a DPP4 inhibitor, prevents LV hypertrophy and improves diastolic function in isoproterenol-treated rats. Methods Male Wistar rats received vehicle (n = 20), subcutaneous isoproterenol (2.4 mg/kg/day, n = 20) (ISO), subcutaneous isoproterenol (2.4 mg/kg/day + oral vildagliptin (30 mg/kg/day, n = 20) (ISO-VL), or vehicle + oral vildagliptin (30 mg/kg/day, n = 20) (vehicle-VL) for 7 days. Results Blood pressure was similar among the four groups, whereas LV hypertrophy was significantly decreased in the ISO-VL group compared with the ISO group (heart weight/body weight, vehicle: 3.2 ± 0.40, ISO: 4.43 ± 0.39, ISO-VL: 4.14 ± 0.29, vehicle-VL: 3.16 ± 0.16, p vildagliptin lowered the elevated LV end-diastolic pressure observed in the ISO group, but other parameters regarding LV diastolic function such as the decreased minimum dp/dt were not ameliorated in the ISO-VL group. Histological analysis showed that vildagliptin attenuated the increased cardiomyocyte hypertrophy and perivascular fibrosis, but it did not affect angiogenesis in cardiac tissue. In the ISO-VL group, quantitative PCR showed attenuation of increased mRNA expression of tumor necrosis factor-α, interleukin-6, insulin-like growth factor-l, and restoration of decreased mRNA expression of glucose transporter type 4. Conclusions Vildagliptin may prevent LV hypertrophy caused by continuous exposure to isoproterenol in rats. PMID:24521405

Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines

International Nuclear Information System (INIS)

Takasawa, Wataru; Ohnuma, Kei; Hatano, Ryo; Endo, Yuko; Dang, Nam H.; Morimoto, Chikao

2010-01-01

Research highlights: → TNF-α or IL-1β induces EC proliferation with reduction of CD26 expression. → CD26 siRNA or DPP-4 inhibition enhances TNF-α or IL-1β-induced EC proliferation. → Loss of CD26/DPP-4 enhances aortic sprouting induced by TNF-α or IL-1β. → Capillary formation induced by TNF-α or IL-1β is enahced in the CD26 -/- mice. -- Abstract: CD26/DPP-4 is abundantly expressed on capillary of inflamed lesion as well as effector T cells. Recently, CD26/dipeptidyl peptidase 4 (DPP-4) inhibition has been used as a novel oral therapeutic approach for patients with type 2 diabetes. While accumulating data indicate that vascular inflammation is a key feature of both micro- and macro-vascular complications in diabetes, the direct role of CD26/DPP-4 in endothelial biology is to be elucidated. We herein showed that proinflammatory cytokines such as tumor necrosis factor or interleukin-1 reduce expression of CD26 on microvascular endothelial cells, and that genetical or pharmacological inhibition of CD26/DPP-4 enhances endothelial growth both in vitro and in vivo. With DPP-4 inhibitors being used widely in the treatment of type 2 diabetes, our data strongly suggest that DPP-4 inhibition plays a pivotal role in endothelial growth and may have a potential role in the recovery of local circulation following diabetic vascular complications.

Preventive effect of dipeptidyl peptidase-4 inhibitor on atherosclerosis is mainly attributable to incretin's actions in nondiabetic and diabetic apolipoprotein E-null mice.

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Michishige Terasaki

Full Text Available AIM: Several recent reports have revealed that dipeptidyl peptidase (DPP-4 inhibitors have suppressive effects on atherosclerosis in apolipoprotein E-null (Apoe (-/- mice. It remains to be seen, however, whether this effect stems from increased levels of the two active incretins, glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP. METHODS: Nontreated Apoe (-/- mice, streptozotocin-induced diabetic Apoe (-/- mice, and db/db diabetic mice were administered the DPP-4 inhibitor vildagliptin in drinking water and co-infused with either saline, the GLP-1 receptor blocker, exendin(9-39, the GIP receptor blocker, (Pro(3GIP, or both via osmotic minipumps for 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages were determined. RESULTS: Vildagliptin increased plasma GLP-1 and GIP levels without affecting food intake, body weight, blood pressure, or plasma lipid profile in any of the animals tested, though it reduced HbA1c in the diabetic mice. Diabetic Apoe (-/- mice exhibited further-progressed atherosclerotic lesions and foam cell formation compared with nondiabetic counterparts. Nondiabetic and diabetic Apoe (-/- mice showed a comparable response to vildagliptin, namely, remarkable suppression of atherosclerotic lesions with macrophage accumulation and foam cell formation in peritoneal macrophages. Exendin(9-39 or (Pro(3GIP partially attenuated the vildagliptin-induced suppression of atherosclerosis. The two blockers in combination abolished the anti-atherosclerotic effect of vildagliptin in nondiabetic mice but only partly attenuated it in diabetic mice. Vildagliptin suppressed macrophage foam cell formation in nondiabetic and diabetic mice, and this suppressive effect was abolished by infusions with exendin(9-39+(Pro(3GIP. Incubation of DPP-4 or vildagliptin in vitro had no effect on macrophage foam cell formation. CONCLUSIONS: Vildagliptin

Human DPP III – Keap1 Interactions: A Combined Experimental And Computational study

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Mario Gundić

2016-06-01

Full Text Available Kelch-like ECH associated protein 1 (Keap1 is a cellular sensor for oxidative stress and a negative regulator of the transcription factor Nrf2. Keap1 and Nrf2 control expression of nearly 500 genes with diverse cytoprotective functions and the Nrf2-Keap1 signaling pathway is a major regulator of cytoprotective responses to oxidative and electrophilic stress. It was found that the metallopeptidase dipeptidyl peptidase III (DPP III contributes to Nrf2 activation by binding to Keap1, probably by binding to the Kelch domain, and thereby influences Nrf2 activity in cancer. We here first determined that the KD of the DPP III-Kelch domain complex is in the submicromolar range. In order to elucidate the molecular details of the DPP III – Kelch interaction we then built models of the complex between human DPP III and the Keap1 Kelch domain and performed coarse-grained and atomistic simulations of the complexes. In the most stable complexes, the ETGE motif in the DPP III flexible loop binds near the central pore of the six-blade β-propeller Kelch domain. According to the preliminary HD exchange experiments DPP III binds to the more unstructured end of Kelch domain. According to the results of MD simulations DPP III binding to the Kelch domain does not influence the overall DPP III structure or the long-range domain fluctuations. We can conclude that DPP III forms the stable complexes with the Keap1 Kelch domain by inserting the flexible loop into the entrance to the central pore of the six blade β-propeller Kelch domain at its more unstructured, N-terminus. This work is licensed under a Creative Commons Attribution 4.0 International License.

Synthesized Peptides from Yam Dioscorin Hydrolysis in Silico Exhibit Dipeptidyl Peptidase-IV Inhibitory Activities and Oral Glucose Tolerance Improvements in Normal Mice.

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Lin, Yin-Shiou; Han, Chuan-Hsiao; Lin, Shyr-Yi; Hou, Wen-Chi

2016-08-24

RRDY, RL, and DPF were the top 3 of 21 peptides for inhibitions against dipeptidyl peptidase-IV (DPP-IV) from the pepsin hydrolysis of yam dioscorin in silico and were further investigated in a proof-of-concept study in normal ICR mice for regulating glucose metabolism by the oral glucose tolerance test (OGTT). The sample or sitagliptin (positive control) was orally administered by a feeding gauge; 30 min later, the glucose loads (2.5 g/kg) were performed. RRDY, yam dioscorin, or sitagliptin preload, but not DPF, lowered the area under the curve (AUC0-120) of blood glucose and DPP-IV activity and elevated the AUC0-120 of blood insulin, which showed significant differences compared to control (P dioscorin might be beneficial in glycemic control in normal mice and need further investigations in diabetic animal models.

Real-World Clinical Effectiveness and Cost Savings of Liraglutide Versus Sitagliptin in Treating Type 2 Diabetes for 1 and 2 Years.

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Li, Qian; Ganguly, Rahul; Ganz, Michael L; Gamble, Cory; Dang-Tan, Tam

2018-06-01

This study compared the clinical and economic outcomes of long-term use of liraglutide versus sitagliptin for the treatment of type 2 diabetes (T2DM) in real-world practice in the USA. We identified adult patients (≥ 18 years old) with T2DM who initiated liraglutide or sitagliptin in 2010-2014 using a large claims database. Quarterly glycemic control measures and annual healthcare costs were assessed during the 1st and 2nd years of persistent medication use. Their associations with medication use (liraglutide or sitagliptin) were estimated using multivariable regression models adjusted for patient demographic and clinical characteristics. A total of 3113 patients persistently used liraglutide (N = 493) or sitagliptin (N = 2620) for ≥ 1 year [mean age (standard deviation, SD): 53 (8.5) vs. 56 (9.7) years; 48.3% vs. 62.3% males; both p < 0.05]; 911 (including 113 liraglutide users) were persistent users for ≥ 2 years. During the 1st-year follow-up, liraglutide users (versus sitagliptin users, after adjustment) experienced larger glycated hemoglobin (HbA1c) reductions from baseline (ranging from 0.34%-point in quarter 1 to 0.21%-point in quarter 4); higher likelihoods of obtaining HbA1c reductions of ≥ 1%-points or ≥ 2%-points [odds ratios (ORs) range 1.47-2.04]; and higher likelihoods of reaching HbA1c goals of < 6.5% or < 7% (ORs range 1.51-2.12) (all p < 0.05). Liraglutide users also experienced HbA1c reductions from baseline in the 2nd-year follow-up (0.53-0.33%-point, all p < 0.05). Although liraglutide users incurred higher healthcare costs than sitagliptin users during the 1st-year follow-up, they had $2674 (per patient) lower all-cause medical costs (adjusted cost ratio: 0.67, p < 0.05) and similar total costs (all-cause and diabetes-related) in the 2nd year. Long-term use of liraglutide for 1 or 2 years was associated with better glycemic control than using sitagliptin. Savings in medical costs

Drug: D09333 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available ... Treatment of type 2 diabetes DPP4 [HSA:1803] [KO:K01278] ... CAS: 852329-66-9 PubChem: 96026013 ... ...601 ... DPP-4 inhibitor Unclassified ... DG02044 ... Hypoglycemics ... DG01601 ... DPP-4 inhibitor Chemical group: DG01282

Active phytochemicals of Pueraria tuberosa for DPP-IV inhibition: in silico and experimental approach.

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Srivastava, Shivani; Shree, Priya; Tripathi, Yamini Bhusan

2017-01-01

We had earlier reported that the extract of Pueraria tuberosa significantly inhibits DPP-IV enzyme, resulting in glucose tolerance response in rats. In this study, we have explored the active phytochemicals responsible for this potential. The results have been validated in both fasting and postprandial states in the plasma of normal rats and also in fasting blood and intestinal homogenates of diabetic models. Pueraria tuberosa water extract (PTWE) was administered to normal Charles Foster rats for 35 days and to diabetic model (65 mg/kg bw) for 10 days. After treatments, oral glucose tolerance test (OGTT) and insulin was done for 90 min, and the changes in the levels of GLP-1, GIP, and DPP-IV activities were monitored in fasting and postprandial states. In the case of the diabetic model, DPP-IV activity was measured in intestinal homogenate and basal insulin in plasma. The components of PTWE were analyzed via HPLC-MS based on their chemical formula, molecular mass, and retention time. Using the molecular docking study, we have selected the top five components having strong binding energy with DPP-IV. The increase in secretion of GLP-1 and GIP was significantly higher in the postprandial state when compared to fasting condition. GLP-1 plasma concentration increased by 5.8 and 2.9 folds and GIP increased by 8.7 and 2.4 folds in PTWE and control rats, respectively. In contrast, the postprandial decrease in DPP-IV specific activities was recorded at 2.3 and 1.4 folds. The response in OGTT and insulin was also consistent with these changes. In comparison to diabetic controls, PTWE-administered rats showed decreased DPP-IV activity in the intestine, leading to enhanced basal insulin concentration. Through molecular docking, we found Puerarone and Robinin to be the most potential phytochemicals of PTWE for DPP-IV inhibition. Binding energy (kcal/mol) and dissociation constant (pM) of Robinin with DPP-IV protein were found to be 7.543 and 2,957,383.75, respectively

Effects of yam dioscorin interventions on improvements of the metabolic syndrome in high-fat diet-induced obese rats.

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Shih, Shen-Liang; Lin, Yin-Shiou; Lin, Shyr-Yi; Hou, Wen-Chi

2015-12-01

The metabolic syndrome (MS) is termed a cluster of multiple metabolic risk criteria which is positively correlated with cardiovascular disease and type 2 diabetes mellitus (DM). Yam dioscorins have been reported to exhibit biological activities, however, little is known their preventive effects on the MS. Therefore, a high-fat (HF) diet was used to induce Wistar rat obesity and then yam dioscorin (50 mg/kg, dio50) was intervened daily concurrent HF diet (HF diet + dio50) for five weeks to check the changes of weights of body and tissues, blood pressures, and impaired glucose tolerances. The in vitro peptic hydrolysates of dioscorin with molecular mass between 3 kDa and 10 kDa and less than 3 kDa were used to determine dipeptidyl peptidase IV (DPP IV) inhibitory activities which DPP IV inhibitor has been reported to prevent and treat type 2 DM. There were no significant difference in body weights, feed intakes, feed conversion, and weights of adipose tissues of obese rats in groups of HF and (HF diet + dio50). However, the systolic blood pressures in obese rats of 2-, 3- and 4-week dioscorin interventions were showed significantly lower (P dioscorin intervention (HF+ dio50) was showed significantly different (P dioscorin peptic hydrolysates (5 mg/ml) showed inhibitory activities against DPP IV using sitagliptin phosphate as positive controls. Yam dioscorins exhibit improved MS activities in obese rats which the related mechanisms may need further investigations.

Diabetes Prevention Program (DPP)

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... Blood Institute (NHLBI) and National Cancer Institute (NCI), began funding a third phase of DPPOS—proposed to ... such as in group settings and over the internet. Ancillary studies of DPP and DPPOS data – Researchers ...

Alogliptin, a potent and selective dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes

DEFF Research Database (Denmark)

Deacon, Carolyn F

2008-01-01

Takeda San Diego Inc is developing alogliptin, a small-molecule, orally available dipeptidyl peptidase IV (DPP IV) inhibitor, for the potential treatment of type 2 diabetes. In January 2008, Takeda announced that an NDA for alogliptin had been submitted to the FDA.......Takeda San Diego Inc is developing alogliptin, a small-molecule, orally available dipeptidyl peptidase IV (DPP IV) inhibitor, for the potential treatment of type 2 diabetes. In January 2008, Takeda announced that an NDA for alogliptin had been submitted to the FDA....

Inwardly rectifying potassium channels influence Drosophila wing morphogenesis by regulating Dpp release.

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Dahal, Giri Raj; Pradhan, Sarala Joshi; Bates, Emily Anne

2017-08-01

Loss of embryonic ion channel function leads to morphological defects, but the underlying reason for these defects remains elusive. Here, we show that inwardly rectifying potassium (Irk) channels regulate release of the Drosophila bone morphogenetic protein Dpp in the developing fly wing and that this is necessary for developmental signaling. Inhibition of Irk channels decreases the incidence of distinct Dpp-GFP release events above baseline fluorescence while leading to a broader distribution of Dpp-GFP. Work by others in different cell types has shown that Irk channels regulate peptide release by modulating membrane potential and calcium levels. We found calcium transients in the developing wing, and inhibition of Irk channels reduces the duration and amplitude of calcium transients. Depolarization with high extracellular potassium evokes Dpp release. Taken together, our data implicate Irk channels as a requirement for regulated release of Dpp, highlighting the importance of the temporal pattern of Dpp presentation for morphogenesis of the wing. © 2017. Published by The Company of Biologists Ltd.

The dipeptidyl peptidase-4 inhibitor vildagliptin does not affect ex vivo cytokine response and lymphocyte function in patients with type 2 diabetes mellitus

NARCIS (Netherlands)

Poppel, P.C.M. van; Gresnigt, M.S.; Smits, P.; Netea, M.G.; Tack, C.J.J.

2014-01-01

AIMS: The enzyme dipeptidyl peptidase-4 (DPP-4) is a key player in the degradation of incretin hormones that are involved in glucose metabolism. DPP-4 is also expressed on immune cells and is associated with several immunological functions. Some studies have reported increased rates of infections in

Characterization of a Decapentapletic Gene (AccDpp from Apis cerana cerana and Its Possible Involvement in Development and Response to Oxidative Stress.

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Guilin Li

Full Text Available To tolerate many acute and chronic oxidative stress-producing agents that exist in the environment, organisms have evolved many classes of signal transduction pathways, including the transforming growth factor β (TGFβ signal pathway. Decapentapletic gene (Dpp belongs to the TGFβ superfamily, and studies on Dpp have mainly focused on its role in the regulation of development. No study has investigated the response of Dpp to oxidative pressure in any organism, including Apis cerana cerana (A. cerana cerana. In this study, we identified a Dpp gene from A. cerana cerana named AccDpp. The 5΄ flanking region of AccDpp had many transcription factor binding sites that relevant to development and stress response. AccDpp was expressed at all stages of A. cerana cerana, with its highest expression in 15-day worker bees. The mRNA level of AccDpp was higher in the poison gland and midgut than other tissues. Furthermore, the transcription of AccDpp could be repressed by 4°C and UV, but induced by other treatments, according to our qRT-PCR analysis. It is worth noting that the expression level of AccDpp protein was increased after a certain time when A. cerana cerana was subjected to all simulative oxidative stresses, a finding that was not completely consistent with the result from qRT-PCR. It is interesting that recombinant AccDpp restrained the growth of Escherichia coli, a function that might account for the role of the antimicrobial peptides of AccDpp. In conclusion, these results provide evidence that AccDpp might be implicated in the regulation of development and the response of oxidative pressure. The findings may lay a theoretical foundation for further genetic studies of Dpp.

[A novel dipeptidyl peptidase IV inhibitors developed through scaffold hopping and drug splicing strategy].

Science.gov (United States)

Wang, Shan-Chun; Zeng, Li-Li; Ding, Yu-Yang; Zeng, Shao-Gao; Song, Hong-Rui; Hu, Wen-Hui; Xie, Hui

2014-01-01

Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC50 = 4.9 nmol.L-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules.

Cost-Effectiveness of Canagliflozin versus Sitagliptin as Add-on to Metformin in Patients with Type 2 Diabetes Mellitus in Mexico.

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Neslusan, Cheryl; Teschemaker, Anna; Johansen, Pierre; Willis, Michael; Valencia-Mendoza, Atanacio; Puig, Andrea

2015-12-01

To assess the cost-effectiveness of canagliflozin versus sitagliptin for the treatment of type 2 diabetes mellitus (T2DM) as an add-on to metformin in Mexico. A validated model (Economic and Health Outcomes [ECHO]-T2DM) was used to estimate the cost-effectiveness of canagliflozin 300 or 100 mg versus sitagliptin 100 mg in patients with T2DM inadequately controlled on metformin monotherapy. Data from a head-to-head, phase III clinical trial, including patients' baseline demographic characteristics, biomarker values, and treatment effects, were used to simulate outcomes and resource use over 20 years from the perspective of the Mexican health care system. Costs of complications and adverse events were tailored to the Mexican setting and discounted at 5%. Cost-effectiveness was assessed using willingness-to-pay thresholds equivalent to 1 times the gross domestic product per capita (locally perceived to be "very cost-effective") and 3 times the gross domestic product per capita (locally perceived to be "cost-effective") on the basis of recommendations of the Mexican government and the World Health Organization. Owing primarily to better glycated hemoglobin (HbA 1c ), body weight, and systolic blood pressure values, canagliflozin 300 and 100 mg were associated with an incremental benefit of 0.16 and 0.06 quality-adjusted life-years (QALYs) versus sitagliptin 100 mg, respectively, over 20 years. The mean differences in cost for canagliflozin 300 and 100 mg versus sitagliptin 100 mg were Mexican pesos (MXP) 1797 (US $134) and MXP 7262 (US $540), respectively, resulting in a cost per QALY gained of MXP 11,210 (US $834) and MXP 128,883 (US $9590), respectively. Both of these cost-effectiveness ratios are below the very cost-effective willingness-to-pay threshold in Mexico. The general finding that canagliflozin is cost-effective versus sitagliptin in Mexico was supported by sensitivity analyses. In Mexico, both doses of canagliflozin are likely to be cost-effective versus

Gemigliptin: An Update of Its Clinical Use in the Management of Type 2 Diabetes Mellitus

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Sung-Ho Kim

2016-09-01

Full Text Available Dipeptidyl peptidase-4 (DPP-4 inhibitors are a new class of oral antidiabetic agent for the treatment of type 2 diabetes mellitus. They increase endogenous levels of incretin hormones, which stimulate glucose-dependent insulin secretion, decrease glucagon secretion, and contribute to reducing postprandial hyperglycemia. Although DPP-4 inhibitors have similar benefits, they can be differentiated in terms of their chemical structure, pharmacology, efficacy and safety profiles, and clinical considerations. Gemigliptin (brand name: Zemiglo, developed by LG Life Sciences, is a potent, selective, competitive, and long acting DPP-4 inhibitor. Various studies have shown that gemigliptin is an optimized DPP-4 inhibitor in terms of efficacy, safety, and patient compliance for treatment of type 2 diabetes mellitus. In this review, we summarize the characteristics of gemigliptin and discuss its potential benefits in clinical practice.

The dipeptidyl peptidase-4 inhibitor vildagliptin improves beta-cell function and insulin sensitivity in subjects with impaired fasting glucose

DEFF Research Database (Denmark)

Utzschneider, Kristina M; Tong, Jenny; Montgomery, Brenda

2007-01-01

OBJECTIVE: To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and beta-cell function in subjects with impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: A total of 22 subjects with IFG (11 female and 11 male, mean +/- SD...... age 59.6 +/- 11.5 years) were treated orally with 100 mg vildagliptin once daily in a single-blind study. Subjects received placebo for 2 weeks (run-in) followed by vildagliptin for 6 weeks (treatment) and then placebo for 2 weeks (washout). A frequently sampled intravenous glucose tolerance test....... RESULTS: Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment, mean +/- SEM AIR(g) increased from 224 +/- 44 to 286 +/- 52 pmol/l (P

Comparative evaluation of safety and efficacy of glimepiride and sitagliptin in combination with metformin in patients with type 2 diabetes mellitus: Indian multicentric randomized trial - START Study

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T V Devarajan

2017-01-01

Full Text Available Background and Objective: Modern sulfonylureas like glimepiride offer effective glycemic control with extrapancreatic benefits and good tolerability. The objective of the present study was to evaluate and compare safety and efficacy of glimepiride and sitagliptin in combination with metformin in patients with type 2 diabetes mellitus (T2DM. Methods: In this open-label, randomized, comparative, multicenter study, a total of 305 T2DM patients who were either drug naïve or uncontrolled on metformin were randomized to glimepiride 1 or 2 mg/sustained-release metformin 1000 mg once daily (glimepiride group, n = 202 or sitagliptin 50 mg/metformin 500 mg twice daily (sitagliptin group, n = 103 for 12 weeks. Primary endpoint was change in glycosylated hemoglobin (HbA1c. Secondary endpoints were change in fasting plasma glucose (FPG, postprandial plasma glucose (PPG, body mass index (BMI and to assess overall safety profile. Results: At 12 weeks, there was a statistically significant difference in the mean HbA1c reduction in glimepiride group (0.42% as compared to sitagliptin group (0.30% (P = 0.001. Mean reduction in FPG and PPG was also statistically significant in the glimepiride group as compared to the sitagliptin group (P = 0.008. There was no significant difference in terms of change in BMI (0.07 ± 0.39 kg/m2 vs. 0.08 ± 0.31 kg/m2 in glimepiride and sitagliptin groups, respectively, (P = 0.644 between both the groups. The incidences of hypoglycemic events were also comparable among both the groups. Conclusion: In T2DM patients, glimepiride/metformin combination exhibited significant reduction in glycemic parameters as compared to sitagliptin/metformin combination. Moreover, there was no significant difference between both the groups in terms of change in BMI and incidence of hypoglycemia.

Four-Year Durability of Initial Combination Therapy with Sitagliptin and Metformin in Patients with Type 2 Diabetes in Clinical Practice; COSMIC Study.

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Eu Jeong Ku

Full Text Available We investigated the efficacy of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes for 4 years in clinical practice.Between 2009 and 2010, we reviewed 1,178 patients with type 2 diabetes (HbA1c ≥7.5% or 58 mmol/mol prescribed initial combination therapy with sitagliptin and metformin. After excluding 288 patients without a second follow-up, 890 individuals (age, 58.0 ± 12.5 years; BMI, 25.4 ± 3.5 kg/m2; HbA1c, 8.6 ± 1.1% were followed up with every 3-6 months for 4 years. Homeostasis model assessments for insulin resistance and β-cell function (HOMA-β were recorded at baseline. The response criterion was HbA1c reduction by ≥0.8% from baseline or attainment of the target HbA1c (≤7.0% or 53 mmol/mol. At the end of every year of treatment, changes in HbA1c from the baseline were assessed.After 1 year, 72.2% of patients with initial combination therapy had responded, defined as HbA1c reduction ≥0.8% or attainment of the target HbA1c ≤7.0%. After 4 years, 35.4% of the patients still showed a response, with an HbA1c level of 7.0 ± 0.9%. A high HbA1c level at baseline was the most significant independent predictor of the long-term response (P<0.001. In addition, low HOMA-β was a significant predictor of a greater reduction in HbA1c. This treatment was generally well tolerated over the 4-year follow-up period, without any serious adverse events.This real-world follow-up study shows a persistent glucose-reducing effect of initial combination therapy with sitagliptin and metformin for up to 4 years.

Specificity of the second binding protein of the peptide ABC-transporter (Dpp) of Lactococcus lactis IL1403

NARCIS (Netherlands)

Sanz, Y; Toldra, F; Renault, P; Poolman, B

2003-01-01

The genome sequence of Lactococcus lactis IL1403 revealed the presence of a putative peptide-binding protein-dependent ABC-transporter (Dpp). The genes for two peptide-binding proteins (dppA and dppP) precede the membrane components, which include two transmembrane protein genes (dppB and dppC) and

Clinical implementetion of vildagliptin: data from recent studies comparing incretin-based medications

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Elena Valer'evna Biryukova

2014-03-01

Full Text Available The introduction of DPP-4 inhibitors substantially increased therapeutic options for type 2 diabetes mellitus (T2DM. The unique mechanism of action allows using these agents both as monotherapy and in combination with conventional anti-diabetes drugs. Evidence base for efficacy and safety of DPP-4 inhibitors deepens every year, but to date only a few studies addressed direct comparison between individual agents within this pharmacological class. Current article presents data from the studies comparing vildagliptin with other DPP-4 inhibitors, as well as GLP-1 agonists.

Loss of Eyebrows and Eyelashes During Concomitant Treatment with Sitagliptin and Metformin.

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Succurro, Elena; Palleria, Caterina; Ruffo, Mariafrancesca; Serra, Raffaele; Arturi, Franco; Gallelli, Luca

2017-01-01

The fixed dose combination of sitagliptin 50 mg and metformin 850 mg (Janumet ®), is indicated for the treatment of type 2 diabetes mellitus in addition to diet and exercise to improve glycemic control in patients treated with metformin alone. We report a 69-year-old man with type 2 diabetes that developed sudden loss of eyebrows and eyelashes about 4 months after the beginning of Janumet®. Clinical and laboratory findings excluded the presence of systemic or skin diseases able to induce these manifestations, while the Naranjo probability scale documented a possible association between the drug and the adverse drug reaction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Asymmetric synthesis of a potent, aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV inhibitor.

Science.gov (United States)

Xu, Feng; Corley, Edward; Zacuto, Michael; Conlon, David A; Pipik, Brenda; Humphrey, Guy; Murry, Jerry; Tschaen, David

2010-03-05

A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl(3) is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl(3). The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.

Cost-consequence analysis of sitagliptin versus sulfonylureas as add-on therapy for the treatment of diabetic patients in Italy.

Science.gov (United States)

Lorenzoni, Valentina; Baccetti, Fabio; Genovese, Stefano; Torre, Enrico; Turchetti, Giuseppe

2017-01-01

Diabetes mellitus is a chronic disease related to a significant impact in both epidemiologic and economic terms. In Italy, around 3.6 million people are affected by diabetes and this number is expected to increase significantly in the next few years. As recommended by current national and international guidelines, metformin (Met) is prescribed as first-line pharmacological treatment, and many pharmacological alternatives are available for patients uncontrolled with Met monotherapy. Despite the availability of many innovative oral antidiabetic drugs (OADs), such as dipeptidyl peptidase 4 inhibitors (DPP4-i) and its first-in-class sitagliptin (SITA), which entered the Italian market in the last 10 years, their usage is consistently lower than traditional drugs such as sulfonylureas (SUs). In fact, due to higher acquisition costs, the prescription of innovative OADs in Italy is restricted to specialist, resulting in a prominent usage of traditional OAD that can be prescribed also by general practitioners (GPs). A cost consequence analysis (CCA) was performed in order to compare SITA with SU, as second-line therapy in add-on to Met, in terms of costs and related clinical events over 36 months. A CCA was conducted on a hypothetical cohort of 100,000 type 2 diabetes mellitus (T2DM) patients uncontrolled with Met monotherapy, from both the Italian National Health Service (INHS) and societal perspective. Therefore, both direct (drugs, self-monitoring, hypoglycemia, major cardiovascular events [MACEs], and switch to insulin) and indirect costs (expressed in terms of productivity losses) were evaluated. Clinical and economic data were collected through Italian national tariffs, literature, and experts' opinions. Three expert clinicians finally validated data inputs. To assess robustness of base case results, a one-way sensitivity analysis (OWSA) and a conservative scenario analysis - excluding MACEs - were carried out. In the base case analysis, the higher drug costs related

Effect of Metformin and Sitagliptin on Doxorubicin-Induced Cardiotoxicity in Rats: Impact of Oxidative Stress, Inflammation, and Apoptosis

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Mina Thabet Kelleni

2015-01-01

Full Text Available Doxorubicin (DOX is a widely used antineoplastic drug whose efficacy is limited by its cardiotoxicity. The aim of this study was to investigate the possible protective role of the antidiabetic drugs metformin (250 mg/kg dissolved in DW p.o. for seven days and sitagliptin (10 mg/kg dissolved in DW p.o. for seven days in a model of DOX-induced (single dose 15 mg/kg i.p. at the fifth day cardiotoxicity in rats. Results of our study revealed that pretreatment with metformin or sitagliptin produced significant (P<0.05 cardiac protection manifested by a significant decrease in serum levels of LDH and CK-MB enzymes and cardiac MDA and total nitrites and nitrates levels, a significant increase in cardiac SOD activity, and remarkable improvement in the histopathological features as well as a significant reduction in the immunohistochemical expression of COX-2, iNOS, and caspase-3 enzymes as compared to DOX group. These results may suggest using metformin and/or sitagliptin as preferable drugs for diabetic patients suffering from cancer and receiving DOX in their chemotherapy regimen.

Stimulation of intestinal growth and function with DPP-IV inhibition in a mouse short bowel syndrome model

DEFF Research Database (Denmark)

Sueyoshi, Ryo; Ignatoski, Kathleen M Woods; Okawada, Manabu

2014-01-01

, and 7 days followed by 23 days washout period. Adaptive response was assessed by morphology, intestinal epithelial cell (IEC) proliferation (PCNA), epithelial barrier function (transepithelial resistance), RT-PCR for intestinal transport proteins, GLP-2R, and IGF-1R, and GLP-2 plasma levels. Glucose-stimulated...... sodium transport was assessed for intestinal absorptive function. Seven days of DPP4-I treatment facilitated an increase in GLP-2R levels, intestinal growth, and IEC proliferation. Treatment led to differential effects over time with greater absorptive function early, and enhanced proliferation at later...... time points. Interestingly, 7 day treatment followed by 23 days of non-treatment showed continued adaptation. DPP-IV-I enhanced IEC proliferative action up to 90-days post-resection, but this action seemed to peak by 30 days, as did GLP-2 plasma levels. Thus, use of DPP4-I treatment may prove...

S28 peptidases: lessons from a seemingly 'dysfunctional' family of two

Directory of Open Access Journals (Sweden)

Kozarich John W

2010-06-01

developed a successful inhibitor of DPP4, the anti-hyperglycemic drug sitagliptin, for the treatment of type 2 diabetes. The DPP enzymes are rich in biological functions and other drug targets emerging from the group are possible 3.

Ultrafast Excited-State Dynamics of Diketopyrrolopyrrole (DPP)-Based Materials: Static versus Diffusion-Controlled Electron Transfer Process

KAUST Repository

Alsulami, Qana

2015-06-25

Singlet-to-triplet intersystem crossing (ISC) and photoinduced electron transfer (PET) of platinum(II) containing diketopyrrolopyrrole (DPP) oligomer in the absence and presence of strong electron-acceptor tetracyanoethylene (TCNE) were investigated using femtosecond and nanosecond transient absorption spectroscopy with broadband capabilities. The role of platinum(II) incorporation in those photophysical properties was evaluated by comparing the excited-state dynamics of DPP with and without the metal centers. The steady-state measurements reveal that platinum(II) incorporation facilitates dramatically the interactions between DPP-Pt(acac) and TCNE, resulting in charge transfer (CT) complex formation. The transient absorption spectra in the absence of TCNE reveal ultrafast ISC of DPP-Pt(acac) followed by their long-lived triplet state. In the presence of TCNE, PET from the excited DPP-Pt(acac) and DPP to TCNE, forming the radical ion pairs. The ultrafast PET which occurs statically from DPP-Pt(acac) to TCNE in picosecond regime, is much faster than that from DPP to TCNE (nanosecond time scale) which is diffusion-controlled process, providing clear evidence that PET rate is eventually controlled by the platinum(II) incorporation.

Ultrafast Excited-State Dynamics of Diketopyrrolopyrrole (DPP)-Based Materials: Static versus Diffusion-Controlled Electron Transfer Process

KAUST Repository

Alsulami, Qana; Aly, Shawkat Mohammede; Goswami, Subhadip; Alarousu, Erkki; Usman, Anwar; Schanze, Kirk S.; Mohammed, Omar F.

2015-01-01

Singlet-to-triplet intersystem crossing (ISC) and photoinduced electron transfer (PET) of platinum(II) containing diketopyrrolopyrrole (DPP) oligomer in the absence and presence of strong electron-acceptor tetracyanoethylene (TCNE) were investigated using femtosecond and nanosecond transient absorption spectroscopy with broadband capabilities. The role of platinum(II) incorporation in those photophysical properties was evaluated by comparing the excited-state dynamics of DPP with and without the metal centers. The steady-state measurements reveal that platinum(II) incorporation facilitates dramatically the interactions between DPP-Pt(acac) and TCNE, resulting in charge transfer (CT) complex formation. The transient absorption spectra in the absence of TCNE reveal ultrafast ISC of DPP-Pt(acac) followed by their long-lived triplet state. In the presence of TCNE, PET from the excited DPP-Pt(acac) and DPP to TCNE, forming the radical ion pairs. The ultrafast PET which occurs statically from DPP-Pt(acac) to TCNE in picosecond regime, is much faster than that from DPP to TCNE (nanosecond time scale) which is diffusion-controlled process, providing clear evidence that PET rate is eventually controlled by the platinum(II) incorporation.

30 CFR 250.266 - After receiving the DPP or DOCD, what will MMS do?

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false After receiving the DPP or DOCD, what will MMS do? 250.266 Section 250.266 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR... Decision Process for the Dpp Or Docd § 250.266 After receiving the DPP or DOCD, what will MMS do? (a...

Measurements of islet function and glucose metabolism with the dipeptidyl peptidase 4 inhibitor vildagliptin in patients with type 2 diabetes

DEFF Research Database (Denmark)

Azuma, Koichiro; Rádiková, Zofia; Mancino, Juliet

2007-01-01

OBJECTIVE: Pharmacological inhibition with the dipeptidyl peptidase 4 (DPP-4) inhibitor vildagliptin prolongs the action of endogenously secreted incretin hormones leading to improved glycemic control in patients with type 2 diabetes mellitus (T2DM). We undertook a double-blinded, randomized......-order, crossover study to examine the vildagliptin mechanisms of action on islet function and glucose utilization. Research DESIGN AND METHODS: Participants with T2DM (n = 16) who had a baseline hemoglobin A(1c) of 7.1 +/- 0.2% completed a crossover study with 6 wk of treatment with vildagliptin and 6 wk...... with placebo. At the completion of each arm, participants had a study of postprandial metabolism and a two-step glucose clamp performed at 20 and 80 mU/min x m(2) insulin infusions. RESULTS: Vildagliptin increased postprandial glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide by 3- and 2...

Evaluation of the long-term cost-effectiveness of liraglutide therapy for patients with type 2 diabetes in France.

Science.gov (United States)

Roussel, Ronan; Martinez, Luc; Vandebrouck, Tom; Douik, Habiba; Emiel, Patrick; Guery, Matthieu; Hunt, Barnaby; Valentine, William J

2016-01-01

The present study aimed to compare the projected long-term clinical and cost implications associated with liraglutide, sitagliptin and glimepiride in patients with type 2 diabetes mellitus failing to achieve glycemic control on metformin monotherapy in France. Clinical input data for the modeling analysis were taken from two randomized, controlled trials (LIRA-DPP4 and LEAD-2). Long-term (patient lifetime) projections of clinical outcomes and direct costs (2013 Euros; €) were made using a validated computer simulation model of type 2 diabetes. Costs were taken from published France-specific sources. Future costs and clinical benefits were discounted at 3% annually. Sensitivity analyses were performed. Liraglutide was associated with an increase in quality-adjusted life expectancy of 0.25 quality-adjusted life years (QALYs) and an increase in mean direct healthcare costs of €2558 per patient compared with sitagliptin. In the comparison with glimepiride, liraglutide was associated with an increase in quality-adjusted life expectancy of 0.23 QALYs and an increase in direct costs of €4695. Based on these estimates, liraglutide was associated with an incremental cost-effectiveness ratio (ICER) of €10,275 per QALY gained vs sitagliptin and €20,709 per QALY gained vs glimepiride in France. Calculated ICERs for both comparisons fell below the commonly quoted willingness-to-pay threshold of €30,000 per QALY gained. Therefore, liraglutide is likely to be cost-effective vs sitagliptin and glimepiride from a healthcare payer perspective in France.

Hibiscus sabdariffa polyphenols prevent palmitate-induced renal epithelial mesenchymal transition by alleviating dipeptidyl peptidase-4-mediated insulin resistance.

Science.gov (United States)

Huang, Chien-Ning; Wang, Chau-Jong; Yang, Yi-Sun; Lin, Chih-Li; Peng, Chiung-Huei

2016-01-01

Diabetic nephropathy has a significant socioeconomic impact, but its mechanism is unclear and needs to be examined. Hibiscus sabdariffa polyphenols (HPE) inhibited high glucose-induced angiotensin II receptor-1 (AT-1), thus attenuating renal epithelial mesenchymal transition (EMT). Recently, we reported HPE inhibited dipeptidyl-peptidase-4 (DPP-4, the enzyme degrades type 1 glucagon-like peptide (GLP-1)), which mediated insulin resistance signals leading to EMT. Since free fatty acids can realistically bring about insulin resistance, using the palmitate-stimulated cell model in contrast with type 2 diabetic rats, in this study we examined if insulin resistance causes renal EMT, and the preventive effect of HPE. Our findings reveal that palmitate hindered 30% of glucose uptake. Treatment with 1 mg mL(-1) of HPE and the DPP-4 inhibitor linagliptin completely recovered insulin sensitivity and palmitate-induced signal cascades. HPE inhibited DPP-4 activity without altering the levels of DPP-4 and the GLP-1 receptor (GLP-1R). HPE decreased palmitate-induced phosphorylation of Ser307 of insulin receptor substrate-1 (pIRS-1 (S307)), AT-1 and vimentin, while increasing phosphorylation of phosphatidylinositol 3-kinase (pPI3K). IRS-1 knockdown revealed its essential role in mediating downstream AT-1 and EMT. In type 2 diabetic rats, it suggests that HPE concomitantly decreased the protein levels of DPP-4, AT-1, vimentin, and fibronectin, but reversed the in vivo compensation of GLP-1R. In conclusion, HPE improves insulin sensitivity by attenuating DPP-4 and the downstream signals, thus decreasing AT-1-mediated tubular-interstitial EMT. HPE could be an adjuvant to prevent diabetic nephropathy.

Comparative treatment between sitagliptin vs. metformin, alone or in combination, in patients with polycystic ovary syndrome. A clinical entity at high risk for developing diabetes mellitus and gestational diabetes: A pilot study

Directory of Open Access Journals (Sweden)

J.C. Paredes Palma

2018-01-01

Conclusion: Therapeutic effect of sitagliptin was observed in patients with PCOS comparable to metformin and the combination of metformin-sitagliptin is more effective in terms of ovulation than the other two treatments alone.

SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats.

Science.gov (United States)

Sa-Nguanmoo, Piangkwan; Tanajak, Pongpan; Kerdphoo, Sasiwan; Jaiwongkam, Thidarat; Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2017-10-15

Dipeptidyl peptidase-4 inhibitor (vildagliptin) has been shown to exert beneficial effects on insulin sensitivity and neuroprotection in obese-insulin resistance. Recent studies demonstrated the neuroprotection of the sodium-glucose co-transporter 2 inhibitor (dapagliflozin) in diabetes. However, the comparative effects of both drugs and a combination of two drugs on metabolic dysfunction and brain dysfunction impaired by the obese-insulin resistance have never been investigated. Forty male Wistar rats were divided into two groups, and received either a normal-diet (ND, n=8) or a high-fat diet (HFD, n=32) for 16weeks. At week 13, the HFD-fed rats were divided into four subgroups (n=8/subgroup) to receive either a vehicle, vildagliptin (3mg/kg/day) dapagliflozin (1mg/kg/day) or combined drugs for four weeks. ND rats were given a vehicle for four weeks. Metabolic parameters and brain function were investigated. The results demonstrated that HFD rats developed obese-insulin resistance and cognitive decline. Dapagliflozin had greater efficacy on improved peripheral insulin sensitivity and reduced weight gain than vildagliptin. Single therapy resulted in equally improved brain mitochondrial function, insulin signaling, apoptosis and prevented cognitive decline. However, only dapagliflozin improved hippocampal synaptic plasticity. A combination of the drugs had greater efficacy in improving brain insulin sensitivity and reducing brain oxidative stress than the single drug therapy. These findings suggested that dapagliflozin and vildagliptin equally prevented cognitive decline in the obese-insulin resistance, possibly through some similar mechanisms. Dapagliflozin had greater efficacy than vildagliptin for preserving synaptic plasticity, thus combined drugs could be the best therapeutic approach for neuroprotection in the obese-insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterisation of oral and i.v. glucose handling in truncally vagotomised subjects with pyloroplasty

DEFF Research Database (Denmark)

Plamboeck, Astrid; Veedfald, Simon; Deacon, Carolyn F

2013-01-01

=16) and matched controls (n=10) underwent 50 g-oral glucose tolerance test (OGTT)±vildagliptin, a DPP4 inhibitor (DPP4i) and isoglycaemic i.v. glucose infusion (IIGI), copying the OGTT without DPP4i. RESULTS: Isoglycaemia was obtained with 25±2 g glucose in vagotomised subjects and 18±2 g in controls...

Triplet State Formation in Photovoltaic Blends of DPP-Type Copolymers and PC71BM

KAUST Repository

Ochsmann, Julian R.; Chandran, Deepak; Gehrig, Dominik W.; Anwar, Husna; Madathil, Pramod Kandoth; Lee, Kwang-Sup; Laquai, Fré dé ric

2015-01-01

The exciton dynamics in pristine films of two structurally related low-bandgap diketopyrrolopyrrole (DPP)-based donor–acceptor copolymers and the photophysical processes in bulk heterojunction solar cells using DPP copolymer:PC71BM blends

Is glucagon-like peptide-1 fully protected by dipeptidyl peptidase-4 inhibitor administration in patients with type 2 diabetes?

DEFF Research Database (Denmark)

Andersen, ES; Lund, A.; Bagger, J. I.

2018-01-01

diabetes (T2D) [n=8; age: 59.9±10.8 (mean±SD) years; body mass index (BMI): 28.8±4.6 kg/m2 ; HbA1c : 43.1±0.5 mmol/mol (6.6±1.7%)] received a 380-minute continuous intravenous infusion of GLP-1 (1.0 pmol × kg body weight-1 × min-1 ) and double-blinded, single-dose oral administration of sitagliptin...

Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer.

Science.gov (United States)

Ross, Breyan; Krapp, Stephan; Augustin, Martin; Kierfersauer, Reiner; Arciniega, Marcelino; Geiss-Friedlander, Ruth; Huber, Robert

2018-02-13

Dipeptidyl peptidases 8 and 9 are intracellular N-terminal dipeptidyl peptidases (preferentially postproline) associated with pathophysiological roles in immune response and cancer biology. While the DPP family member DPP4 is extensively characterized in molecular terms as a validated therapeutic target of type II diabetes, experimental 3D structures and ligand-/substrate-binding modes of DPP8 and DPP9 have not been reported. In this study we describe crystal and molecular structures of human DPP8 (2.5 Å) and DPP9 (3.0 Å) unliganded and complexed with a noncanonical substrate and a small molecule inhibitor, respectively. Similar to DPP4, DPP8 and DPP9 molecules consist of one β-propeller and α/β hydrolase domain, forming a functional homodimer. However, they differ extensively in the ligand binding site structure. In intriguing contrast to DPP4, where liganded and unliganded forms are closely similar, ligand binding to DPP8/9 induces an extensive rearrangement at the active site through a disorder-order transition of a 26-residue loop segment, which partially folds into an α-helix (R-helix), including R160/133, a key residue for substrate binding. As vestiges of this helix are also seen in one of the copies of the unliganded form, conformational selection may contributes to ligand binding. Molecular dynamics simulations support increased flexibility of the R-helix in the unliganded state. Consistently, enzyme kinetics assays reveal a cooperative allosteric mechanism. DPP8 and DPP9 are closely similar and display few opportunities for targeted ligand design. However, extensive differences from DPP4 provide multiple cues for specific inhibitor design and development of the DPP family members as therapeutic targets or antitargets.

Chronic administration of ethanol leaf extract of Moringa oleifera Lam. (Moringaceae) may compromise glycaemic efficacy of Sitagliptin with no significant effect in retinopathy in a diabetic rat model.

Science.gov (United States)

Olurishe, Comfort; Kwanashie, Helen; Zezi, Abdulkadiri; Danjuma, Nuhu; Mohammed, Bisalla

2016-12-24

Moringa oleifera Lam. (Moringaceae) has gained awareness for its antidiabetic effect, and is used as alternative therapy or concurrently with orthodox medicines such as sitagliptin in diabetes mellitus. This is without ascertaining the possibility of drug-herb interactions, which could either lead to enhanced antidiabetic efficacy, increased toxicity, or compromised glycaemic control with negative consequence in diabetic retinopathy. To investigate the effect, of sitagliptin (50mg/kg), Moringa oleifera (300mg/kg) leaf extract, and a combination of both on glycaemic control parameters, lenticular opacity and changes in retinal microvasculature in alloxan (150mg/kg i.p) induced diabetic rat model. Seven groups of eight rats per group were used, with groups I, II and VII as normal (NC), diabetic (DC) and post-prandial controls (PPC). Groups III to VI were diabetic rats on sitagliptin (III), M. oleifera (IV), sitagliptin and M. oleifera (SM) (V), for 42 days with 2 weeks delayed treatment in a post-prandial hyperglycaemic group (PPSM) (VI). Glycaemic control parameters, insulin levels, body weights, and effects of retinal microvasculature on lenticular opacity/morphology were investigated. A significant decrease in fasting blood glucose (FBG) levels was displayed in SM group from day 14(60%) (p<0.01) to day 28 (38%) (p<0.01) of treatment, compared to day 1. Thereafter, a steady increase of up to 57% on day 42 compared to day 28 was observed. A significant decrease in random blood glucose (RBG) levels, were demonstrated on day 42 (24%) (p<0.001), compared to day 1. No significant difference was seen in mean serum levels of insulin across groups. No significant changes in body weights. Evidence of mild lenticular opacity was observed, with no significant effect in pathologic lesions in the retina. The chronic co-administration of sitagliptin and M. oleifera showed a progressive decrease in anti-hyperglycaemic effect of sitagliptin, and although it delayed the onset of

Identification of novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides in camel milk protein hydrolysates.

Science.gov (United States)

Nongonierma, Alice B; Paolella, Sara; Mudgil, Priti; Maqsood, Sajid; FitzGerald, Richard J

2018-04-01

Nine novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides (FLQY, FQLGASPY, ILDKEGIDY, ILELA, LLQLEAIR, LPVP, LQALHQGQIV, MPVQA and SPVVPF) were identified in camel milk proteins hydrolysed with trypsin. This was achieved using a sequential approach combining liquid chromatography tandem mass spectrometry (LC-MS/MS), qualitative/quantitative structure activity relationship (QSAR) and confirmatory studies with synthetic peptides. The most potent camel milk protein-derived DPP-IV inhibitory peptides, LPVP and MPVQA, had DPP-IV half maximal inhibitory concentrations (IC 50 ) of 87.0 ± 3.2 and 93.3 ± 8.0 µM, respectively. DPP-IV inhibitory peptide sequences identified within camel and bovine milk protein hydrolysates generated under the same hydrolysis conditions differ. This was linked to differences in enzyme selectivity for peptide bond cleavage of camel and bovine milk proteins as well as dissimilarities in their amino acid sequences. Camel milk proteins contain novel DPP-IV inhibitory peptides which may play a role in the regulation of glycaemia in humans. Copyright © 2017 Elsevier Ltd. All rights reserved.

Studies on the crystal structure and arrangement of water in sitagliptin L-tartrate hydrates

Czech Academy of Sciences Publication Activity Database

Tieger, E.; Kiss, V.; Pokol, G.; Finta, Z.; Dušek, Michal; Rohlíček, Jan; Skořepová, E.; Brázda, Petr

2016-01-01

Roč. 18, č. 21 (2016), s. 3819-3831 ISSN 1466-8033 R&D Projects: GA MŠk LO1603; GA ČR GA16-10035S EU Projects: European Commission(XE) CZ.2.16/3.1.00/24510 Institutional support: RVO:68378271 Keywords : sitagliptin tartarate * crystal structure * channel hydrates * hydration * dehydration Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 3.474, year: 2016

PTP1B, α-glucosidase, and DPP-IV inhibitory effects for chromene derivatives from the leaves of Smilax china L.

Science.gov (United States)

Zhao, Bing Tian; Le, Duc Dat; Nguyen, Phi Hung; Ali, Md Yousof; Choi, Jae-Sue; Min, Byung Sun; Shin, Heung Mook; Rhee, Hae Ik; Woo, Mi Hee

2016-06-25

Two new flavonoids, bismilachinone (11) and smilachinin (14), were isolated from the leaves of Smilax china L. together with 14 known compounds. Their structures were elucidated using spectroscopic methods. The PTP1B, α-glucosidase, and DPP-IV inhibitory activities of compounds 1-16 were evaluated at the molecular level. Among them, compounds 4, 7, and 10 showed moderate DPP-IV inhibitory activities with IC50 values of 20.81, 33.12, and 32.93 μM, respectively. Compounds 3, 4, 6, 11, 12, and 16 showed strong PTP1B inhibitory activities, with respective IC50 values of 7.62, 10.80, 0.92, 2.68, 9.77, and 24.17 μM compared with the IC50 value for the positive control (ursolic acid: IC50 = 1.21 μM). Compounds 2-7, 11, 12, 15, and 16 showed potent α-glucosidase inhibitory activities, with respective IC50 values of 8.70, 81.66, 35.11, 35.92, 7.99, 26.28, 11.28, 62.68, 44.32, and 70.12 μM. The positive control, acarbose, displayed an IC50 value of 175.84 μM. In the kinetic study for the PTP1B enzyme, compounds 6, 11, and 12 displayed competitive inhibition with Ki values of 3.20, 8.56, and 5.86 μM, respectively. Compounds 3, 4, and 16 showed noncompetitive inhibition with Ki values of 18.75, 5.95, and 22.86 μM, respectively. Molecular docking study for the competitive inhibitors (6, 11, and 12) radically corroborates the binding affinities and inhibition of PTP1B enzymes. These results indicated that the leaves of Smilax china L. may contain compounds with anti-diabetic activity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Sitagliptin reduces cardiac apoptosis, hypertrophy and fibrosis primarily by insulin-dependent mechanisms in experimental type-II diabetes. Potential roles of GLP-1 isoforms.

Directory of Open Access Journals (Sweden)

Belén Picatoste

Full Text Available BACKGROUND: Myocardial fibrosis is a key process in diabetic cardiomyopathy. However, their underlying mechanisms have not been elucidated, leading to a lack of therapy. The glucagon-like peptide-1 (GLP-1 enhancer, sitagliptin, reduces hyperglycemia but may also trigger direct effects on the heart. METHODS: Goto-Kakizaki (GK rats developed type-II diabetes and received sitagliptin, an anti-hyperglycemic drug (metformin or vehicle (n=10, each. After cardiac structure and function assessment, plasma and left ventricles were isolated for biochemical studies. Cultured cardiomyocytes and fibroblasts were used for in vitro assays. RESULTS: Untreated GK rats exhibited hyperglycemia, hyperlipidemia, plasma GLP-1 decrease, and cardiac cell-death, hypertrophy, fibrosis and prolonged deceleration time. Moreover, cardiac pro-apoptotic/necrotic, hypertrophic and fibrotic factors were up-regulated. Importantly, both sitagliptin and metformin lessened all these parameters. In cultured cardiomyocytes and cardiac fibroblasts, high-concentration of palmitate or glucose induced cell-death, hypertrophy and fibrosis. Interestingly, GLP-1 and its insulinotropic-inactive metabolite, GLP-1(9-36, alleviated these responses. In addition, despite a specific GLP-1 receptor was only detected in cardiomyocytes, GLP-1 isoforms attenuated the pro-fibrotic expression in cardiomyocytes and fibroblasts. In addition, GLP-1 receptor signalling may be linked to PPARδ activation, and metformin may also exhibit anti-apoptotic/necrotic and anti-fibrotic direct effects in cardiac cells. CONCLUSIONS: Sitagliptin, via GLP-1 stabilization, promoted cardioprotection in type-II diabetic hearts primarily by limiting hyperglycemia e hyperlipidemia. However, GLP-1 and GLP-1(9-36 promoted survival and anti-hypertrophic/fibrotic effects on cultured cardiac cells, suggesting cell-autonomous cardioprotective actions.

Hibiscus sabdariffa polyphenols alleviate insulin resistance and renal epithelial to mesenchymal transition: a novel action mechanism mediated by type 4 dipeptidyl peptidase.

Science.gov (United States)

Peng, Chiung-Huei; Yang, Yi-Sun; Chan, Kuei-Chuan; Wang, Chau-Jong; Chen, Mu-Lin; Huang, Chien-Ning

2014-10-08

The epithelial to mesenchymal transition (EMT) is important in renal fibrosis. Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1 (S307)) is a hallmark of insulin resistance. We report that polyphenol extracts of Hibiscus sabdariffa (HPE) ameliorate diabetic nephropathy and EMT. Recently it has been observed that type 4 dipeptidyl peptidase (DPP-4) inhibitor linagliptin is effective for treating type 2 diabetes and albuminuria. We investigated if DPP-4 and insulin resistance are involved in renal EMT and explored the role of HPE. In high glucose-stimulated tubular cells, HPE, like linagliptin, inhibited DPP-4 activation, thereby regulating vimentin (EMT marker) and IRS-1 (S307). IRS-1 knockdown revealed its essential role in mediating downstream EMT. In type 2 diabetic rats, pIRS-1 (S307) abundantly surrounds the tubular region, with increased vimentin in kidney. Both the expressions were reduced by HPE. In conclusion, HPE exerts effects similar to those of linagliptin, which improves insulin resistance and EMT, and could be an adjuvant to prevent diabetic nephropathy.

Molecular design and ordering effects of alkoxy aromatic donor in a DPP copolymer on OTFTs and OPVs

Energy Technology Data Exchange (ETDEWEB)

Kim, Myeong-Jong [School of Materials Science and Engineering and ERI, Gyeongsang National University, Jinju 660-701 (Korea, Republic of); An, Tae Kyu [POSTECH Organic Electronics Laboratory, Polymer Research Institute, Department of Chemical Engineering, Pohang University of Science and Technology, Pohang 790-784 (Korea, Republic of); Kim, Seul-Ong [School of Materials Science and Engineering and ERI, Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Cha, Hyojung [POSTECH Organic Electronics Laboratory, Polymer Research Institute, Department of Chemical Engineering, Pohang University of Science and Technology, Pohang 790-784 (Korea, Republic of); Kim, Hyoung Nam [Department of Chemistry & Research Institute of Natural Science, Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Xiofeng, Tan [School of Materials Science and Engineering and ERI, Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Park, Chan Eon, E-mail: cep@postech.ac.kr [POSTECH Organic Electronics Laboratory, Polymer Research Institute, Department of Chemical Engineering, Pohang University of Science and Technology, Pohang 790-784 (Korea, Republic of); Kim, Yun-Hi, E-mail: ykim@gnu.ac.kr [Department of Chemistry & Research Institute of Natural Science, Gyeongsang National University, Jinju 660-701 (Korea, Republic of)

2015-03-01

Two p-type polymers, PONDPP and PTADPP were synthesized by Suzuki coupling reaction to investigate the effect of alkoxy aromatic donor units in diketopyrrolopyrrole (DPP)-based copolymers on OTFTs and OPVs. PONDPP containing dialkoxynaphthalene exhibits excellent field-effect performances, with a hole mobility of 0.324 cm{sup 2}/V while PTADPP containing dialkoxyanthracene exhibits mobility of 4.5 × 10{sup −3} cm{sup 2}/V at 200 °C annealing. Bulk heterojunction type polymer solar cells based on these polymers as the electron donor materials, with PC{sub 71}BM as the acceptor, showed maximum power conversion efficiency (PCE) of 0.9% for PONDPP and 1.1% for PTADPP under AM 1.5 illumination. From photophysical and structural studies, we found that naphthalene unit was introduced to the DPP unit to enhance more the molecular ordering compared to anthracene unit. - Highlights: • Two diketopyrrolopyrrole (DPP)-based copolymers, PONDPP and PTADPP were synthesized. • We investigated the effect of alkoxy aromatic donor units on OTFTs and OPVs. • PONDPP and PTADTT exhibit mobilities of 0.324 and 4.5 × 10{sup −3} cm{sup 2}/V. • OPVs showed power conversion efficiency of 0.9% for PONDPP and 1.1% for PTADPP.

Genetically Targeted Dipeptidyl Peptidase-4 Inhibitor Use in a Patient with a Novel Mutation of MODY type 4

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Christian Mangrum

2015-01-01

Full Text Available Maturity onset diabetes of the young (MODY is a rare form of diabetes mellitus typically seen in young adults that results from pancreatic beta-cell dysfunction. MODY4 is a rare subtype caused by a PDX1 mutation. In this case, we present a nonobese 26-year-old male with polyuria and polydipsia. Lab work showed a blood glucose of 511 mg/dL, no ketones or antibodies (insulin, islet cell, and glutamic acid decarboxylase [GAD], C-peptide of 1.6 ng/mL, and A1c 9.3%. Genetic analysis revealed a novel nonsense mutation in the PDX1 gene, consistent with MODY type 4. Given this patient's particular genetic mutation affecting the incretin pathway, sitagliptin was substituted for glyburide, which led to significant improvement in glycemic control. Our case report identifies a unique mutation in a rare form of MODY and outlines management of ensuing diabetes through targeting its inherent genetic mutation.

Dipeptidyl peptidase-4 impairs insulin signaling and promotes lipid accumulation in hepatocytes

International Nuclear Information System (INIS)

Rufinatscha, Kerstin; Radlinger, Bernhard; Dobner, Jochen; Folie, Sabrina; Bon, Claudia; Profanter, Elisabeth; Ress, Claudia; Salzmann, Karin; Staudacher, Gabriele; Tilg, Herbert; Kaser, Susanne

2017-01-01

Dipeptidyl-peptidase 4 [DPP-4) has evolved into an important target in diabetes therapy due to its role in incretin hormone metabolism. In contrast to its systemic effects, cellular functions of membranous DPP-4 are less clear. Here we studied the role of DPP-4 in hepatic energy metabolism. In order to distinguish systemic from cellular effects we established a cell culture model of DPP-4 knockdown in human hepatoma cell line HepG2. DPP-4 suppression was associated with increased basal glycogen content due to enhanced insulin signaling as shown by increased phosphorylation of insulin-receptor substrate 1 (IRS-1), protein kinase B/Akt and mitogen-activated protein kinases (MAPK)/ERK, respectively. Additionally, glucose-6-phosphatase cDNA expression was significantly decreased in DPP-4 deficiency. Reduced triglyceride content in DPP-4 knockdown cells was paralleled by enhanced expressions of peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase −1 (CPT-1) while sterol regulatory element-binding protein 1c (SREBP-1c) expression was significantly decreased. Our data suggest that hepatic DPP-4 induces a selective pathway of insulin resistance with reduced glycogen storage, enhanced glucose output and increased lipid accumulation in the liver. Hepatic DPP-4 might be a novel target in fatty liver disease in patients with glucose intolerance. - Highlights: • DPP-IV knockdown results in increased insulin signaling in hepatocytes. • Increased fatty acid oxidation and decreased lipogenesis result in reduced hepatic triglyceride content in DPP-IV deficiency. • Hepatic DPP-IV induces a selective pathway of insulin resistance with increased triglyceride accumulation in the liver.

Biocatalytic ammonolysis of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester: preparation of an intermediate to the dipeptidyl peptidase IV inhibitor Saxagliptin.

Science.gov (United States)

Gill, Iqbal; Patel, Ramesh

2006-02-01

An efficient biocatalytic method has been developed for the conversion of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester (1) into the corresponding amide (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl)ester (2), which is a critical intermediate in the synthesis of the dipeptidyl peptidase IV (DPP4) inhibitor Saxagliptin (3). Candida antartica lipase B mediates ammonolysis of the ester with ammonium carbamate as ammonia donor to yield up to 71% of the amide. The inclusion of Ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol byproducts, respectively, increases the yield to 98%, thereby offering an efficient and practical alternative to chemical routes which yield 57-64%.

30 CFR 250.251 - If I propose activities in the Alaska OCS Region, what planning information must accompany the DPP?

Science.gov (United States)

2010-07-01

... Region, what planning information must accompany the DPP? 250.251 Section 250.251 Mineral Resources... Region, what planning information must accompany the DPP? If you propose development and production activities in the Alaska OCS Region, the following planning information must accompany your DPP: (a...

Inhibitors of dipeptidyl peptidase IV: a novel approach for the prevention and treatment of Type 2 diabetes?

DEFF Research Database (Denmark)

Deacon, Carolyn F; Ahrén, Bo; Holst, Jens J

2004-01-01

that has warranted the design of inhibitor-based drugs. At the molecular level, DPP IV cleaves two amino acids from the N-terminus of the intact, biologically active forms of both so-called incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (formerly known......, prevent the progressive impairment of glucose metabolism in patients with impaired glucose tolerance and Type 2 diabetes. DPP IV has become a focus of attention for drug design, as it has a pivotal role in the rapid degradation of at least two of the hormones released during food ingestion, a property...

Hollow-fiber micro-extraction combined with HPLC for the determination of sitagliptin in urine samples

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Rezaee Raheme

2015-01-01

Full Text Available This study successfully developed a three-phase hollow-fiber liquid phase micro extraction coupled with high performance liquid chromatography for determination of trace levels of an anti-diabetic drug, sitagliptin (STG, in urine samples. Sitagliptin was extracted from 15 mL of the basic sample solution with a pH of 8.5 into an organic extracting solvent (n-octanol impregnated in the pores of a hollow fiber and then back extracted into an acidified aqueous solution in the lumen of the hollow fiber with a pH of 3. After extraction, 20 µL of the acceptor phase was injected into HPLC. In order to obtain high extraction efficiency, the parameters affecting the HF-LPME including pH of the source and receiving phases, type of organic phase, ionic strength, stirring rate, extraction time, the volume ratio of donor phase to acceptor phase and temperature were studied and optimized. Under the optimized conditions, enrichment factors up to 88 were achieved and the relative standard deviation of the method was in the range of 3 % to 6%. The results indicated that HF-LPME method has an excellent clean-up capacity and a high preconcentration factor and can serve as a simple and sensitive method for monitoring the drug in the urine samples.

Vildagliptin , a DPP-4 inhibitor for the twice-daily treatment of type 2 diabetes mellitus with or without metformin.

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Forst, Thomas; Bramlage, Peter

2014-06-01

Dipeptidyl peptidase-4 inhibitors increase circulating levels of glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide regulating glucose-dependent insulin secretion. In addition, GLP-1 suppresses glucagon secretion, delays gastric emptying and increases satiety. The combination of vildagliptin with the biguanide metformin is of particular interest because of its complementary mode of action, addressing insulin resistance, alpha- and beta cell function in the islet of the pancreas. Because of the abundance of data supporting the use of vildagliptin alone and in combination with metformin, the present paper aims at giving an overview on the current evidence for its use in patients with type 2 diabetes mellitus. The data suggest that vildagliptin offers similar glycemic control compared to sulfonylureas and thiazolidinediones, while having the benefit of being associated with fewer cases of hypoglycemia and less body weight gain. There is increasing evidence that compared with sulfonylureas, vildagliptin has favorable effects on pancreatic alpha- and beta-cell function. Vildagliptin in combination with metformin, improve glycemic control with a favorable safety and tolerability profile, making it an attractive therapeutic option in patients where metformin monotherapy alone is not sufficient.

NEW IN THE TREATMENT OF TYPE 2 DIABETES

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V. G. Kadzharyan

2014-02-01

�-cells. They include the following drugs: exenatide, exenatide-LAR, liraglutide, liksizenatid, albiglyutid, dulaglyutid. GLP-1 is splited by dipeptidyl peptidase type 4 (DPP-4, which formed the basis for the creation of inhibitors of the enzyme DPP-4 and thus the maintaince of GLP-1 effect. There are the following inhibitors of DPP-4: sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin. Inhibitors of sodium-glucose cotransporter 2 (SGLT2. Their mechanism of action is reduced to the suppression of glucose reabsorption in the kidney, followed by reduction of hyperglycemia. Representatives of the group are dapagliflozin and kanagliflozin. The other three groups of drugs: amylin mimetics (pramlintide, bile acid sequestrants (cholestyramine and colestipol and dopamine-2 agonists (bromocriptine are used only in addition to the treatment of diabetes. Conclusions. The choice of drug therapy is a difficult and complex task. The heterogeneity of patients with type 2 diabetes suggests, that for effective treatment of this chronic progressive disease may not be an optimal use of only one class of glucose-lowering drugs. When physicians select treatment strategy against type 2 diabetes, he should rely on the national and international clinical guidelines and research results, as well as on his own clinical experience, and be sure to take into account the individual characteristics of the patient.

Purification, identification and molecular mechanism of two dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from Antarctic krill (Euphausia superba) protein hydrolysate.

Science.gov (United States)

Ji, Wei; Zhang, Chaohua; Ji, Hongwu

2017-10-01

Dipeptidyl peptidase IV (DPP-IV) played an important role in blood glucose regulation. Inhibition of DPP-IV may improve glycemic control in diabetics by preventing the rapid breakdown of incretin hormones and prolonging their physiological action. In this study, Antarctic krill (Euphausia superba) protein was hydrolyzed using animal proteolytic enzymes. The hydrolysate was purified sequentially by ultrafiltration, gel filtration chromatography and reversed phase high-performance liquid chromatography (RP-HPLC). DPP-IV inhibitory activity of the fractions achieved from Antarctic krill protein was determined by DPP-IV screening reagent kit. Two purified peptides were identified by Xevo G2-XS QTof mass spectrometer (QTOF-MS). One peptide purified was Ala-Pro (AP) with IC 50 values of 0.0530mg/mL, the other Ile-Pro-Ala (IPA) with IC 50 values of 0.0370mg/mL. They both exhibited strong DPP-IV inhibitory activity. The molecular docking analysis revealed that DPP-IV inhibition by AP and IPA was mainly due to formation of a strong interaction surface force with the 91-96 and 101-105 amino acids of the DPP-IV. Our results suggested that the protein hydrolysate from Antarctic krill can be considered as a promising natural source of DPP-IV inhibitory peptides in the management of diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

Time to exacerbation of heart failure is longer in Malaysian population on dipeptidyl peptidase-4 inhibitor

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J Hasan

2017-01-01

Conclusions: Higher CV events were seen in diabetic patients with known CAD treated with DPP4i between 20 and 30 weeks of therapy and occurred earlier in patients with chronic kidney disease. This is later than published data and raises the need to monitor this group of patients for symptoms of heart failure beyond conventional monitoring.

Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke (MAAS): study protocol for a randomized controlled trial.

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Osei, Elizabeth; Fonville, Susanne; Zandbergen, Adrienne A M; Brouwers, Paul J A M; Mulder, Laus J M M; Lingsma, Hester F; Dippel, Diederik W J; Koudstaal, Peter J; den Hertog, Heleen M

2015-08-05

Impaired glucose tolerance is present in one third of patients with a TIA or ischemic stroke and is associated with a two-fold risk of recurrent stroke. Metformin improves glucose tolerance, but often leads to side effects. The aim of this study is to explore the feasibility, safety, and effects on glucose metabolism of metformin and sitagliptin in patients with TIA or minor ischemic stroke and impaired glucose tolerance. We will also assess whether a slow increase in metformin dose and better support and information on this treatment will reduce the incidence of side effects in these patients. The Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke trial (MAAS trial) is a phase II, multicenter, randomized, controlled, open-label trial with blinded outcome assessment. Non-diabetic patients (n = 100) with a recent (TIA, amaurosis fugax or minor ischemic stroke (modified Rankin scale ≤ 3) and impaired glucose tolerance, defined as 2-hour post-load glucose levels between 7.8 and 11.0 mmol/L after repeated standard oral glucose tolerance test, will be included. Patients with renal or liver impairment, heart failure, chronic hypoxic lung disease stage III-IV, history of lactate acidosis or diabetic ketoacidosis, pregnancy or breastfeeding, pancreatitis and use of digoxin will be excluded. The patients will be randomly assigned in a 1:1:2 ratio to metformin, sitagliptin or "no treatment." Patients allocated to metformin will start with 500 mg twice daily, which will be slowly increased during a 6-week period to a twice daily dose of 1000 mg. Patients allocated to sitagliptin will be treated with a daily fixed dose of 100 mg. The study has been registered as NTR 3196 in The Netherlands Trial Register. Primary outcomes include percentage still on treatment, percentage of (serious) adverse events, and the baseline adjusted difference in 2-hour post-load glucose levels at 6 months. This study will give more

Crystallization and preliminary X-ray diffraction studies of the putative haloalkane dehalogenase DppA from Plesiocystis pacifica SIR-I

International Nuclear Information System (INIS)

Bogdanović, Xenia; Hesseler, Martin; Palm, Gottfried J.; Bornscheuer, Uwe T.; Hinrichs, Winfried

2010-01-01

The crystallization and preliminary X-ray diffraction studies of DppA from P. pacifica SIR-I are reported. DppA from Plesiocystis pacifica SIR-I is a putative haloalkane dehalogenase (EC 3.8.1.5) and probably catalyzes the conversion of halogenated alkanes to the corresponding alcohols. The enzyme was expressed in Escherichia coli BL21 and purified to homogeneity by ammonium sulfate precipitation and reversed-phase and ion-exchange chromatography. The DppA protein was crystallized by the vapour-diffusion method and protein crystals suitable for data collection were obtained in the orthorhombic space group P2 1 2 1 2. The DppA crystal diffracted X-rays to 1.9 Å resolution using an in-house X-ray generator

30 CFR 250.244 - What geological and geophysical (G&G) information must accompany the DPP or DOCD?

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false What geological and geophysical (G&G... Operations Coordination Documents (docd) § 250.244 What geological and geophysical (G&G) information must accompany the DPP or DOCD? The following G&G information must accompany your DPP or DOCD: (a) Geological...

Diabetes and Ramadan: an update on use of glycemic therapies during fasting.

Science.gov (United States)

Ahmed, Mohamed H; Abdu, Tarig A M

2011-01-01

The fasting of Ramadan is observed by a large proportion of Muslims with diabetes. Recommendations for the management of diabetes during Ramadan were last published in 2005 by the American Diabetes Association. Several studies in this field have since been published, some addressing the use of new pharmacological agents in managing diabetes during Ramadan. The incritin memetics are potentially safe during Ramadan; the DPP4 inhibitors vildagliptin and sitagliptin provide an effective and safe therapeutic option, administered either alone or in combination with metformin or sulfonylureas. There are no published studies on the use of GLP-1 receptor agonists during Ramadan. Among the sulfonylureas, gliclazide MR (modified release) and glimepride can be safely used during Ramadan, but glibenclamide should be avoided due to the associated risk of hypoglycemia. In selected patients with type 1 and type 2 diabetes, the long-acting insulin analogues glargine and detemir, as well as the premixed insulin analogues, can be used with minimal risk of metabolic derangement or hypoglycemia; the risk is higher in type 1 diabetes. Insulin pumps can potentially empower patients with diabetes and enable safe fasting during the month of Ramadan. Further clinical trials are needed to evaluate the safety and efficacy of new antidiabetic agents and new diabetes-related technologies during Ramadan.

Type 2 diabetes mellitus and heart failure

DEFF Research Database (Denmark)

Seferović, Petar M; Petrie, Mark C; Filippatos, Gerasimos S

2018-01-01

, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium-glucose co-transporter-2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown...... a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM........ Sulphonylureas and insulin have been the traditional second- and third-line therapies although their safety in HF is equivocal. Neither glucagon-like preptide-1 (GLP-1) receptor agonists, nor dipeptidyl peptidase-4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin...

Comparative effectiveness of oral antidiabetic drugs in preventing cardiovascular mortality and morbidity: A network meta-analysis.

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Gyeongsil Lee

Full Text Available In the Guidance for Industry from the Food and Drug Administration in 2008, excess cardiovascular risk should be ruled out in trials of all new antidiabetic drugs; however, relatively few studies have focused on cardiovascular safety with antidiabetic drug use. We aimed to examine mortality and cardiovascular risk using a network meta-analysis. We searched the Medline, Embase, Cochrane, and ClinicalTrials.gov registry databases in March 2016 to identify randomized controlled trials reporting cardiovascular risk with the following oral antidiabetic drugs: metformin, sulfonylureas, thiazolidinedione (TZD, dipeptidyl peptidase-4 (DPP4 inhibitors, and sodium-glucose co-transporter-2 (SGLT2 inhibitors. We assessed the differences in the risks of all-cause mortality, cardiovascular-related mortality, acute coronary syndrome (ACS, and myocardial infarction (MI among antidiabetic drugs with fixed effect models for direct pairwise comparisons and Bayesian network meta-analyses to integrate direct and indirect comparisons. Of the 101,183 patients in 73 randomized controlled trials, 3,434 (3.4% died. The relative risks of all-cause mortality with SGLT2 inhibitor use were 0.68 (95% credible interval: 0.57-0.80, 0.74 (0.49-1.10, 0.63 (0.46-0.87, 0.71 (0.55-0.90, and 0.65 (0.54-0.78, compared with placebo, metformin, sulfonylurea, TZD, and DPP4 inhibitor, respectively. The relative risks of cardiovascular-related mortality with SGLT2 inhibitor use were 0.61 (0.50-0.76, 0.81(0.36-1.90, 0.52(0.31-0.88, 0.66(0.49-0.91, and 0.61(0.48-0.77, compared with placebo, metformin, sulfonylurea, TZD, and DPP4 inhibitor, respectively. The relative risks of ACS with SGLT2 inhibitor use was consistent with that of all-cause mortality. SGLT2 inhibitor use was associated with a lower risk of ACS than the other OADs and placebo. The relative risks of MI with SGLT2 inhibitor use were 0.77 (0.63-0.93 and 0.75 (0.60-0.94, compared with placebo and DPP4 inhibitor, respectively. The

The combination of colesevelam with sitagliptin enhances glycemic control in diabetic ZDF rat model

DEFF Research Database (Denmark)

Shang, Quan; Liu, Matthew K; Saumoy, Monica

2012-01-01

. In the present study, we tested whether adding sitagliptin (Januvia) (SIT), which prolongs bioactive GLP-1 half life, to COL would further enhance glycemic control. Male Zucker diabetic fatty (ZDF) rats were assigned to four groups: diabetic model without treatment (the model), the model treated with 2% COL or 0...... to levels similar to the model. Histological examination of the pancreatic ß-cell islets showed that islet sizes were larger, proliferation enhanced, and cell apoptosis reduced in the COL+SIT but not the SIT alone group compared with the model. We hypothesize that the combination of COL with SIT extends...

Berry and Citrus Phenolic Compounds Inhibit Dipeptidyl Peptidase IV: Implications in Diabetes Management

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Junfeng Fan

2013-01-01

Full Text Available Beneficial health effects of fruits and vegetables in the diet have been attributed to their high flavonoid content. Dipeptidyl peptidase IV (DPP-IV is a serine aminopeptidase that is a novel target for type 2 diabetes therapy due to its incretin hormone regulatory effects. In this study, well-characterized anthocyanins (ANC isolated from berry wine blends and twenty-seven other phenolic compounds commonly present in citrus, berry, grape, and soybean, were individually investigated for their inhibitory effects on DPP-IV by using a luminescence assay and computational modeling. ANC from blueberry-blackberry wine blends strongly inhibited DPP-IV activity (IC50, 0.07 ± 0.02 to >300 μM. Of the twenty-seven phenolics tested, the most potent DPP-IV inhibitors were resveratrol (IC50, 0.6 ± 0.4 nM, luteolin (0.12 ± 0.01 μM, apigenin (0.14 ± 0.02 μM, and flavone (0.17 ± 0.01 μM, with IC50 values lower than diprotin A (4.21 ± 2.01 μM, a reference standard inhibitory compound. Analyses of computational modeling showed that resveratrol and flavone were competitive inhibitors which could dock directly into all three active sites of DPP-IV, while luteolin and apigenin docked in a noncompetitive manner. Hydrogen bonding was the main binding mode of all tested phenolic compounds with DPP-IV. These results indicate that flavonoids, particularly luteolin, apigenin, and flavone, and the stilbenoid resveratrol can act as naturally occurring DPP-IV inhibitors.

Molecular and clinical roles of incretin-based drugs in patients with heart failure.

Science.gov (United States)

Orabi, Bassant; Kaddoura, Rasha; Omar, Amr S; Carr, Cornelia; Alkhulaifi, Abdulaziz

2018-05-01

Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors produce some beneficial and deleterious effects in diabetic patients not mediated by their glycemic lowering effects, and there is a need for better understanding of the molecular basis of these effects. They possess antioxidant and anti-inflammatory effects with some direct vasodilatory action (animal and human trial data) that may indirectly influence heart failure (HF). Unlike GLP-1R agonists, signaling for HF adverse effects was observed with two DPP-4 inhibitors, saxagliptin and alogliptin. Accordingly, these drugs should be used with caution in heart failure patients.

Combination therapy with sitagliptin and lansoprazole in patients with recent-onset type 1 diabetes (REPAIR-T1D): 12-month results of a multicentre, randomised, placebo-controlled, phase 2 trial.

Science.gov (United States)

Griffin, Kurt J; Thompson, Paul A; Gottschalk, Michael; Kyllo, Jennifer H; Rabinovitch, Alex

2014-09-01

Type 1 diabetes results from autoimmune destruction of pancreatic β cells. Findings from preclinical studies suggest that dipeptidyl peptidase-4 inhibitors and proton-pump inhibitors might enhance β-cell survival and regeneration. We postulated that sitagliptin and lansoprazole would preserve β-cell function in patients with recent-onset type 1 diabetes. We did a double-blind, placebo-controlled, phase 2 trial (REPAIR-T1D). Participants aged 11-36 years, diagnosed with type 1 diabetes within the past 6 months were recruited from Sanford Health Systems (Sioux Falls, SD, USA; Fargo, ND, USA), Children's Hospitals and Clinics of Minnesota (St Paul, MN, USA), and Rady Children's Hospital (San Diego, CA, USA). Participants were randomly assigned (2:1) to receive oral sitagliptin (100 mg for participants ≥18 years, 50 mg for those lansoprazole (60 mg for participants ≥18 years, 30 mg for those <18 years) or matched placebo for 12 months. Randomisation was done by a blocked randomisation process (blocks of three and six), with separate streams for younger (<18 years) and older (≥18 years) participants, and males and females. All participants and personnel remained masked until after the completion of the final 12 month visit, at which time data were unmasked to the analysis team. The primary endpoint was C-peptide response to a mixed meal challenge at 12 months measured as 2 h area under curve. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01155284. Between Sept 21, 2010, and May 29, 2012, 46 participants were randomly assigned to the treatment group and 22 to the placebo group; of whom 40 participants in the treatment group and 18 in the placebo group completed the 12-month treatment. At 12 months, the mean change in C-peptide area under curve was -229 pmol/L (95% CI -316 to -142) for the treatment group and -253 pmol/L (-383 to -123) for the placebo group; this difference was not significant (p=0·77). No

Development and analytical performance of a new ARCHITECT automated dipeptidyl peptidase-4 immunoassay

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Philip M. Hemken

2017-12-01

Full Text Available Background: Dipeptidyl peptidase-4 (DPP-4 may be a suitable biomarker to identify people with severe asthma who have greater activation of the interleukin-13 (IL-13 pathway and may therefore benefit from IL-13-targeted treatments. We report the analytical performance of an Investigational Use Only immunoassay and provide data on the biological range of DPP-4 concentrations. Methods: We assessed assay performance, utilising analyses of precision, linearity and sensitivity; interference from common endogenous assay interferents, and from asthma and anti-diabetic medications, were also assessed. The assay was used to measure the range of serum DPP-4 concentrations in healthy volunteers and subjects with diabetes and severe, uncontrolled asthma. Results: The total precision of DPP-4 concentration measurement (determined using percentage coefficient of variation was ≤5% over 20 days. Dilution analysis yielded linear results from 30 to 1305 ng/mL; the limit of quantitation was 19.2 ng/mL. No notable endogenous or drug interferences were observed at the expected therapeutic concentration. Median DPP-4 concentrations in healthy volunteers and subjects with asthma or Type 1 diabetes were assessed, with concentrations remaining similar in subjects with diabetes and asthma across different demographics. Conclusion: These analyses indicate that the ARCHITECT DPP-4 Immunoassay is a reliable and robust method for measuring serum DPP-4 concentration. Keywords: Asthma, Automated immunoassay, Biomarker, Dipeptidyl peptidase-4, IL-13

Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with in vivo antiresorptive activity

Science.gov (United States)

Shakespeare, William; Yang, Michael; Bohacek, Regine; Cerasoli, Franklin; Stebbins, Karin; Sundaramoorthi, Raji; Azimioara, Mihai; Vu, Chi; Pradeepan, Selvi; Metcalf, Chester; Haraldson, Chad; Merry, Taylor; Dalgarno, David; Narula, Surinder; Hatada, Marcos; Lu, Xiaode; van Schravendijk, Marie Rose; Adams, Susan; Violette, Shelia; Smith, Jeremy; Guan, Wei; Bartlett, Catherine; Herson, Jay; Iuliucci, John; Weigele, Manfred; Sawyer, Tomi

2000-01-01

Targeted disruption of the pp60src (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Herein we describe the discovery of a nonpeptide inhibitor (AP22408) of Src that demonstrates in vivo antiresorptive activity. Based on a cocrystal structure of the noncatalytic Src homology 2 (SH2) domain of Src complexed with citrate [in the phosphotyrosine (pTyr) binding pocket], we designed 3′,4′-diphosphonophenylalanine (Dpp) as a pTyr mimic. In addition to its design to bind Src SH2, the Dpp moiety exhibits bone-targeting properties that confer osteoclast selectivity, hence minimizing possible undesired effects on other cells that have Src-dependent activities. The chemical structure AP22408 also illustrates a bicyclic template to replace the post-pTyr sequence of cognate Src SH2 phosphopeptides such as Ac-pTyr-Glu-Glu-Ile (1). An x-ray structure of AP22408 complexed with Lck (S164C) SH2 confirmed molecular interactions of both the Dpp and bicyclic template of AP22408 as predicted from molecular modeling. Relative to the cognate phosphopeptide, AP22408 exhibits significantly increased Src SH2 binding affinity (IC50 = 0.30 μM for AP22408 and 5.5 μM for 1). Furthermore, AP22408 inhibits rabbit osteoclast-mediated resorption of dentine in a cellular assay, exhibits bone-targeting properties based on a hydroxyapatite adsorption assay, and demonstrates in vivo antiresorptive activity in a parathyroid hormone-induced rat model. PMID:10944210

Sodium-glucose co-transporter-2 inhibitors, the latest residents on the block: Impact on glycaemic control at a general practice level in England.

Science.gov (United States)

Heald, Adrian H; Fryer, Anthony A; Anderson, Simon G; Livingston, Mark; Lunt, Mark; Davies, Mark; Moreno, Gabriela Y C; Gadsby, Roger; Young, Robert J; Stedman, Mike

2018-03-08

To determine, using published general practice-level data, how differences in Type 2 diabetes mellitus (T2DM) prescribing patterns relate to glycaemic target achievement levels. Multiple linear regression modelling was used to link practice characteristics and defined daily dose (DDD) of different classes of medication in 2015/2016 and changes between that year and the year 2014/2015 in medication to proportion of patients achieving target glycaemic control (glycated haemoglobin A1c [HbA1c] ≤58 mmol/mol [7.5%]) and proportion of patients at high glycaemic risk (HbA1c >86 mmol/mol [10.0%]) for practices in the National Diabetes Audit with >100 people with T2DM on their register. Overall, HbA1c outcomes were not different between the years studied. Although, in percentage terms, most practices increased their use of sodium-glucose co-transporter-2 (SGLT2) inhibitors (96%), dipeptidyl peptidase-4 (DPP-4) inhibitors (76%) and glucagon-like peptide 1 (GLP-1) analogues (53%), there was wide variation in the use of older and newer therapies. For example, 12% of practices used >200% of the national average for some newer agents. In cross-sectional analysis, greater prescribing of metformin and analogue insulin were associated with a higher proportion of patients achieving HbA1c ≤58 mmol/mol; the use of SGLT2 inhibitors and metformin was associated with a reduced proportion of patients with HbA1c >86 mol/mol; otherwise associations for sulphonylureas, GLP-1 analogues, SGLT2 inhibitors and DPP-4 inhibitors were neutral or negative. In year-on-year analysis there was ongoing deterioration in glycaemic control, which was offset to some extent by increased use of SGLT2 inhibitors and GLP-1 analogues, which were associated with a greater proportion of patients achieving HbA1c levels ≤58 mmol/mol and a smaller proportion of patients with HbA1c levels >86 mmol/mol. SGLT2 inhibitor prescribing was associated with significantly greater improvements than those found

Saxagliptin for type 2 diabetes

OpenAIRE

Chacra,

2010-01-01

Antonio R Chacra, MDDiabetes Center, Federal University of São Paulo, BrazilAbstract: Saxagliptin (Onglyza™) is a potent, selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor indicated for improving glycemic control in patients with type 2 diabetes (T2D). By blocking DPP-4, saxagliptin increases and prolongs the effects of incretins, a group of peptide hormones released by intestinal cells after meals, which stimulate glucose-dependent insulin secretion to lower...

The Role of Dipeptidyl Peptidase IV in Lung Metastasis of Breast Cancer Cells

Science.gov (United States)

1999-05-01

Our studies focused on (1) cloning and sequencing of wild-type endothelial DPP IV (wtDPP IV) and preparation of truncated DPP IV ( tDPP IV); (2...that was identical to hepatic DPP IV. Acid extraction of rat lung yielded a tDPP IV, which was an effective inhibitor of breast cancer cell adhesion to

Enabling high-mobility, ambipolar charge-transport in a DPP-benzotriazole copolymer by side-chain engineering

DEFF Research Database (Denmark)

Gruber, Mathias; Jung, Seok-Heon; Schott, Sam

2015-01-01

In this article we discuss the synthesis of four new low band-gap co-polymers based on the diketopyrrolopyrrole (DPP) and benzotriazole (BTZ) monomer unit. We demonstrate that the BTZ unit allows for additional solubilizing side-chains on the co-monomer and show that the introduction of a linear...... side-chain on the DPP-unit leads to an increase in thin-film order and charge-carrier mobility if a sufficiently solubilizing, branched, side chain is attached to the BTZ. We compare two different synthetic routes, direct arylation and Suzuki-polycondensation, by a direct comparison of polymers...

Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes

NARCIS (Netherlands)

Fulcher, G.; Matthews, D. R.; Perkovic, V.; de Zeeuw, D.; Mahaffey, K. W.; Mathieu, C.; Woo, V.; Wysham, C.; Capuano, G.; Desai, M.; Shaw, W.; Vercruysse, F.; Meininger, G.; Neal, B.

Aims: To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or

Characterization of a morphogenetic furrow specific Gal4 driver in the developing Drosophila eye.

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Ankita Sarkar

Full Text Available The ability to express a gene of interest in a spatio-temporal manner using Gal4-UAS system has allowed the use of Drosophila model to study various biological phenomenon. During Drosophila eye development, a synchronous wave of differentiation called Morphogenetic furrow (MF initiates at the posterior margin resulting in differentiation of retinal neurons. This synchronous differentiation is also observed in the differentiating retina of vertebrates. Since MF is highly dynamic, it can serve as an excellent model to study patterning and differentiation. However, there are not any Gal4 drivers available to observe the gain- of- function or loss- of- function of a gene specifically along the dynamic MF. The decapentaplegic (dpp gene encodes a secreted protein of the transforming growth factor-beta (TGF-beta superfamily that expresses at the posterior margin and then moves with the MF. However, unlike the MF associated pattern of dpp gene expression, the targeted dpp-Gal4 driver expression is restricted to the posterior margin of the developing eye disc. We screened GMR lines harboring regulatory regions of dpp fused with Gal4 coding region to identify MF specific enhancer of dpp using a GFP reporter gene. We employed immuno-histochemical approaches to detect gene expression. The rationale was that GFP reporter expression will correspond to the dpp expression domain in the developing eye. We identified two new dpp-Gal4 lines, viz., GMR17E04-Gal4 and GMR18D08-Gal4 that carry sequences from first intron region of dpp gene. GMR17E04-Gal4 drives expression along the MF during development and later in the entire pupal retina whereas GMR18D08-Gal4 drives expression of GFP transgene in the entire developing eye disc, which later drives expression only in the ventral half of the pupal retina. Thus, GMR18D08-Gal4 will serve as a new reagent for targeting gene expression in the ventral half of the pupal retina. We compared misexpression phenotypes of Wg, a

Saxagliptin for type 2 diabetes

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Chacra

2010-09-01

Full Text Available Antonio R Chacra, MDDiabetes Center, Federal University of São Paulo, BrazilAbstract: Saxagliptin (Onglyza™ is a potent, selective, once-daily dipeptidyl peptidase-4 (DPP-4 inhibitor indicated for improving glycemic control in patients with type 2 diabetes (T2D. By blocking DPP-4, saxagliptin increases and prolongs the effects of incretins, a group of peptide hormones released by intestinal cells after meals, which stimulate glucose-dependent insulin secretion to lower blood glucose. In controlled clinical trials, saxagliptin administered as monotherapy or in combination with metformin, glyburide, or a thiazolidinedione improved glycemic control in a clinically significant manner, reflected by significant decreases in glycated hemoglobin (monotherapy, -0.5%; add-on to metformin, thiazolidinedione, or sulfonylurea, -0.6% to 0.9%; initial combination with metformin, -2.5%, fasting plasma glucose, and postprandial glucose compared with controls. Additionally, saxagliptin improved β-cell function, reflected as increases in homeostasis model assessment (HOMA-2β. Saxagliptin was generally well tolerated; it did not increase hypoglycemia compared with controls, and was weight neutral. A meta-analysis of Phase II and III trials showed that saxagliptin did not increase the risk of major cardiovascular events. Professional organizations have updated their guidelines for T2D to include a DPP-4 inhibitor as an early treatment option—either as initial therapy in combination with metformin, or as add-on therapy for patients whose glycemia is inadequately controlled by a single oral antidiabetic drug.Keywords: saxagliptin, dipeptidyl peptidase-4 (DPP-4 inhibitor, type 2 diabetes

Triple therapy in type 2 diabetes; a systematic review and network meta-analysis

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Martin J. Downes

2015-12-01

Full Text Available Aims. The purpose was to evaluate the evidence for triple therapy regimen using medicines available in Australia for type 2 diabetes.Methods. A systematic literature review was performed to update the relevant evidence from 2002 to 2014 on triple therapy for type 2 diabetes. A multiple-treatments network meta-analysis was undertaken to summarise the comparative efficacy and harms of different triple therapies.Results. Twenty seven trials were identified, most were six months of duration. The following combinations were included in the network meta-analysis: metformin (MET + sulfonylureas (SU (used as reference combination; MET + SU+ dipeptidyl peptidase 4 inhibitors (DPP-4-i; MET + SU+ thiazolidinediones (TZD; MET + SU+ glucagon-like peptide-1 receptor agonists (GLP-1-RA; MET + SU+ insulins; MET + TZD + DPP-4-i; and MET + SU+ sodium/glucose cotransporter 2 inhibitors (SGLT2-i. For HbA1c reduction, all triple therapies were statistically superior to MET+SU dual therapy, except for MET + TZD + DPP-4-i. None of the triple therapy combinations demonstrated differences in HbA1c compared with other triple therapies. MET + SU + SGLT2-i and MET + SU + GLP-1-RA resulted in significantly lower body weight than MET + SU + DPP-4-i, MET+SU+insulin and MET + SU + TZDs; MET + SU + DPP-4-i resulted in significantly lower body weight than MET + SU + insulin and MET + SU + TZD. MET + SU + insulin, MET + SU + TZD and MET + SU + DPP-4-i increased the odds of hypoglycaemia when compared to MET + SU. MET + SU + GLP-1-RA reduced the odds of hypoglycaemia compared to MET + SU + insulin.Conclusion. Care when choosing a triple therapy combination is needed as there is often a risk of increased hypoglycaemia events associated with this regimen and there are very limited data surrounding the long-term effectiveness and safety of combined therapies.

30 CFR 250.272 - If a State objects to the DPP's or DOCD's coastal zone consistency certification, what can I do?

Science.gov (United States)

2010-07-01

... coastal zone consistency certification, what can I do? 250.272 Section 250.272 Mineral Resources MINERALS... objects to the DPP's or DOCD's coastal zone consistency certification, what can I do? If an affected State objects to the coastal zone consistency certification accompanying your proposed or disapproved DPP or...

Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease.

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Chong, Jimmy; Leung, Bonnie; Poole, Phillippa

2017-09-19

Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea and a reduction in lung function, quality of life and life expectancy. Apart from smoking cessation, there are no other treatments that slow lung function decline. Roflumilast and cilomilast are oral phosphodiesterase 4 (PDE 4 ) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This is an update of a Cochrane review first published in 2011 and updated in 2013. To evaluate the efficacy and safety of oral PDE 4 inhibitors in the management of stable COPD. We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search October 2016). We found other trials from web-based clinical trials registers. We included RCTs if they compared oral PDE 4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy. One review author extracted data and a second review author checked the data. We reported pooled data in Review Manager as mean differences (MD), standardised mean differences (SMD) or odds ratios (OR). We converted the odds ratios into absolute treatment effects in a 'Summary of findings' table. Thirty-four separate RCTs studying roflumilast (20 trials with 17,627 participants) or cilomilast (14 trials with 6457 participants) met the inclusion criteria, with a duration of between six weeks and one year. These included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II-IV), with a mean age of 64 years.We considered that the methodological quality of the 34 published and unpublished trials was acceptable overall. Treatment with a PDE 4 inhibitor was associated with a significant improvement in forced expiratory volume in one second (FEV 1 ) over the trial period compared with placebo (MD 51.53 mL, 95% confidence interval (CI) 43.17 to 59.90, 27

Dipeptidyl peptidase-4 greatly contributes to the hydrolysis of vildagliptin in human liver.

Science.gov (United States)

Asakura, Mitsutoshi; Fujii, Hideaki; Atsuda, Koichiro; Itoh, Tomoo; Fujiwara, Ryoichi

2015-04-01

The major metabolic pathway of vildagliptin in mice, rats, dogs, and humans is hydrolysis at the cyano group to produce a carboxylic acid metabolite M20.7 (LAY151), whereas the major metabolic enzyme of vildagliptin has not been identified. In the present study, we determined the contribution rate of dipeptidyl peptidase-4 (DPP-4) to the hydrolysis of vildagliptin in the liver. We performed hydrolysis assay of the cyano group of vildagliptin using mouse, rat, and human liver samples. Additionally, DPP-4 activities in each liver sample were assessed by DPP-4 activity assay using the synthetic substrate H-glycyl-prolyl-7-amino-4-methylcoumarin (Gly-Pro-AMC). M20.7 formation rates in liver microsomes were higher than those in liver cytosol. M20.7 formation rate was significantly positively correlated with the DPP-4 activity using Gly-Pro-AMC in liver samples (r = 0.917, P vildagliptin hydrolysis in the liver. Additionally, we established stable single expression systems of human DPP-4 and its R623Q mutant, which is the nonsynonymous single-nucleotide polymorphism of human DPP-4, in human embryonic kidney 293 (HEK293) cells to investigate the effect of R623Q mutant on vildagliptin-hydrolyzing activity. M20.7 formation rate in HEK293 cells expressing human DPP-4 was significantly higher than that in control HEK293 cells. Interestingly, R623Q mutation resulted in a decrease of the vildagliptin-hydrolyzing activity. Our findings might be useful for the prediction of interindividual variability in vildagliptin pharmacokinetics. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Bioactive compounds from culinary herbs inhibit a molecular target for type 2 diabetes management, dipeptidyl peptidase IV.

Science.gov (United States)

Bower, Allyson M; Real Hernandez, Luis M; Berhow, Mark A; de Mejia, Elvira Gonzalez

2014-07-02

Greek oregano (Origanum vulgare), marjoram (Origanum majorana), rosemary (Rosmarinus officinalis), and Mexican oregano (Lippia graveolens) are concentrated sources of bioactive compounds. The aims were to characterize and examine extracts from greenhouse-grown or commercially purchased herbs for their ability to inhibit dipeptidyl peptidase IV (DPP-IV) and protein tyrosine phosphatase 1B (PTP1B), enzymes that play a role in insulin secretion and insulin signaling, respectively. Greenhouse herbs contained more polyphenols (302.7-430.1 μg of gallic acid equivalents/mg of dry weight of extract (DWE)) and flavonoids (370.1-661.4 μg of rutin equivalents/mg of DWE) compared to the equivalent commercial herbs. Greenhouse rosemary, Mexican oregano, and marjoram extracts were the best inhibitors of DPP-IV (IC₅₀=16, 29, and 59 μM, respectively). Commercial rosemary, Mexican oregano, and marjoram were the best inhibitors of PTP1B (32.4-40.9% at 500 μM). The phytochemicals eriodictyol, naringenin, hispidulin, cirsimaritin, and carnosol were identified by LC-ESI-MS as being present in greenhouse-grown Mexican oregano and rosemary. Computational modeling indicated that hispidulin, carnosol, and eriodictyol would have the best binding affinities for DPP-IV. Biochemically, the best inhibitors of DPP-IV were cirsimaritin (IC₅₀=0.43±0.07 μM), hispidulin (IC₅₀=0.49±0.06 μM), and naringenin (IC₅₀=2.5±0.29 μM). Overall, herbs contain several flavonoids that inhibit DPP-IV and should be investigated further regarding their potential in diabetes management.

Circulating dipeptidyl peptidase-4 activity correlates with measures of hepatocyte apoptosis and fibrosis in non-alcoholic fatty liver disease in type 2 diabetes mellitus and obesity: A dual cohort cross-sectional study.

Science.gov (United States)

Williams, Kathryn H; Vieira De Ribeiro, Ana Júlia; Prakoso, Emilia; Veillard, Anne-Sophie; Shackel, Nicholas A; Brooks, Belinda; Bu, Yangmin; Cavanagh, Erika; Raleigh, Jim; McLennan, Susan V; McCaughan, Geoffrey W; Keane, Fiona M; Zekry, Amany; Gorrell, Mark D; Twigg, Stephen M

2015-11-01

Intrahepatic expression of dipeptidyl peptidase-4 (DPP4), and circulating DPP4 (cDPP4) levels and its enzymatic activity, are increased in non-alcoholic fatty liver disease (NAFLD) and in type 2 diabetes mellitus and/or obesity. DPP4 has been implicated as a causative factor in NAFLD progression but few studies have examined associations between cDPP4 activity and NAFLD severity in humans. This study aimed to examine the relationship of cDPP4 activity with measures of liver disease severity in NAFLD in subjects with diabetes and/or obesity. cDPP4 was measured in 106 individuals with type 2 diabetes who had transient elastography (Cohort 1) and 145 individuals with morbid obesity who had liver biopsy (Cohort 2). Both cohorts had caspase-cleaved keratin-18 (ccK18) measured as a marker of apoptosis. Natural log increases in cDPP4 activity were associated with increasing quartiles of ccK18 (Cohorts 1 and 2) and with median liver stiffness ≥10.3 kPa (Cohort 1) and significant fibrosis (F ≥ 2) on liver biopsy (Cohort 2). In diabetes and/or obesity, cDPP4 activity is associated with current apoptosis and liver fibrosis. Given the pathogenic mechanisms by which DPP4 may progress NAFLD, measurement of cDPP4 activity may have utility to predict disease progression and DPP4 inhibition may improve liver histology over time. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

The Vildagliptin Experience - 25 Years Since the Initiation of the Novartis Glucagon-like Peptide-1 Based Therapy Programme and 10 Years Since the First Vildagliptin Registration.

Science.gov (United States)

Foley, James E; Ahrén, Bo

2017-08-01

The discovery of the incretin hormone glucagon like peptide-1 (GLP-1), and its usefulness in the treatment of type 2 diabetes mellitus (T2DM) followed by the finding that dipeptidyl peptidase-4 (DPP-4) inhibition prevents GLP-1 inactivation, led to the discovery of DPP-728. In 1999, studies with DPP-728 established the first proof-of-concept that DPP-4 inhibition improves glycaemic control in patients with T2DM. Further efforts to improve the binding kinetics of DPP-728 resulted in the discovery of vildagliptin (LAF237). In the last 20 years, a plethora of studies conducted by Novartis in collaboration with external investigators has demonstrated the mechanism of action of vildagliptin and its efficacy as monotherapy and as an add-on therapy for patients with T2DM. The studies establish that vildagliptin is a selective DPP-4 inhibitor that blocks GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) inactivation, thereby prolonging their action, resulting in improved glycaemic control. This review aims to discuss the discovery and development of vildagliptin, with an emphasis on mechanism of action and clinical efficacy.

Linagliptin increases incretin levels, lowers glucagon, and improves glycemic control in type 2 diabetes mellitus

DEFF Research Database (Denmark)

Rauch, Thomas; Graefe-Mody, Ulrike; Deacon, Carolyn F

2012-01-01

Linagliptin is a xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor that is now available in numerous countries worldwide for the treatment of type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate further the mechanisms underlying the improvements in glycemic control observed...... with linagliptin. The effects of linagliptin on DPP-4, pharmacodynamic parameters, and glycemic control versus placebo were assessed in patients with inadequately controlled T2DM....

Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes mellitus

DEFF Research Database (Denmark)

Holst, Jens Juul; McGill, Maria A

2012-01-01

Type 2 diabetes mellitus is associated with a progressive decline in insulin-producing pancreatic ß-cells, an increase in hepatic glucose production, and a decrease in insulin sensitivity. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1....... The currently available incretin-based therapies, GLP-1 receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 (DPP-4) inhibitors (CD26 antigen inhibitors) [incretin enhancers], are safe and effective in the treatment of type 2 diabetes. However, they may be unable to halt the progression of type 2...... diabetes, perhaps because they do not increase secretion of endogenous GLP-1. Therapies that directly target intestinal L cells to stimulate secretion of endogenous GLP-1 could possibly prove more effective than treatment with GLP-1 receptor agonists and DPP-4 inhibitors. Potential new approaches...

A novel data-mining approach leveraging social media to monitor consumer opinion of sitagliptin.

Science.gov (United States)

Akay, Altug; Dragomir, Andrei; Erlandsson, Björn-Erik

2015-01-01

A novel data mining method was developed to gauge the experience of the drug Sitagliptin (trade name Januvia) by patients with diabetes mellitus type 2. To this goal, we devised a two-step analysis framework. Initial exploratory analysis using self-organizing maps was performed to determine structures based on user opinions among the forum posts. The results were a compilation of user's clusters and their correlated (positive or negative) opinion of the drug. Subsequent modeling using network analysis methods was used to determine influential users among the forum members. These findings can open new avenues of research into rapid data collection, feedback, and analysis that can enable improved outcomes and solutions for public health and important feedback for the manufacturer.

Fasting during Ramadan: efficacy, safety, and patient acceptability of vildagliptin in diabetic patients

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Aziz KMA

2015-04-01

Full Text Available Kamran MA Aziz Aseer Diabetes Center, Aseer Central Hospital, Ministry of Health, Abha, Saudi Arabia Abstract: Diabetes management during Ramadan fasting is challenging to the physician in terms of minimizing the risk of hypoglycemia. As compared to oral hypoglycemic agents (OHAs and sulfonylureas (SUs, which carry a higher and significant risk of hypoglycemia, newer antidiabetic agents such as dipeptidyl peptidase-4 (DPP-4 inhibitors have demonstrated lower risk of hypoglycemia during Ramadan fasting, with better patient compliance. In addition to diabetes education and pre-Ramadan assessments, the physician should also consider use of DPP-4 inhibitors (such as vildagliptin during Ramadan fasting to minimize the risk of hypoglycemia in type 2 diabetic subjects. Severe episodes of hypoglycemia have been demonstrated in recent research and clinical trials with OHAs/SUs. Conversely, these research observations have also demonstrated comparative safety and efficacy with lower risk of hypoglycemia associated with vildagliptin. Current research review has collected evidence-based clinical trials and observations for the drug vildagliptin to minimize the risk of hypoglycemia during Ramadan fasting, while at the same time focusing the role of diabetes self-management education (DSME, pre-Ramadan assessments, and patient care. Keywords: hypoglycemia, DPP4-inhibitors, oral hypoglycemic agents, Ramadan fasting, type 2 diabetes, vildagliptin

Iro/IRX transcription factors negatively regulate Dpp/TGF-β pathway activity during intestinal tumorigenesis.

Science.gov (United States)

Martorell, Òscar; Barriga, Francisco M; Merlos-Suárez, Anna; Stephan-Otto Attolini, Camille; Casanova, Jordi; Batlle, Eduard; Sancho, Elena; Casali, Andreu

2014-11-01

Activating mutations in Wnt and EGFR/Ras signaling pathways are common in colorectal cancer (CRC). Remarkably, clonal co-activation of these pathways in the adult Drosophila midgut induces "tumor-like" overgrowths. Here, we show that, in these clones and in CRC cell lines, Dpp/TGF-β acts as a tumor suppressor. Moreover, we discover that the Iroquois/IRX-family-protein Mirror downregulates the transcription of core components of the Dpp pathway, reducing its tumor suppressor activity. We also show that this genetic interaction is conserved in human CRC cells, where the Iro/IRX proteins IRX3 and IRX5 diminish the response to TGF-β. IRX3 and IRX5 are upregulated in human adenomas, and their levels correlate inversely with the gene expression signature of response to TGF-β. In addition, Irx5 expression confers a growth advantage in the presence of TGF-β, but is selected against in its absence. Together, our results identify a set of Iro/IRX proteins as conserved negative regulators of Dpp/TGF-β activity. We propose that during the characteristic adenoma-to-carcinoma transition of human CRC, the activity of IRX proteins could reduce the sensitivity to the cytostatic effect of TGF-β, conferring a growth advantage to tumor cells prior to the acquisition of mutations in TGF-β pathway components. © 2014 The Authors.

Dipeptidyl peptidase 4 – an important digestive peptidase in Tenebrio molitor larvae

Science.gov (United States)

Dipeptidyl peptidase 4 (DPP 4) is a proline specific serine peptidase that plays an important role in different regulatory processes in mammals. In this report, we isolated and characterized a unique secreted digestive DPP 4 from the anterior midgut of a stored product pest, Tenebrio molitor larvae ...

Cultural adaptation of a peer-led lifestyle intervention program for diabetes prevention in India: the Kerala diabetes prevention program (K-DPP).

Science.gov (United States)

Mathews, Elezebeth; Thomas, Emma; Absetz, Pilvikki; D'Esposito, Fabrizio; Aziz, Zahra; Balachandran, Sajitha; Daivadanam, Meena; Thankappan, Kavumpurathu Raman; Oldenburg, Brian

2018-01-04

Type 2 diabetes mellitus (T2DM) is now one of the leading causes of disease-related deaths globally. India has the world's second largest number of individuals living with diabetes. Lifestyle change has been proven to be an effective means by which to reduce risk of T2DM and a number of "real world" diabetes prevention trials have been undertaken in high income countries. However, systematic efforts to adapt such interventions for T2DM prevention in low- and middle-income countries have been very limited to date. This research-to-action gap is now widely recognised as a major challenge to the prevention and control of diabetes. Reducing the gap is associated with reductions in morbidity and mortality and reduced health care costs. The aim of this article is to describe the adaptation, development and refinement of diabetes prevention programs from the USA, Finland and Australia to the State of Kerala, India. The Kerala Diabetes Prevention Program (K-DPP) was adapted to Kerala, India from evidence-based lifestyle interventions implemented in high income countries, namely, Finland, United States and Australia. The adaptation process was undertaken in five phases: 1) needs assessment; 2) formulation of program objectives; 3) program adaptation and development; 4) piloting of the program and its delivery; and 5) program refinement and active implementation. The resulting program, K-DPP, includes four key components: 1) a group-based peer support program for participants; 2) a peer-leader training and support program for lay people to lead the groups; 3) resource materials; and 4) strategies to stimulate broader community engagement. The systematic approach to adaptation was underpinned by evidence-based behavior change techniques. K-DPP is the first well evaluated community-based, peer-led diabetes prevention program in India. Future refinement and utilization of this approach will promote translation of K-DPP to other contexts and population groups within India as

Aryl- and heteroaryl-substituted aminobenzo[a]quinolizines as dipeptidyl peptidase IV inhibitors.

Science.gov (United States)

Boehringer, Markus; Fischer, Holger; Hennig, Michael; Hunziker, Daniel; Huwyler, Joerg; Kuhn, Bernd; Loeffler, Bernd M; Luebbers, Thomas; Mattei, Patrizio; Narquizian, Robert; Sebokova, Elena; Sprecher, Urs; Wessel, Hans Peter

2010-02-01

Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Comparison of newly developed anti-bone morphogenetic protein 4 llama-derived antibodies with commercially available BMP4 inhibitors.

Science.gov (United States)

Calpe, Silvia; Correia, Ana C P; Sancho-Serra, Maria Del Carmen; Krishnadath, Kausilia K

2016-01-01

Due to improved understanding of the role of bone morphogenetic protein 4 (BMP4) in an increasing number of diseases, the development of selective inhibitors of BMP4 is an attractive therapeutic option. The currently available BMP4 inhibitors are not suitable as therapeutics because of their low specificity and low effectiveness. Here, we compared newly generated anti-BMP4 llama-derived antibodies (VHHs) with 3 different types of commercially available BMP4 inhibitors, natural antagonists, small molecule BMPR inhibitors and conventional anti-BMP4 monoclonal antibodies. We found that the anti-BMP4 VHHs were as effective as the natural antagonist or small molecule inhibitors, but had higher specificity. We also showed that commercial anti-BMP4 antibodies were inferior in terms of both specificity and effectiveness. These findings might result from the fact that the VHHs C4C4 and C8C8 target a small region within the BMPR1 epitope of BMP4, whereas the commercial antibodies target other areas of the BMP4 molecule. Our results show that the newly developed anti-BMP4 VHHs are promising antibodies with better specificity and effectivity for inhibition of BMP4, making them an attractive tool for research and for therapeutic applications.

Reduced Airway Hyperresponsiveness by Phosphodiesterase 3 and 4 Inhibitors in Guinea-Pigs

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Nöella Germain

1999-01-01

Full Text Available The aim of the present study was to compare the effects of selective phosphodiesterase (PDE 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg, and studied 48 h after OA, a significant reduction (p<0.01 of the leftward shift of the dose-response curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg. Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg also elicited a significant reduction (p<0.01 of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE inhibitors in the treatment of asthma.

Cycling Towards Progress: Ribociclib, CDK 4/6 inhibitor for Breast Cancer.

Science.gov (United States)

Spring, Laura; Bardia, Aditya

2018-04-23

Ribociclib is an orally active, highly selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6. It is the second CDK 4/6 inhibitor approved for hormone receptor-positive breast cancer. The addition of ribociclib to an aromatase inhibitor has resulted in marked improvements in progression-free survival for patients with metastatic breast cancer. Copyright ©2018, American Association for Cancer Research.

Mothers After Gestational Diabetes in Australia Diabetes Prevention Program (MAGDA-DPP) post-natal intervention

DEFF Research Database (Denmark)

Shih, Sophy T F; Davis-Lameloise, Nathalie; Janus, Edward D.

2014-01-01

Background: The Mothers After Gestational Diabetes in Australia Diabetes Prevention Program (MAGDA-DPP) is a randomized controlled trial (RCT) that aims to assess the effectiveness of a structured diabetes prevention intervention for women who had gestational diabetes.Methods/Design: The original...

Choosing a Gliptin

Directory of Open Access Journals (Sweden)

Vishal Gupta

2011-01-01

Full Text Available The treatment of type 2 diabetes mellitus (T2DM has included the use of metformin and sulfonylurea (SU as first-line anti-diabetic therapies world over since years. This remains, despite the knowledge that the combination results in a progressive decline in [beta]-cell function and by 3 years up to 50% of diabetic patients can require an additional pharmacological agent to maintain the glycosylated hemoglobin (HbA1c <7.0% (UKPDS. Gliptins represent a novel class of agents that improve beta cell health and suppress glucagon, resulting in improved post-prandial and fasting hyperglycemia. They function by augmenting the incretin system (GLP-1 and GIP preventing their metabolism by dipeptidyl peptidase-4 (DPP-4. Not only are they efficacious but also safe (weight neutral and do not cause significant hypoglycemia, making it a unique class of drugs. This review focuses on gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin discussing pharmacokinetics, pharmacodynamics, efficacy, and safety.

4-Hydroxyphenylpyruvate Dioxygenase Inhibitors: From Chemical Biology to Agrochemicals.

Science.gov (United States)

Ndikuryayo, Ferdinand; Moosavi, Behrooz; Yang, Wen-Chao; Yang, Guang-Fu

2017-10-04

The development of new herbicides is receiving considerable attention to control weed biotypes resistant to current herbicides. Consequently, new enzymes are always desired as targets for herbicide discovery. 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an enzyme engaged in photosynthetic activity and catalyzes the transformation of 4-hydroxyphenylpyruvic acid (HPPA) into homogentisic acid (HGA). HPPD inhibitors constitute a promising area of discovery and development of innovative herbicides with some advantages, including excellent crop selectivity, low application rates, and broad-spectrum weed control. HPPD inhibitors have been investigated for agrochemical interests, and some of them have already been commercialized as herbicides. In this review, we mainly focus on the chemical biology of HPPD, discovery of new potential inhibitors, and strategies for engineering transgenic crops resistant to current HPPD-inhibiting herbicides. The conclusion raises some relevant gaps for future research directions.

Clinical Safety and Tolerability of Vildagliptin - Insights from Randomised Trials, Observational Studies and Post-marketing Surveillance.

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Mathieu, Chantal; Kozlovski, Plamen; Paldánius, Päivi M; Foley, James E; Modgill, Vikas; Evans, Marc; Serban, Carmen

2017-08-01

Vildagliptin is one of the most extensively studied dipeptidyl peptidase-4 (DPP-4) inhibitors in terms of its clinical utility. Over the last decade, a vast panorama of evidence on the benefit-risk profile of vildagliptin has been generated in patients with type 2 diabetes mellitus (T2DM). In this article, we review the cumulative evidence on the safety of vildagliptin from the clinical development programme, as well as reports of rare adverse drug reactions detected during the post-marketing surveillance of the drug. Across clinical studies, the overall safety and tolerability profile of vildagliptin was similar to placebo, and it was supported by real-world data in a broad population of patients with T2DM, making DPP-4 inhibitors, like vildagliptin, a safe option for managing patients with T2DM.

Alogliptin after acute coronary syndrome in patients with type 2 diabetes

DEFF Research Database (Denmark)

White, William B; Cannon, Christopher P; Heller, Simon R

2013-01-01

BACKGROUND: To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes...... with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. METHODS: We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring...... of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. CONCLUSIONS: Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin...

Discovery of Dengue Virus NS4B Inhibitors

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Wang, Qing-Yin; Dong, Hongping; Zou, Bin; Karuna, Ratna; Wan, Kah Fei; Zou, Jing; Susila, Agatha; Yip, Andy; Shan, Chao; Yeo, Kim Long; Xu, Haoying; Ding, Mei; Chan, Wai Ling; Gu, Feng; Seah, Peck Gee; Liu, Wei; Lakshminarayana, Suresh B.; Kang, CongBao; Lescar, Julien; Blasco, Francesca; Smith, Paul W.

2015-01-01

ABSTRACT The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo. The inhibitor was identified through screening of a 1.8-million-compound library by using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (50% effective concentration [EC50], 10 to 80 nM) but not DENV-1 and -4 (EC50, >20 μM). Resistance analysis showed that a mutation at amino acid 63 of DENV-2 NS4B (a nonenzymatic transmembrane protein and a component of the viral replication complex) could confer resistance to compound inhibition. Genetic studies demonstrate that variations at amino acid 63 of viral NS4B are responsible for the selective inhibition of DENV-2 and -3. Medicinal chemistry improved the physicochemical properties of the initial “hit” (compound 1), leading to compound 14a, which has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound 14a suppressed viremia, even when the treatment started after viral infection. The results have proven the concept that inhibitors of NS4B could potentially be developed for clinical treatment of DENV infection. Compound 14a represents a potential preclinical candidate for treatment of DENV-2- and -3-infected patients. IMPORTANCE Dengue virus (DENV) threatens up to 2.5 billion people and is now spreading in many regions in the world where it was not previously endemic. While there are several promising vaccine candidates in clinical trials, approved vaccines or antivirals are not yet available. Here we describe the identification and characterization of a spiropyrazolopyridone as a novel inhibitor of DENV by targeting the viral NS4B protein. The compound potently inhibits two of the four serotypes of DENV (DENV-2 and -3) both in vitro and in vivo. Our

Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias?

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Suissa, Samy

2018-01-01

Two recent observational studies reported a remarkably lower rate of all-cause death associated with sodium-glucose cotransporter 2 inhibitor (-SGLT2i) use in all patients with type 2 diabetes and not only those at increased cardiovascular risk. The >50% lower mortality rates reported in these studies are much greater than those found in the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and CANagliflozin cardioVascular Assessment Study (CANVAS) randomized trials. We show that these observational studies are affected by time-related biases, including immortal time bias and time-lag bias, which tend to exaggerate the benefits observed with a drug. The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) study, based on 166,033 users of SGLT2i and 1,226,221 users of other glucose-lowering drugs (oGLD) identified from health care databases of six countries, was affected by immortal time bias. Indeed, the immortal time between the first oGLD prescription and the first SGLT2i prescription was omitted from the analysis, which resulted in increasing the rate of death in the oGLD group and thus producing the appearance of a lower risk of death with SGLT2i use. The Swedish study compared 10,879 SGLT2i/dipeptidyl peptidase 4 inhibitor (DPP-4i) users with 10,879 matched insulin users. Such comparisons involving second-line therapies with a third-line therapy can introduce time-lag bias, as the patients may not be at the same stage of diabetes. This bias is compounded by the fact that the users of insulin had already started their insulin before cohort entry, unlike the new users of SGLT2i. Finally, the study also introduces immortal time bias with respect to the effects of SGLT2i relative to DPP-4i. In conclusion, the >50% lower rate of death with SGLT2i in type 2 diabetes reported by two recent observational studies is likely exaggerated by immortal time and time

Antioxidative, DPP-IV and ACE inhibiting peptides from fish protein hydrolysed with intestinal proteases

DEFF Research Database (Denmark)

Falkenberg, Susan Skanderup; Stagsted, Jan; Nielsen, Henrik Hauch

amino groups, antioxidative capacity by ABTS (2,2-azinobis(3-ethylbenzothiazoline-6-sulfonicacid)), DPP-IV and ACE inhibiting activity. Degree of hydrolysis (DH) of hydrolysates was approximately 13% and 10% for belly flap and skin respectively. No clear difference was observed in DH between pancreatin...

The role of dipeptidyl peptidase 4 inhibitors in fat metabolism in patients with type 2 diabetes and obesity

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Aleksander Sergeevich Ametov

2015-07-01

Full Text Available Objective. To evaluate the influence of combined therapy of sitagliptin and metformin on fat metabolism in patients with type 2 diabetes mellitus.Methods. The study included 82 patients (age, 55.3±9.1 years with obesity and lipid metabolism disorders. None of the patients had reached their target glycated haemoglobin levels after metformin and diet therapy. Patients in group 1 (n=42 received 1.5–2-g metformin daily before the study and were switched to a formulation of 100-mg sitagliptin and 2-g metformin once a day. Patients in group 2 (n=40 were on a diet therapy before inclusion and were started on 2-g metformin/day. The following were evaluated at baseline and after 6 months of therapy: fasting glucose levels, postprandial glucose levels, glycated haemoglobin, weight, body mass index, waist circumference and lipid profile; insulin, proinsulin, leptin and adiponectin levels; insulin resistance using the homeostatic model assessment (HOMA of β-cell function (HOMA-β and insulin resistance (HOMA-IR. In addition, magnetic resonance imaging was performed to assess the amount of visceral fat for the total cohort.Results. After 6 months, glycated haemoglobin decreased by 18.52% (p <0.001 in group 1 and by 8.17% (p <0.001 in group 2. Fasting plasma glucose and postprandial glucose levels in group 1 were reduced by 21% (p <0.001 and 26.35% (p <0.001, respectively; the corresponding reductions in group 2 were 1.45% (p >0.05 and 5.31% (p <0.05, respectively. HOMA-β increased by 33% in group 1 (p <0.001 and by 11% in group 2 (p >0.05. Adiponectin levels increased by 27.06% (p <0.001 in group 1 and by 7.16% in group 2 (p <0.001. Leptin levels were reduced by 30.47% (p <0.001 in group 1 and by 5.41% in group 2 (p <0.001. Magnetic resonance imaging showed a 7.52% reduction in visceral fat for group 1 (p <0.001 and a 1.76% reduction for group 2 (p <0.01. The comparison of subcutaneous fat dynamics did not show statistically significant differences

Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors.

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Liu, Shuang; Zha, Congxiang; Nacro, Kassoum; Hu, Min; Cui, Wenge; Yang, Yuh-Lin; Bhatt, Ulhas; Sambandam, Aruna; Isherwood, Matthew; Yet, Larry; Herr, Michael T; Ebeltoft, Sarah; Hassler, Carla; Fleming, Linda; Pechulis, Anthony D; Payen-Fornicola, Anne; Holman, Nicholas; Milanowski, Dennis; Cotterill, Ian; Mozhaev, Vadim; Khmelnitsky, Yuri; Guzzo, Peter R; Sargent, Bruce J; Molino, Bruce F; Olson, Richard; King, Dalton; Lelas, Snjezana; Li, Yu-Wen; Johnson, Kim; Molski, Thaddeus; Orie, Anitra; Ng, Alicia; Haskell, Roy; Clarke, Wendy; Bertekap, Robert; O'Connell, Jonathan; Lodge, Nicholas; Sinz, Michael; Adams, Stephen; Zaczek, Robert; Macor, John E

2014-07-10

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

Neuroprotective Mechanisms of Glucagon-like Peptide-1-based Therapies in Ischaemic Stroke

DEFF Research Database (Denmark)

Marlet, Ida R; Ölmestig, Joakim N E; Vilsbøll, Tina

2018-01-01

Review was to systematically evaluate the proposed mechanism of action for GLP-1-based therapies in ischaemic brain damage in animals. We performed a literature search using MEDLINE, EMBASE and The Cochrane Library. GLP-1-based therapies administered before, during or after experimental stroke in diabetic and non......Glucagon-like peptide-1 (GLP-1)-based therapies, GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) are widely used for the treatment of type 2 diabetes. Increasing evidence suggests that they may provide neuroprotection. The aim of this Mini......-diabetic animals were evaluated. We reviewed 27 studies comprised of 20 involving GLP-1RAs and seven involving DPP-4Is. Both GLP-1RAs and DPP-4Is affected the acute inflammatory response secondary to ischaemia by reducing inflammation, endothelial leakage and excitotoxicity. Both treatments also reduced oxidative...

Bisbibenzyls, a new type of antifungal agent, inhibit morphogenesis switch and biofilm formation through upregulation of DPP3 in Candida albicans.

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Li Zhang

Full Text Available The yeast-to-hypha transition plays a crucial role in the pathogenesis of C. albicans. Farnesol, a quorum sensing molecule (QSM secreted by the fungal itself, could prevent the formation of hyphae and subsequently lead to the defect of biofilm formation. The DPP3, encoding phosphatase, is a key gene in regulating farnesol synthesis. In this study, we screened 24 bisbibenzyls and 2 bibenzyls that were isolated from bryophytes or chemically synthesized by using CLSI method for antifungal effect. Seven bisbibenzyls were found to have antifungal effects with IC(80 less than 32 µg/ml, and among them, plagiochin F, isoriccardin C and BS-34 were found to inhibit the hyphae and biofilm formation of C. albicans in a dose-dependent manner. To uncover the underlying relationship between morphogenesis switch and QSM formation, we measured the farnesol production by HPLC-MS and quantified Dpp3 expression by detecting the fluorescent intensity of green fluorescent protein tagged strain using Confocal Laser Scanning microscopy and Multifunction Microplate Reader. The DPP3 transcripts were determined by real-time PCR. The data indicated that the bisbibenzyls exerted antifungal effects through stimulating the synthesis of farnesol via upregulation of Dpp3, suggesting a potential antifungal application of bisbibenzyls. In addition, our assay provides a novel, visual and convenient method to measure active compounds against morphogenesis switch.

Effect of the Side Chains and Anode Material on Thermal Stability and Performance of Bulk-Heterojunction Solar Cells Using DPP(TBFu2 Derivatives as Donor Materials

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Alexander Kovalenko

2015-01-01

Full Text Available An optimized fabrication of bulk-heterojunction solar cells (BHJ SCs based on previously reported diketopyrrolopyrrole donor, ethyl-hexylated DPP(TBFu2, as well as two new DPP(TBFu2 derivatives with ethyl-hexyl acetate and diethyl acetal solubilizing side-chains and PC60BM as an acceptor is demonstrated. Slow gradual annealing of the solar cell causing the effective donor-acceptor reorganization, and as a result higher power conversion efficiency (PCE, is described. By replacing a hole transporting layer PEDOT:PSS with MoO3 we obtained higher PCE values as well as higher thermal stability of the anode contact interface. DPP(TBFu2 derivative containing ethyl-hexyl acetate solubilizing side-chains possessed the best as-cast self-assembly and high crystallinity. However, the presence of ethyl-hexyl acetate and diethyl acetal electrophilic side-chains stabilizes HOMO energy of isolated DPP(TBFu2 donors with respect to the ethyl-hexylated one, according to cyclic voltammetry.

Effect of alogliptin on hypertensive chronic kidney disease patients with type 2 diabetes mellitus

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Amira Said

2018-02-01

Full Text Available Background Diabetes mellitus (DM is a leading cause of chronic kidney disease (CKD. The antihyperglycemic treatment options for patients with Type 2 DM are limited because of safety and tolerability concerns. Aims To retrospectively assess the effect of using Alogliptin; a dipeptidyl peptidase-4 inhibitor (DPP-4i along with conventional gliclazide: a sulphonylurea (SU on renal outcomes and glycaemic control in T2DM patients with mild CKD and hypertension. Methods A total of 76 patient records (38 males and 38 females of patient ages 40–60 were analysed from the kidney unit at Punjab Care hospital, Lahore, Pakistan. All patients had a confirmed history of T2DM with mild CKD and established hypertension. Eligible patients were divided into two groups of 38 individuals each. Group SU received gliclazide monotherapy (SU or Alogliptin (DPP-4i+gliclazide (SU add on therapy. All patients were followed up for 12 months. Results The alogliptin (DPP-4i plus gliclazide (SU add on therapy group, in comparison to the group only receiving gliclazide (SU, showed a significant difference in eGFR values. The mean±SD GFR values post 12 months were 74.8±0.31 (95%CI:74.8±0.09;74.7–74.9 and 76.1±0.25 (95%CI: 76.1±0.08;76.0-76.2 for SU vs. SU+DPP-4i, respectively, with mean calculated effect size of 1.6,. HbA1c, 1,5 AG and ipid profile values have significantly changed (p<0.05 while blood pressure values showed no change. The mean±SD systolic blood pressure readings post 12 months for for SU vs. SU+DPP-4i were 131.4±10.4 (95% CI 131.4±3.3;128.1– 134.7, and 131.8±9.9 (95%CI 131.8±3; 128.8–134.8, respectively. Conclusion In the present study, patients using alogliptin in addition to sulfonyl urea showed improved glycaemic control and lipid profile without increased occurrence of hypoglycaemia. We concluded that, DPP-4i inhibitors are safe treatment options for patients with type 2 diabetes and mild degree of renal impairment.

30 CFR 250.252 - What environmental monitoring information must accompany the DPP or DOCD?

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2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false What environmental monitoring information must accompany the DPP or DOCD? 250.252 Section 250.252 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT... incidental take of marine mammals as may be necessary under the MMPA. (c) Flower Garden Banks National Marine...

Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker.

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Gábor Firneisz

Full Text Available BACKGROUND: In a cross-sectional study we studied the fasting serum DPP-4 enzymatic activity (sDPP-4 and the insulin resistance index (HOMA2-IR in gliptin naïve patients with type 2 diabetes and in non-alcoholic fatty liver disease (NAFLD and in healthy controls (CNTRL. METHODS AND FINDINGS: sDPP-4 was measured by kinetic assay in 39 NAFLD (F/M:19/20, mean age: 47.42 yrs and 82 type 2 diabetes (F/M:48/34, 62.8 yrs patients and 26 (F/M:14/12, 35.3 yrs controls. Definition of T2D group as patients with type 2 diabetes but without clinically obvious liver disease created non-overlapping study groups. Diagnosis of NAFLD was based on ultrasonography and the exclusion of other etiololgy. Patients in T2D and NAFLD groups were similarly obese. 75 g CH OGTT in 39 NAFLD patients: 24-NGT, 4-IGT or IFG ("prediabetes", 11-type 2 diabetes. HOMA2-IR: CNTRL: 1.44; T2D-group: 2.62 (p = 0.046 vs CNTRL, parametric tests; NAFLD(NGTonly: 3.23 (p = 0.0013 vs CNTRL; NAFLD(IFG/IGT/type 2 diabetes: 3.82 (p<0.001 vs CNTRL, p = 0.049 vs 2TD group. sDPP-4 activity was higher in NAFLD both with NGT (mean:33.08U/L and abnormal glucose metabolism (30.38U/L than in CNTRL (25.89U/L, p<0.001 and p = 0.013 or in T2D groups (23.97U/L, p<0.001 and p = 0.004. Correlations in NAFLD among sDPP-4 and ALT: r = 0.4637,p = 0.0038 and gammaGT: r = 0.4991,p = 0.0017 and HOMA2-IR: r = 0.5295,p = 0.0026 and among HOMA2-IR and ALT: r = 0.4340,p = 0.0147 and gammaGT: r = 0.4128,p = 0.0210. CONCLUSIONS: The fasting serum DPP-4 activity was not increased in T2D provided that patients with liver disease were intentionally excluded. The high serum DPP-4 activities in NAFLD were correlated with liver tests but not with the fasting plasma glucose or HbA1C supporting that the excess is of hepatic origin and it might contribute to the speedup of metabolic deterioration. The correlation among gammaGT, ALT and serum DPP-4 activity and also between serum DPP-4 activity and HOMA2-IR in NAFLD strongly

Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus.

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Scheen, André J

2015-01-01

Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12-104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin

ТАБЛЕТИРОВАННАЯ САХАРОСНИЖАЮЩАЯ ТЕРАПИЯ: ВЧЕРА, СЕГОДНЯ, ЗАВТРА

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Н. И. Волкова

2013-01-01

Full Text Available In this review there are discussed main steps in oral antidiabetic drugs development. There are presented modern data that concern DPP-4 inhibitors. New advanced perspectives of antidiabetic drugs are also marked.

Morphology impact on oxygen sensing ability of Ru(dpp){sub 3}Cl{sub 2} containing biocompatible polymers

Energy Technology Data Exchange (ETDEWEB)

Zhao, Susan Y.; Harrison, Benjamin S., E-mail: bharriso@wakehealth.edu

2015-08-01

Especially for tissue engineering applications, the diffusion of oxygen is a critical factor affecting spatial distribution and migration of cells. The cellular oxygen demand also fluctuates depending on tissue type and growth phase. Sensors that determine dissolved oxygen levels under biological conditions provide critical metabolic information about the growing cells as well as the state of the tissue culture within the tissue scaffold. This work focused on the effect of the scaffold morphology on the oxygen sensing response time. It was found that electrospun scaffolds had a faster oxygen-sensing response time than their bulk film counterparts. Tris-(4,7-diphenyl-1,10-phenanthroline) ruthenium (II) dichloride doped electrospun fiber mats of polycaprolactone (PCL) were found to be the most responsive to the presence of oxygen, followed by polyethylene (PEO) glycol mats. Systems containing poly vinyl alcohol were found to be the least responsive. This would suggest that, out of all the polymers tested, PCL and PEO are the most suitable biomaterials for oxygen-sensing applications. - Highlights: • Ru(DPP){sub 3}Cl{sub 2} was blended into common biocompatible polymers such as PEO, PCL, and PVA. • Oxygen sensing was more responsive when polymers were electrospun compared to bulk. • Electrospun PEO and PCL with Ru(dpp){sub 3}Cl{sub 2} showed similar oxygen sensing responses. • PVA showed a slight improvement in oxygen sensing rate when electrospun.

Generation of dipeptidyl peptidase IV (DPP-IV) inhibitory peptides during the enzymatic hydrolysis of tropical banded cricket (Gryllodes sigillatus) proteins.

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Nongonierma, Alice B; Lamoureux, Candice; FitzGerald, Richard J

2018-01-24

Tropical banded crickets (Gryllodes sigillatus) were studied for their ability to yield hydrolysates with dipeptidyl peptidase IV (DPP-IV) inhibitory properties. A cricket protein isolate (CPI) was prepared following extraction of the water soluble proteins from G. sigillatus powder (CP). The extraction yield and purity were 20.90 ± 0.35% and 57.0 ± 2.23%, respectively. Endogenous proteinase activities were detected in the CP, which were linked to the significant protein breakdown seen in this sample. Fifteen CPI hydrolysates (H1-H15) were generated with Protamex™ using a design of experiments (DOE) approach combining three parameters, temperature (40, 50 and 60 °C), enzyme to substrate ratio (E : S, 0.50, 1.25 and 2.00% (w/w)) and hydrolysis time (60, 150 and 240 min). The DPP-IV half maximal inhibitory concentrations (IC 50 ) of the CPI hydrolysates ranged from 0.40 ± 0.03/0.40 ± 0.02 (H2/H3) to 1.01 ± 0.07 mg mL -1 (H7). Following simulated gastrointestinal digestion (SGID), the DPP-IV IC 50 of CPI decreased (>3.57 vs. 0.78 ± 0.04 mg mL -1 ) while that of H5 increased (0.47 ± 0.03 vs. 0.71 ± 0.06 mg mL -1 ). This study has demonstrated for the first time that G. sigillatus protein hydrolysates are able to inhibit DPP-IV. The study of these hydrolysates in vivo is needed to evaluate their potential role in glycaemic management.

Increased plasma dipeptidyl peptidase-4 activities are associated with high prevalence of subclinical atherosclerosis in Chinese patients with newly diagnosed type 2 diabetes: a cross-sectional study.

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Zheng, T P; Liu, Y H; Yang, L X; Qin, S H; Liu, H B

2015-10-01

Hyperglycemia, insulin resistance, dislipidemia, oxidative stress and inflammation are well-documented risk factors for subclinical atherosclerosis. Dipeptidyl peptidase-4(DPP4) is a newly identified adipokine related to these risk factors. Hence, we aimed to investigate the association between plasma DPP4 activities and subclinical atherosclerosis in type 2 diabetes. A total of 985 newly diagnosed type 2 diabetic subjects were studied. Plasma DPP4 activity, mannose 6-phosphate receptor (M6P-R), oxidative stress parameters, inflammatory markers and common carotid artery Intima-Media Thickness (c-IMT) were measured in all participants. Participants in the highest quartile of DPP4 activity had higher HbA1c, homeostatic model assessment of insulin resistance(HOMA-IR), triglyceride, low-density lipoprotein cholesterol(LDL-C), oxidized LDL, nitrotyrosine, 8-iso-PGF2a, interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), M6P-R, c-IMT compared with participants in the lowest quartile (all P dislipidemia, oxidative stress and inflammation were higher with increasing DPP4 quartiles (P < 0.001 for trend). In the highest DPP4 quartile, subclinical atherosclerosis risk was significantly higher (OR 4.97; 95% CI 3.03-8.17) than in the lowest quartile. This association remained strong (2.17; 1.21-3.89) after further controlling for HbA1c, HOMA-IR, triglyceride, oxidized LDL, nitrotyrosine, and IL-6. This study shows that increased DPP4 activities are positively and independently associated with subclinical atherosclerosis in type 2 diabetes. Our findings suggest of potential role of DPP4 in the pathogenesis of subclinical atherosclerosis and in the prevention and management of this disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

An overview of once-weekly glucagon-like peptide-1 receptor agonists--available efficacy and safety data and perspectives for the future

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Madsbad, S; Kielgast, U; Asmar, M

2011-01-01

Incretin-based therapies, such as the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and orally administered dipeptidyl peptidase-4 (DPP-4) inhibitors, have recently been introduced into clinical practice. At present, the GLP-1 receptor agonists need to be administered once or twice...

High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of multidrug resistance protein 4 (MRP4).

Science.gov (United States)

Cheung, Leanna; Flemming, Claudia L; Watt, Fujiko; Masada, Nanako; Yu, Denise M T; Huynh, Tony; Conseil, Gwenaëlle; Tivnan, Amanda; Polinsky, Alexander; Gudkov, Andrei V; Munoz, Marcia A; Vishvanath, Anasuya; Cooper, Dermot M F; Henderson, Michelle J; Cole, Susan P C; Fletcher, Jamie I; Haber, Michelle; Norris, Murray D

2014-09-01

Multidrug resistance protein 4 (MRP4/ABCC4), a member of the ATP-binding cassette (ABC) transporter superfamily, is an organic anion transporter capable of effluxing a wide range of physiologically important signalling molecules and drugs. MRP4 has been proposed to contribute to numerous functions in both health and disease; however, in most cases these links remain to be unequivocally established. A major limitation to understanding the physiological and pharmacological roles of MRP4 has been the absence of specific small molecule inhibitors, with the majority of established inhibitors also targeting other ABC transporter family members, or inhibiting the production, function or degradation of important MRP4 substrates. We therefore set out to identify more selective and well tolerated inhibitors of MRP4 that might be used to study the many proposed functions of this transporter. Using high-throughput screening, we identified two chemically distinct small molecules, Ceefourin 1 and Ceefourin 2, that inhibit transport of a broad range of MRP4 substrates, yet are highly selective for MRP4 over other ABC transporters, including P-glycoprotein (P-gp), ABCG2 (Breast Cancer Resistance Protein; BCRP) and MRP1 (multidrug resistance protein 1; ABCC1). Both compounds are more potent MRP4 inhibitors in cellular assays than the most widely used inhibitor, MK-571, requiring lower concentrations to effect a comparable level of inhibition. Furthermore, Ceefourin 1 and Ceefourin 2 have low cellular toxicity, and high microsomal and acid stability. These newly identified inhibitors should be of great value for efforts to better understand the biological roles of MRP4, and may represent classes of compounds with therapeutic application. Copyright © 2014 Elsevier Inc. All rights reserved.

Lower dipeptidyl peptidase-4 following exercise training plus weight loss is related to increased insulin sensitivity in adults with metabolic syndrome.

Science.gov (United States)

Malin, Steven K; Huang, Hazel; Mulya, Anny; Kashyap, Sangeeta R; Kirwan, John P

2013-09-01

Dipeptidyl peptidase-4 (DPP-4) is a circulating glycoprotein that impairs insulin-stimulated glucose uptake and is linked to obesity and metabolic syndrome. However, the effect of exercise on plasma DPP-4 in adults with metabolic syndrome is unknown. Therefore, we determined the effect of exercise on DPP-4 and its role in explaining exercise-induced improvements in insulin sensitivity. Fourteen obese adults (67.9±1.2 years, BMI: 34.2±1.1kg/m(2)) with metabolic syndrome (ATP III criteria) underwent a 12-week supervised exercise intervention (60min/day for 5 days/week at ∼85% HRmax). Plasma DPP-4 was analyzed using an enzyme-linked immunosorbent assay. Insulin sensitivity was measured using the euglycemic-hyperinsulinemic clamp (40mU/m(2)/min) and estimated by HOMA-IR. Visceral fat (computerized tomography), 2-h glucose levels (75g oral glucose tolerance), and basal fat oxidation as well as aerobic fitness (indirect calorimetry) were also determined before and after exercise. The intervention reduced visceral fat, lowered blood pressure, glucose and lipids, and increased aerobic fitness (PExercise improved clamp-derived insulin sensitivity by 75% (PExercise training reduces plasma DPP-4, which may be linked to elevated insulin sensitivity and fat oxidation. Maintaining low plasma DPP-4 concentrations is a potential mechanism whereby exercise plus weight loss prevents/delays the onset of type 2 diabetes in adults with metabolic syndrome. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparison of the Effects of Continuous Subcutaneous Insulin Infusion and Add-On Therapy with Sitagliptin in Patients with Newly Diagnosed Type 2 Diabetes Mellitus

Directory of Open Access Journals (Sweden)

Heng Wan

2016-01-01

Full Text Available To identify a new regimen to optimize treatment for patients with newly diagnosed type 2 diabetes (T2DM by short-term continuous subcutaneous insulin infusion (CSII alone. Methods. 60 patients with newly diagnosed T2DM were randomized into two groups (n=30 each and treated for 2 weeks with CSII alone (CSII group or with CSII plus sitagliptin (CSII + Sig group. The glycemic variability of the patients was measured using a continuous glucose monitoring system (CGMS for the last 72 hours. A standard meal test was performed before and after the interventions, and the levels of glycated albumin, fasting glucose, fasting C-peptide, postprandial 2 h blood glucose, and postprandial 2 h C-peptide were examined. Results. Compared with the CSII group, the indicators of glycemic variability, such as the mean amplitude of glycemic excursion (MAGE and the standard deviation of blood glucose (SDBG, were decreased significantly in the CSII + Sig group. The changes before and after treatment in the C-peptide reactivity index (ΔCPI and the secretory unit of islet in transplantation index (ΔSUIT indicated a significant improvement in the CSII + Sig group. Conclusions. Add-on therapy with sitagliptin may be an optimized treatment for patients with newly diagnosed T2DM compared with short-term CSII alone.

Cardiovascular safety of combination therapies with incretin-based drugs and metformin compared with a combination of metformin and sulphonylurea in type 2 diabetes mellitus – a retrospective nationwide study

DEFF Research Database (Denmark)

Mogensen, U M; Andersson, Charlotte; Fosbøl, E L

2014-01-01

AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are widely used in combinations with metformin in the treatment of type 2 diabetes; however, data on long-term safety compared with conventional combination therapies are limited. METHODS: Danish individuals...... of myocardial infarction, stroke and CV mortality. Rate ratios (RR) were calculated using time-dependent multivariable Poisson regression analysis. RESULTS: A total of 40 028 patients (59% men, mean age 60 ± 13 years) used metformin with SU (n = 25 092), DPP-4 inhibitor (n = 11 138), GLP-1 agonist (n = 4345...... with metformin were safe compared with conventional combinations of glucose-lowering therapy. Use of incretin-based therapy may be target for strategies to lower CV risk in type 2 diabetes, although it should be recognized that the multivariable analysis may not have fully accounted for important baseline...

Dipeptidyl peptidase-4 inhibitor induced angioedema - an overlooked and potentially lethal adverse drug reaction?

DEFF Research Database (Denmark)

Scott, Susanne Irene; Andersen, Michelle Fog; Aagaard, Lise

2018-01-01

to vasodilatation and increase in vascular permeability in the capillaries. Objective To assess the risk and pathomechanism of angioedema due to inhibition of dipeptidyl peptidase-4 inhibitors when used as monotherapy and in combination with angiotensin converting enzyme-inhibitors. Method PubMed, Embase......, the Cochrane Library, PubMed Central, Web of Science, Google Scholar and clinicaltrials.gov were searched using different combinations of keywords "angioedema", "dipeptidyl peptidase 4", "dipeptidyl peptidase 4 inhibitors", "gliptins", "bradykinin", "substance P" and "angiotensin converting enzyme...

Important species differences regarding lymph contribution to gut hormone responses

DEFF Research Database (Denmark)

Hansen, Marie; Hjøllund, Karina R; Hartmann, Bolette

2015-01-01

pigs of the YDL-strain were catheterized in the portal vein, carotid artery and cisterna chyli (lymph). Neuromedin C (NC) was infused through an ear vein catheter, before and after injection of a selective DPP-4 inhibitor (vildagliptin). Total and intact GLP-1 levels were measured throughout the 150min....../presence of vildagliptin. In contrast, total and intact GLP-1 levels increased significantly in the portal vein and carotid artery. DPP-4 activity was lower in lymph than plasma, and was reduced further by vildagliptin. CONCLUSION: Our observations indicate that the lymphatic system does not transport high levels...

Preconception Prebiotic and Sitagliptin Treatment in Obese Rats Affects Pregnancy Outcomes and Offspring Microbiota, Adiposity, and Glycemia

Directory of Open Access Journals (Sweden)

Carol A. Dennison

2017-10-01

Full Text Available Maternal obesity is associated with increased risk of pregnancy complications and greater risk of obesity in offspring, but studies designed to examine preconception weight loss are limited. The objective of this study was to determine if a combined dietary [oligofructose (OFS] and pharmacological (sitagliptin preconception intervention could mitigate poor pregnancy outcomes associated with maternal obesity and improve offspring metabolic health and gut microbiota composition. Diet-induced obese female Sprague-Dawley rats were randomized to one of four intervention groups for 8 weeks: (1 Obese-Control (consumed control diet during intervention; (2 Obese-OFS (10% OFS diet; (3 Obese-S (sitagliptin drug; (4 Obese-OFS + S (combination treatment. Two reference groups were also included: (5 Obese-HFS (untreated obese consumed high fat/sucrose diet throughout study; (6 Lean-Control (lean reference group that were never obese and consumed control diet throughout. Offspring consumed control diet until 11 weeks of age followed by HFS diet until 17 weeks of age. The Obese-OFS + S rats lost weight during the intervention phase whereas the OFS and S treatments attenuated weight gain compared with Obese-HFS (p < 0.05. Gestational weight gain was lowest in Obese-OFS + S rats and highest in Obese-HFS rats (p < 0.05. Prepregnancy intervention did not affect reproductive parameters but did affect pregnancy outcomes including litter size. Male Obese-OFS offspring had significantly lower percent body fat than Obese-HFS at 17 weeks. Female Obese-S and Obese-OFS offspring had significantly lower fasting glucose at 17 weeks compared with Obese-Control and Obese-HFS. Clostridium cluster XI was higher in Obese-HFS and Obese-S dams at birth compared with all other groups. Dams with an adverse pregnancy outcome had significantly lower (p = 0.035 Lactobacillus spp. compared with dams with normal or small litters. At weaning, male offspring

V3-independent competitive resistance of a dual-X4 HIV-1 to the CXCR4 inhibitor AMD3100.

Directory of Open Access Journals (Sweden)

Yosuke Maeda

Full Text Available A CXCR4 inhibitor-resistant HIV-1 was isolated from a dual-X4 HIV-1 in vitro. The resistant variant displayed competitive resistance to the CXCR4 inhibitor AMD3100, indicating that the resistant variant had a higher affinity for CXCR4 than that of the wild-type HIV-1. Amino acid sequence analyses revealed that the resistant variant harbored amino acid substitutions in the V2, C2, and C4 regions, but no remarkable changes in the V3 loop. Site-directed mutagenesis confirmed that the changes in the C2 and C4 regions were principally involved in the reduced sensitivity to AMD3100. Furthermore, the change in the C4 region was associated with increased sensitivity to soluble CD4, and profoundly enhanced the entry efficiency of the virus. Therefore, it is likely that the resistant variant acquired the higher affinity for CD4/CXCR4 by the changes in non-V3 regions. Taken together, a CXCR4 inhibitor-resistant HIV-1 can evolve using a non-V3 pathway.

Small intestinal glucose delivery affects the glucose-lowering effect of acute vildagliptin in type 2 diabetes

DEFF Research Database (Denmark)

Wu, T; Zhang, X; Trahair, LG

2016-01-01

of the DPP-4 inhibitor, vildagliptin (VILD), during intraduodenal (ID) glucose infusion at 2 different rates within the physiological range of gastric emptying, in type 2 diabetes. Participants and Design: A total of 16 diet-controlled type 2 diabetic patients were studied on 4 separate days in double...

A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

International Nuclear Information System (INIS)

Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young; Chun, Sung Hak; Han, Jeong Yun; Kim, Sung Dae; Lee, Janet; Lee, Chang-Woo; Yang, Kwangmo; Lee, Chang Geun

2013-01-01

Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24 − /CD44 + ) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer

Fluorescent Inhibitors as Tools To Characterize Enzymes: Case Study of the Lipid Kinase Phosphatidylinositol 4-Kinase IIIβ (PI4KB).

Science.gov (United States)

Humpolickova, Jana; Mejdrová, Ivana; Matousova, Marika; Nencka, Radim; Boura, Evzen

2017-01-12

The lipid kinase phosphatidylinositol 4-kinase IIIβ (PI4KB) is an essential host factor for many positive-sense single-stranded RNA (+RNA) viruses including human pathogens hepatitis C virus (HCV), Severe acute respiratory syndrome (SARS), coxsackie viruses, and rhinoviruses. Inhibitors of PI4KB are considered to be potential broad-spectrum virostatics, and it is therefore critical to develop a biochemical understanding of the kinase. Here, we present highly potent and selective fluorescent inhibitors that we show to be useful chemical biology tools especially in determination of dissociation constants. Moreover, we show that the coumarin-labeled inhibitor can be used to image PI4KB in cells using fluorescence-lifetime imaging microscopy (FLIM) microscopy.

Angiotensin converting enzyme inhibitors and Alzheimer disease in the presence of the apolipoprotein E4 allele.

Science.gov (United States)

Qiu, Wendy Wei Qiao; Lai, Angela; Mon, Timothy; Mwamburi, Mkaya; Taylor, Warren; Rosenzweig, James; Kowall, Neil; Stern, Robert; Zhu, Haihao; Steffens, David C

2014-02-01

The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers. Copyright © 2014. Published by Elsevier Inc.

Vildagliptin restores renal myogenic function and attenuates renal sclerosis independently of effects on blood glucose or proteinuria in Zucker Diabetic Fatty rat

NARCIS (Netherlands)

Vavrinec, Peter; Henning, Robert H.; Landheer, Sjoerd W.; Wang, Yumei; Deelman, Leo E.; van Dokkum, Richard P. E.; Buikema, Hendrik

Type 2 diabetes mellitus (T2DM) is associated with risk for chronic kidney disease (CKD), which is associated with a decrease in renal myogenic tone - part of renal autoregulatory mechanisms. Novel class of drugs used for the treatment of T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitors, have

Tetomilast: new promise for phosphodiesterase-4 inhibitors?

Science.gov (United States)

Bickston, Stephen J; Snider, Kenneth R; Kappus, Matthew R

2012-12-01

Tetomilast is a novel thiazole phosphodiesterase-4 (PDE-4) inhibitor, which may prove useful in both the treatment of inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD). Here, the authors review the pharmacology of the drug, and offer critical review of the available data for use of tetomilast in the treatment of IBD. Peer-reviewed publications, including Phase I and II clinical trials, all other formats included. Tetomilast may be beneficial in IBD. Small differences in molecules and in recombinant proteins can translate into substantial differences in clinical effects and toxicity in IBD. This is a reasonable approach when exploring new options like tetomilast.

The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices

NARCIS (Netherlands)

Kistemaker, Loes E M; Oenema, Tjitske A; Baarsma, Hoeke A; Bos, I. Sophie T.; Schmidt, Martina; Facchinetti, Fabrizio; Civelli, Maurizio; Villetti, Gino; Gosens, Reinoud

2017-01-01

Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced

Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT).

Science.gov (United States)

Ding, Yun; O'Keefe, Heather; DeLorey, Jennifer L; Israel, David I; Messer, Jeffrey A; Chiu, Cynthia H; Skinner, Steven R; Matico, Rosalie E; Murray-Thompson, Monique F; Li, Fan; Clark, Matthew A; Cuozzo, John W; Arico-Muendel, Christopher; Morgan, Barry A

2015-08-13

The aggrecan degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. Here, we use DNA-encoded Library Technology (ELT) to identify novel ADAMTS-4 inhibitors from a DNA-encoded triazine library by affinity selection. Structure-activity relationship studies based on the selection information led to the identification of potent and highly selective inhibitors. For example, 4-(((4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(((4-methylpiperazin-1-yl)methyl)amino)-1,3,5-triazin-2-yl)amino)methyl)-N-ethyl-N-(m-tolyl)benzamide has IC50 of 10 nM against ADAMTS-4, with >1000-fold selectivity over ADAMT-5, MMP-13, TACE, and ADAMTS-13. These inhibitors have no obvious zinc ligand functionality.

30 CFR 250.261 - What environmental impact analysis (EIA) information must accompany the DPP or DOCD?

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false What environmental impact analysis (EIA) information must accompany the DPP or DOCD? 250.261 Section 250.261 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Plans and Information Contents of...

The Evaluation of Dipeptidyl Peptidase (DPP)-IV, α-Glucosidase and Angiotensin Converting Enzyme (ACE) Inhibitory Activities of Whey Proteins Hydrolyzed with Serine Protease Isolated from Asian Pumpkin (Cucurbita ficifolia).

Science.gov (United States)

Konrad, Babij; Anna, Dąbrowska; Marek, Szołtysik; Marta, Pokora; Aleksandra, Zambrowicz; Józefa, Chrzanowska

2014-01-01

In the present study, whey protein concentrate (WPC-80) and β-lactoglobulin were hydrolyzed with a noncommercial serine protease isolated from Asian pumpkin ( Cucurbita ficifolia ). Hydrolysates were further fractionated by ultrafiltration using membranes with cut-offs equal 3 and 10 kDa. Peptide fractions of molecular weight lower than 3 and 3-10 kDa were further subjected to the RP-HPLC. Separated preparations were investigated for their potential as the natural inhibitors of dipeptidyl peptidase (DPP-IV), α-glucosidase and angiotensin converting enzyme (ACE). WPC-80 hydrolysate showed higher inhibitory activities against the three tested enzymes than β-lactoglobulin hydrolysate. Especially high biological activities were exhibited by peptide fractions of molecular weight lower than 3 kDa, with ACE IC50 food ingredients in the diet of patients with type 2 diabetes.

Checkpoint inhibitors in cancer immunotherapy: Cross reactivity of a CTLA-4 antibody and IDO-inhibitor L-1MT in pigs

DEFF Research Database (Denmark)

Al-Shatrawi, Zina Adil; Frøsig, Thomas Mørch; Jungersen, Gregers

a non-specific activation of porcine T cells. This will be further investigated to provide the basis for in vivo studies investigating checkpoint inhibitor blockade in combination with other cancer immunotherapies. Eventually our goal is to establish pigs as an alternative large animal model......Blockade of checkpoint inhibitors has recently shown very convincing results in the treatment of cancer. One key target is CTLA-4, which has been demonstrated to be a potent negative regulator of lymphocyte activation. The treatment with the FDA-approved fully human CTLA-4 monoclonal antibody...... Ipilimumab increases anticancer T-cell reactivity and overall survival of metastatic cancer patients. Indole-amine 2,3-dioxygenase (IDO) is another checkpoint inhibitor which suppresses T-cell immunity by the depletion of tryptophan in the T-cell microenvironment, and also inhibition of IDO by L-1...

Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial

NARCIS (Netherlands)

Foley, J.E.; Bunck, M.C.M.; Moller-Goede, D.L.; Poelma, M.; Nijpels, G.; Eekhoff, E.M.; Schweizer, A.; Heine, R.J.; Diamant, M.

2011-01-01

Aims/hypothesis: Traditional blood glucose lowering agents do not prevent the progressive loss of beta cell function in patients with type 2 diabetes. The dipeptidylpeptidase (DPP)-4 inhibitor vildagliptin improves beta cell function both acutely and chronically (up to 2 years). Whether this effect

30 CFR 250.260 - What Coastal Zone Management Act (CZMA) information must accompany the DPP or DOCD?

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false What Coastal Zone Management Act (CZMA) information must accompany the DPP or DOCD? 250.260 Section 250.260 Mineral Resources MINERALS MANAGEMENT... Operations Coordination Documents (docd) § 250.260 What Coastal Zone Management Act (CZMA) information must...

Triplet State Formation in Photovoltaic Blends of DPP-Type Copolymers and PC71BM

KAUST Repository

Ochsmann, Julian R.

2015-04-29

The exciton dynamics in pristine films of two structurally related low-bandgap diketopyrrolopyrrole (DPP)-based donor–acceptor copolymers and the photophysical processes in bulk heterojunction solar cells using DPP copolymer:PC71BM blends are investigated by broadband transient absorption (TA) pump-probe experiments covering the vis–near-infrared spectral and fs–μs dynamic range. The experiments reveal surprisingly short exciton lifetimes in the pristine poly­mer films in conjunction with fast triplet state formation. An in-depth analysis of the TA data by multivariate curve resolution analysis shows that in blends with fullerene as acceptor ultrafast exciton dissociation creates charge carriers, which then rapidly recombine on the sub-ns timescale. Furthermore, at the carrier densities created by pulsed laser excitation the charge carrier recombination leads to a substantial population of the polymer triplet state. In fact, virtually quantitative formation of triplet states is observed on the sub-ns timescale. However, the quantitative triplet formation on the sub-ns timescale is not in line with the power conversion efficiencies of devices indicating that triplet state formation is an intensity-dependent process in these blends and is reduced under solar illumination conditions, as free charge carriers can be extracted from the photoactive layer in devices.

Hypertension Control in Adults With Diabetes Mellitus and Recurrent Cardiovascular Events: Global Results From the Trial Evaluating Cardiovascular Outcomes With Sitagliptin.

Science.gov (United States)

Navar, Ann Marie; Gallup, Dianne S; Lokhnygina, Yuliya; Green, Jennifer B; McGuire, Darren K; Armstrong, Paul W; Buse, John B; Engel, Samuel S; Lachin, John M; Standl, Eberhard; Van de Werf, Frans; Holman, Rury R; Peterson, Eric D

2017-11-01

Systolic blood pressure (SBP) treatment targets for adults with diabetes mellitus remain unclear. SBP levels among 12 275 adults with diabetes mellitus, prior cardiovascular disease, and treated hypertension were evaluated in the TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) randomized trial of sitagliptin versus placebo. The association between baseline SBP and recurrent cardiovascular disease was evaluated using multivariable Cox proportional hazards modeling with restricted cubic splines, adjusting for clinical characteristics. Kaplan-Meier curves by baseline SBP were created to assess time to cardiovascular disease and 2 potential hypotension-related adverse events: worsening kidney function and fractures. The association between time-updated SBP and outcomes was examined using multivariable Cox proportional hazards models. Overall, 42.2% of adults with diabetes mellitus, cardiovascular disease, and hypertension had an SBP ≥140 mm Hg. The association between SBP and cardiovascular disease risk was U shaped, with a nadir ≈130 mm Hg. When the analysis was restricted to those with baseline SBP of 110 to 150 mm Hg, the adjusted association between SBP and cardiovascular disease risk was flat (hazard ratio per 10-mm Hg increase, 0.96; 95% confidence interval, 0.91-1.02). There was no association between SBP and risk of fracture. Above 150 mm Hg, higher SBP was associated with increasing risk of worsening kidney function (hazard ratio per 10-mm Hg increase, 1.10; 95% confidence interval, 1.02-1.18). Many patients with diabetes mellitus have uncontrolled hypertension. The U-shaped association between SBP and cardiovascular disease events was largely driven by those with very high or low SBP, with no difference in cardiovascular disease risk between 110 and 150 mm Hg. Lower SBP was not associated with higher risks of fractures or worsening kidney function. © 2017 American Heart Association, Inc.

Vildagliptin and its role in the treatment of diabetes mellitus

Directory of Open Access Journals (Sweden)

Yury Shavkatovich Khalimov

2010-09-01

Full Text Available Type 2 diabetes mellitus is a most serious medical problem throughout the world. Traditional hypoglycemic agents do not ensure long-term control ofglycemia and fail to affect the natural course of DM. An ideal hypoglycemic medicine must be efficacious, safe, and convenient to use for the preventionof progressive deterioration of beta-cell function during prolonged therapy; also, it should have positive effect on the outcome of DM. The use of incretinsin the recent decade is a new promising approach to the management of DM2. The group of incretins includes gastrointestinal hormones released inresponse to food intake to stimulate insulin secretion. Dipeptidyl peptidase-4 (DPP-4 inhibitors, a new class of hypoglycemic agents, have been inuse in this country for over 3 years. Vildaglyptin (Galvus is a representative of DPP-4 inhibitors and GalvusMet is the sole combination of DPP-4inhibitor with metformin registered in Russia. The advent of incretin mimetics necessiatate revision of national and international guidelines for DM2therapy. Results of international clinical studies show that Galvus and GalvusMet are efficacious and safe, they ensure adequate control of glycemiafree from complications and side effects. An important advantage of these preparations is the possibility of their use by elderly patients with arterialhypertension and moderate renal dysfunction and by those at risk of cardiovascular disorders. The evidence-based Galvus information is highly convincing.The advantages of Galvus over traditional agents give reason to recommend it as a medicine of choice for the initiation of DM2 therapy. Approvedcombinations of Galvus with other hypoglycemic agents may be used at all stages of intensive therapy of DM2.

Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors.

Science.gov (United States)

Swarbrick, Martin E; Beswick, Paul J; Gleave, Robert J; Green, Richard H; Bingham, Sharon; Bountra, Chas; Carter, Malcolm C; Chambers, Laura J; Chessell, Iain P; Clayton, Nick M; Collins, Sue D; Corfield, John A; Hartley, C David; Kleanthous, Savvas; Lambeth, Paul F; Lucas, Fiona S; Mathews, Neil; Naylor, Alan; Page, Lee W; Payne, Jeremy J; Pegg, Neil A; Price, Helen S; Skidmore, John; Stevens, Alexander J; Stocker, Richard; Stratton, Sharon C; Stuart, Alastair J; Wiseman, Joanne O

2009-08-01

A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.

Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy.