Search

Aim: To thoroughly investigate the impact of sustained neuropeptide Y4 receptor (NPY4R) activation in obesity‐associated diabetes. Methods: Initially, the prolonged pharmacodynamic profile of the enzymatically stable pancreatic polypeptide (PP) analogue, [P3]PP, was confirmed in normal mice up to 24 h after injection. Subsequent to this, [P3]PP was administered twice daily (25 nmol/kg) for 28 days to high‐fat‐fed mice with streptozotocin‐induced insulin deficiency, known as HFF/STZ mice. Results: Treatment with [P3]PP for 28 days reduced energy intake and was associated with notable weight loss. In addition, circulating glucose was returned to values of approximately 8 mmol/L in [P3]PP‐treated mice, with significantly increased plasma insulin and decreased glucagon concentrations. Glucose tolerance and glucose‐stimulated insulin secretion were improved in [P3]PP‐treated HFF/STZ mice, with no obvious effect on peripheral insulin sensitivity. Benefits on insulin secretion were associated with elevated pancreatic insulin content as well as islet and beta‐cell areas. Positive effects on islet architecture were linked to increased beta‐cell proliferation and decreased apoptosis. Treatment intervention also decreased islet alpha‐cell area, but pancreatic glucagon content remained unaffected. In addition, [P3]PP‐treated HFF/STZ mice presented with reduced plasma alanine transaminase and aspartate transaminase levels, with no change in circulating amylase concentrations. In terms of plasma lipid profile, triglyceride and cholesterol levels were significantly decreased by [P3]PP treatment, when compared to saline controls. Conclusion: Collectively, these data highlight for the first time the potential of enzymatically stable PP analogues for the treatment of obesity and related diabetes. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the inhibitory effects of Plantago asiatica L. on DPP-4 and to determine the active compounds responsible for this inhibition. Extracts were prepared from the root and aerial portions of the plant using various polar solvents. The DPP-4 inhibition of these extracts was analyzed in an extracellular assay and then assigned to either the high or low inhibition group. The chemical profiles of these extracts were analyzed using an LC-MS method. The ion fragments that were potent in the high inhibition extracts were selected through OPLS-DA and correlation analysis, and then identified and obtained for verification of DPP-4 inhibition in both the extracellular assay and the Caco-2 cell line. The extracts showed various inhibitory activities with an average inhibition of 28.4 %. A total of 20 compounds were selected from the extracts with higher inhibitory activity and identified. Six of them, baicalein, scutellarein, calceolarioside B, isoacteoside, verbascoside, and plantamajoside, exhibited DPP-4 inhibition with IC 50 values of 44.32, 59.90, 112.71, 157.02, 154.58, and 195.07 μg/mL, respectively, in extracellular assays. They also showed inhibition of DPP-4 on the Caco-2 cell line, with IC 50 values of 31.56, 34.71, 20.29, 33.29, 24.52, and 87.88 μg/mL, respectively. The extracts from PAL showed inhibitory activity towards DPP-4, and the related compounds were identified and verified. [Display omitted] • Plantago asiatica L. was shown to have inhibitory activity against DPP-4 based on the evidence provided. • Active chemicals were screened and identified by comparing the chemical profiles of high and low activity extracts. • The activity of six compounds was confirmed on both extracellular and Caco-2 cell line tests with their IC 50. [ABSTRACT FROM AUTHOR]

Diabetes mellitus, often known as hyperglycemia, is a serious worldwide disease now. In clinical pharmacology, the dipeptidyl peptidase IV (DPP-4) enzyme is important for glucose homeostasis. The clinical DPP-4 blockers are essential oral antidiabetic medications used as alternate treatment following metformin inability as insulinotropic drugs with no inherent risk of hypoglycemia. The objective of this study is to create novel and potent DPP-4 inhibitors by molecular hybridization of eight clinically licensed DPP-4 inhibitors. Molecular hybridization process led to the creation of five novel hybridized DPP-4 inhibitors, which preliminary computational studies suggest may exhibit improved selectivity compared to authorized DPP-4 inhibitors. The pharmacokinetic features of the hybridized inhibitors, including their solubility and potential to pass through biological tissues, were evaluated using Lipinski's rule of five and other druglikeness filters, indicating favorable properties for reaching the DPP-4 active site. Furthermore, the possible toxicity of suggested inhibitors was investigated using basic toxicity filters and PASS, indicating no immediate red flags regarding their potential toxicity and metabolism. In addition, a mechanism for synthesizing the proposed compounds has been developed via machine learning and artificial intelligence algorithms. At the biomolecular level, using the Gromacs package, molecular dynamics simulations (100 ns) were performed for all the studied systems. Following analyzing the molecular dynamics trajectories and evaluating the dynamic shifts of DPP-4 after its molecular interactions with the designed compounds via dynamic cross-correlation matrix, free energy landscape and MM-PBSA calculations, all data show that the proposed DPP-4 inhibitors create extremely stable complexes when compared to the clinical DPP-4 inhibitor (alogliptin). Finally, the findings of this study might greatly contribute to the development of novel and potent DPP-4 inhibitors and assist in the search for new medications for diabetes type 2. [ABSTRACT FROM AUTHOR]

Background and purposes: It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect. Methods: First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX. Results: A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal Emax model and sigmoidal Emax with E0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (Tmax=0.11 h, t1/2, ka=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC50, EC50, 5−OH SAX=0.46EC50, SAX(parent), it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature. Conclusions: The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data. [ABSTRACT FROM AUTHOR]

Diabetes is one of the most rapidly growing health problems globally, and researchers working hard to develop novel efficient therapies against it. In this regard, hydrazine carboximidamide has a great deal of attention owing to its diverse biological activities. Herein, a new series of N, N-disubstituted hydrazine carboximidamide derivatives was designed, synthesized, and assessed for their antidiabetic activity. Docking studies were performed to initially evaluate the binding of the designed compounds to the target enzyme. It was found that all of the pivotal ligand-enzyme interactions, including the interactions with Glu205/Glu206 aminoacids were observed in docking studies. The molecular dynamic analysis showed that the antidiabetic activity of the newly developed compounds may be implemented through the inhibition of dipeptidyl peptidase 4 (DPP-4), an important target that involves enhancing insulin release and suppressing glucagon discharge from the pancreas. The target molecules were synthesized practically and all the newly-developed chemical structures were confirmed via spectrophotometric methods, including IR, LC-MS, 1H NMR, and 13C NMR techniques. Finally, the in-vivo studies were carried out to confirm the results obtained from the docking and molecular dynamics studies. Compounds 6b and 6d demonstrated improved glucose tolerance through oral glucose tolerance tests in NMRI mice (at a dose of 10 mg/kg). Furthermore, prolonged administration of compounds 6b and 6d to diabetic Wistar rats for 14 days led to a noteworthy reduction in blood levels of glucose, akin to the effects observed with sitagliptin, a standard diabetes medication.

Diospyros malabarica (Desr.) Kostel is widely used in traditional medicine as an antioxidant and anti-diabetic agent. This study aims to evaluate the phytochemical constituents, the antioxidant and anti-diabetic activities of the methanol leaf extract (MLE) and methanol stem bark extract (MBE) of Diospyros malabarica. The extracts were obtained by Ultrasound-Assisted Extraction (UAE). Phytochemical screening was done using standard methods. The total phenolic content (TPC) and total flavonoid content (TFC) were determined using the Folin-Ciocalteau and Aluminium chloride colorimetric methods, respectively. The antidiabetic activity was assessed using α-glucosidase and dipeptidyl peptidase-4 (DPP-4) inhibitory assays. The antioxidant activity was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging, and Ferric Reducing Antioxidant Power (FRAP) assays. The results showed that the TPC (621.31 ± 0.74 mgGAE/g) and TFC (32.86 ± 0.31 mgQE/g) of MBE are 14 times higher than that of MLE with TPC and TFC of 42.83 ± 0.15 mgGAE/g, and 2.37 ± 0.02 mgQE/g, respectively. MBE also showed higher antioxidant and anti-diabetic activities than MLE. The IC50 values of MBE for DPPH radical scavenging, ABTS radical scavenging, and FRAP activities were 8.04 ± 0.05 µg/mL, 2.61 ± 0.03 µg/mL, and 6803.86 µMFSE/g, respectively. For the anti-diabetic activity, MBE had IC50 values of 14.36 ± 0.21 µg/mL, and 205.39 ± 2.94 µg/mL for α-glucosidase, and DPP-4 inhibitory activities, respectively. Therefore, the stem bark of D. malabarica has better anti-diabetic and antioxidant activities than the leaves, and thus has a potential for use as an antioxidant and antidiabetic agent. [ABSTRACT FROM AUTHOR]

Summary: Background: Growing evidence indicates that incretin‐based therapies (IBTs), glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), and dipeptidyl peptidase‐4 inhibitors (DPP4is) are effective and safe for treating pediatric obesity patients with or without type 2 diabetes. Therefore, we aimed to perform a systematic review and meta‐analysis for updating current evidence. Methods: We searched the PubMed, the Cochrane Library, and the EMBASE database for articles published until September 15, 2023, and limited to randomized control trials. The primary outcomes were changed from baseline in weight metrics and the cardiometabolic profile. A random effects model will be used, as high heterogeneity is expected. All analyses were performed using STATA 17.0. Results: Fifteen trials with a total number of 1286 participants were included in our meta‐analysis. Overall, the mean difference in weight change between the IBTs group and the control group was −2.89 kg (95% confidence interval, −5.12 to −0.65, p = 0.011). Additionally, IBTs significantly reduced the HbA1c level and fasting plasma glucose by 0.37% and 6.99 mg/dl, compared with control groups. IBTs showed a little increased risk of GI side effects and hypoglycemia events, but none of the severe hypoglycemia events were occurred in IBTs group. Conclusions: Our study results have proved that GLP‐1 RAs are safe, acceptable, and effective in weight reduction and sugar control for children with obesity. In addition, DPP‐4is seems to have no effect on glycemic control and weight loss in childhood obesity. Further research is needed to confirm these findings, especially in younger children. [ABSTRACT FROM AUTHOR]

Vildagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i) is a widely used type 2 diabetes medication that is associated with an up-to 10-fold increased risk for the development of bullous pemphigoid (BP), an autoimmune skin disease. The mechanism by which vildagliptin promotes the development of BP remains unknown. To elucidate effects of vildagliptin treatment on the mouse cutaneous proteome. We analyzed the cutaneous proteome of nondiabetic mice treated for 12 weeks with vildagliptin using label-free shotgun mass spectrometry (MS), two-dimensional difference gel electrophoresis (2D-DIGE), immunohistochemistry, immunoblotting, and quantitative real-time polymerase chain reaction. Although vildagliptin treatment did not cause any clinical signs or histological changes in the skin, separate MS and 2D-DIGE analyses revealed altered cutaneous expression of several proteins, many of which were related to actin cytoskeleton remodeling. Altogether 18 proteins were increased and 40 were decreased in the vildagliptin-treated mouse skin. Both methods revealed increased levels of beta-actin and C->U-editing enzyme APOBEC2 in vildagliptin-treated mice. However, elevated levels of a specific moesin variant in vildagliptin-treated animals were only detected with 2D-DIGE. Immunohistochemical staining showed altered cutaneous expression of DPP-4, moesin, and galectin-1. The changed proteins detected by MS and 2D-DIGE were linked to actin cytoskeleton remodeling, transport, cell movement and organelle assembly. Vildagliptin treatment alters the cutaneous proteome of nondiabetic mice even without clinical signs in the skin. Cytoskeletal changes in the presence of other triggering factors may provoke a break of immune tolerance and further promote the development of BP. • No clinical signs of adverse effects on vildagliptin-treated mice. • Cutaneous proteomic changes detected in vildagliptin-treated nondiabetic mice. • Vildagliptin exposure elevates proteins that are linked to actin. • Vildagliptin exposure decreases cytoskeleton-interacting proteins. [ABSTRACT FROM AUTHOR]

The review addresses publications on genetic polymorphisms that potentially impact the effectiveness of therapy with hypoglycemic drugs of the dipeptidyl peptidase-4 inhibitor group. The literature was searched in the PubMed database from 2017 to 2023. Polymorphisms of several genes (GLP1R, TCF7L2, DPP-4, KCNQ1, KCNJ11, PNPLA3, PRKD1) are associated with the pharmacokinetic values and efficacy of dipeptidyl peptidase-4 inhibitors, which may be promising for personalizing the treatment of patients with type 2 diabetes mellitus.

Periodontitis is a common condition affecting the tissues surrounding and supporting teeth. In addition to oral health concerns, periodontal disease increases the chance of developing systemic illnesses including type 2 diabetes mellitus. Porphyromonas gingivalis, a key-stone pathogen that has been linked to the pathophysiology of periodontal disease, can generate a series of dipeptide producing exopeptidases, dipeptidyl peptidases (DPP). DPP-4 levels in gingival crevicular fluid have been shown to increase during active periodontal disease, which may lead to their association with the disease's progression. Following oral glucose administration, mice injected with DPP-4 had higher blood glucose than the control group. DPP-4 inhibitors are used to treat patients with type 2 diabetes mellitus in order to extend the half-life of incretins. Elevated glucagon-like peptide-1 (GLP-1) levels following periodontal therapy could be considered new and applicable real-world evidence confirming the experimental findings of a beneficial interaction between oral microbiota and incretin axis. GLP-1 receptor agonist exendin-4 enhanced the osteoblast proliferation and development of these stem cells and inhibited the effects of glucose on the cells. In addition to lowering blood sugar, liraglutide, a GLP-1 receptor agonist, also possesses anti-inflammatory and bone-protective properties. These findings support the use of GLP-1 in the management and prevention of diabetic periodontitis. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is considered one of the most common diseases that occur during pregnancy. In addition to increasing the risk of numerous complications throughout gestation, it is also believed to have a long-term potential to impact the risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease for the mother and her offspring. While there are clear guidelines for healthy weight gain in pregnancy depending on pre-pregnancy BMI, as well as dietary and training recommendations to achieve this, an increasing number of women are experiencing excessive gestational weight gain (EGWG). Such patients have a higher risk of developing GDM and gestational hypertension, as well as requiring caesarian delivery. Dipeptidyl peptidase-4 (DPP-4) is a glycoprotein that seems to play an important role in glucose metabolism, and inhibition of its activity positively affects glucose regulation. The aim of our study was to compare DPP-4 concentrations in patients with GDM and EGWG with healthy women. DPP-4 levels were assessed in serum and urine samples collected on the day of delivery. The bioelectrical impedance analysis (BIA) method was also used to analyze the body composition of patients on the second day of the postpartum period. DPP-4 serum concentrations were significantly higher in patients in the GDM and EGWG groups compared to healthy women. Urinary DPP-4 concentrations were significantly higher in the control and GDM groups than in the EGWG group. Serum DPP-4 levels were positively correlated with BMI measured before pregnancy, on the delivery day, and in the early postpartum period, among other factors. According to our knowledge, this is the first study to determine DPP-4 levels in EGWG patients. DPP-4 may be related to the occurrence of GDM and EGWG; however, this requires further research. [ABSTRACT FROM AUTHOR]

Aim: This trial was designed to assess the efficacy and safety of cetagliptin added to metformin in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. Methods: In total, 446 patients with type 2 diabetes on metformin monotherapy were randomized to receive the addition of once‐daily cetagliptin 100 mg, cetagliptin 50 mg and placebo in a 2:2:1 ratio for 24‐week double‐blind treatment. At week 24, patients initially randomized to cetagliptin 50 mg and placebo were switched to cetagliptin 100 mg for 28 weeks open‐label treatment. The primary endpoint was the change in haemoglobin A1c (HbA1c) from baseline, and the efficacy analyses were based on an all‐patients‐treated population using an analysis of co‐variance. Results: After 24 weeks, both add‐on therapies led to greater glycaemic control. Reductions in HbA1c from baseline were −1.17 ± 0.794%, −1.23 ± 0.896% in cetagliptin 100 mg and 50 mg plus metformin group, respectively. No difference was observed between the cetagliptin 100 mg and 50 mg plus metformin group. Patients with higher baseline HbA1c levels (≥8.5%) experienced greater reductions in HbA1c. A significantly greater proportion of patients achieved an HbA1c <7.0% with cetagliptin 100 mg (49.4%) and cetagliptin 50 mg (51.1%) plus metformin than metformin monotherapy (14.4%). Both combination therapies also improved the homeostasis model assessment β‐function index and decreased systolic blood pressure. There was no increased risk of adverse effects with combination therapy, and both combination therapies were generally well tolerated. Conclusions: The addition of cetagliptin once daily to metformin was more efficacious and well tolerated than metformin monotherapy in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. Materials and Methods: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double‐blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open‐label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. Results: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (−1.08%) and cetagliptin 100 mg (−1.07%) compared with placebo (−0.35%). The placebo‐subtracted HbA1c reduction was −0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2‐hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug‐related hypoglycaemia was reported. Conclusions: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet. [ABSTRACT FROM AUTHOR]

Introduction:Different homeostatic models for the assessment of beta cell function in patients with insulin resistance in type 2 diabetes mellitus suggest that Dipeptidyl Peptidase (DPP-4) inhibitors cause less beta cell stress. Aims: The present study aimed to compare and contrast insulin resistance in two groups of patients taking oral hypoglycemic agents, DPP-4 plus metformin and glimepiride plus metformin, on the basis of fasting and postprandial c-peptide and insulin resistance estimated by homeostatic model assessment of insulin resistance (HOMA-IR). Methods: This preliminary descriptive observational study was conducted from 2018 to 2019 in the service Laboratory of the Department of Biochemistry, in collaboration with the Endocrinology Department, Nil Ratan Sircar Medical College and Hospital, Kolkata. Serum C-peptide, serum insulin, and plasma glucose levels were measured in both fasting and post-prandial states along with glycated hemoglobin. Result: In the fasting and fed state, the secretagogue effect of glimepiride-metformin combination was significantly higher (p = 0.017) than that of the linagliptin-metformin combination. Conclusion: Patients treated with glimepiride showed high post prandial insulin levels and high post prandial glucose excursion. This finding can be explained by the probable increase in insulin resistance, which is reflected in their post-prandial C peptide level. However, in the case of linagliptin, one mechanism of decreased post-prandial glucose is believed to be the inhibition of α-cell glucagon release, thereby relieving β-cell stress

Dipeptidyl Peptidase 4 (DPP-4) expressed on the surface of many different cells is a promising target to develop new candidates for Type 2 diabetes mellitus (T2DM) management. In this light, we performed a computer-aided simulation involving 3-D pharmacophore screening, molecular docking, and drug-likeness assessment to identify novel potential DPP-4 inhibitors with an improved physicochemical profile to treat T2DM. In addition, global reactivity descriptors, including HOMO and LUMO energies, HOMO-LUMO gaps, and Fukui indices, were computed to confirm the essential structural features to achieve DPP-4 activity. The gathered outcomes recommend that eight out of 240 million compounds collected from eight pre-built databases (Molport, Chembl30, ChemDiv, ChemSpace, Mcule, Mcule-ultimate, LabNetwork, and ZINC) are drug-like and nontoxic, and may serve as starting points for designing novel, selective, and potent DPP-4 inhibitors. Furthermore, the success of the current workflow to identify DPP-4-potential inhibitors strengthens its potential efficiency to also predict natural compounds as novel adjutants or main therapy for T2DM or discover hit compounds of other targets. [ABSTRACT FROM AUTHOR]

Andrographolide (ADG) is contained in bitter plants, and its effects are widely thought to be associated with taste receptors. The current study used animal studies and cell lines to investigate the role of ADG in diabetic models. The Takeda G-protein-coupled receptor (TGR5) was directly influenced by ADG, and this boosted GLP-1 synthesis in CHO-K1 cells transfected with the TGR5 gene. However, this was not seen in TGR5-mutant cells. The human intestinal L-cell line NCI-H716 showed an increase in GLP-1 production in response to ADG. In NCI-H716 cells, the TGR5 inhibitor triamterene reduced the effects of ADG, including the rise in TGR5 mRNA levels that ADG caused. Additionally, as with the antihyperglycemic impact in type-1 diabetic rats, the increase in plasma-active GLP-1 level caused by ADG was enhanced by a DPP-4 inhibitor. The recovery of the hypoglycemic effect in diabetic rats and the increase in plasma GLP-1 caused by ADG were both suppressed by TGR5 blockers. As a result, after activating TGR5, ADG may boost GLP-1 synthesis in diabetic rats, enhancing glucose homeostasis. In Min-6 cells, a pancreatic cell line grown in culture, ADG-induced insulin secretion was also examined. Blocking GLP-1 receptors had little impact, suggesting that ADG directly affects TGR5 activity in Min-6 cells. A TGR5 mRNA level experiment in Min-6 cells further confirmed that TGR5 is activated by ADG. The current study revealed a novel finding suggesting that ADG may activate TGR5 in diabetic rats in a way that results in enhanced insulin and GLP-1 production, which may be helpful for future research and therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: The prevalence of certain cancers is high in the diabetic population. Dipeptidyl peptidase (DPP)-4, a therapeutic target for type 2 diabetes mellitus, is also involved in autophagic flux and cancer biology. In this paper, we reported that DPP-4 inhibition promotes breast cancer cell survival via induction of autophagy by the C-X-C motif chemokine 12/C-X-C receptor 4/mammalian target of rapamycin/hypoxia-inducible factor-1α axis. Metformin counteracts such an undesirable influence of DPP-4 inhibition on cancer biology. Our findings suggest that DPP-4 inhibitor, one of the most prescribed anti-diabetic drugs, could harm patients with certain cancers. The combination with metformin use could provide some clues to the use of DPP-4 inhibitors via the modulation of cancer autophagy-dependent survival signaling. Autophagy plays a complex role in breast cancer cell survival, metastasis, and chemotherapeutic resistance. Dipeptidyl peptidase (DPP)-4, a therapeutic target for type 2 diabetes mellitus, is also involved in autophagic flux. The potential influence of DPP-4 suppression on cancer biology remains unknown. Here, we report that DPP-4 deficiency promotes breast cancer cell survival via the induction of autophagy by the C-X-C motif chemokine 12 (CXCL12)/C-X-C receptor 4 (CXCR4)/mammalian target of rapamycin (mTOR)/hypoxia inducible factor (HIF)-1α axis. DPP-4 knockdown and DPP-4 inhibitor KR62436 (KR) treatment both increased the levels of LC3II and HIF-1α in cultured human breast and mouse mammary cancer cells. The KR-induced autophagic phenotype in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 and rapamycin. HIF-1α knockdown also suppressed breast cancer autophagy induced by KR. The autophagy inhibitor 3-methyladenine significantly blocked the KR-mediated suppression of cleaved caspase-3 levels and apoptosis in breast cancer cell lines. Finally, we found that the metformin-induced apoptosis of DPP-4-deficient 4T1 mammary cancer cells was associated with the suppression of autophagy. Our findings identify a novel role for DPP-4 inhibition in the promotion of breast cancer survival by inducing CXCL12/CXCR4/mTOR/HIF-1α axis-dependent autophagy. Metformin is a potential drug that counteracts the breast cancer cell survival system. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) and its associated complications and comorbidities often require polypharmacotherapy, resulting in a high pill burden and reduced therapy adherence, thereby increasing the risk of adverse outcomes. Given this, we evaluated the pharmacokinetic and pharmacodynamic profile of the vildagliptin 100 mg sustained release (SR) administered once daily compared to vildagliptin 50 mg immediate release (IR) administered twice daily in healthy, adult human subjects under fed conditions. Material and methods: This was a randomized, balanced, open-label, two-treatment, two-period, twosequence, crossover multiple oral dose study in healthy adult subjects under fed conditions. The subjects were randomized to receive either a test product, i.e., vildagliptin SR 100 mg once daily, or a reference product, i.e., vildagliptin 50 mg twice daily. The duration of the study was 25 days. The primary pharmacokinetic parameter evaluated was the area under the concentration-time curve for one dosing interval at steady-state (AUC0-τ, ss). Bioequivalence was determined by assessing whether the 90% confidence intervals (CIs) for the geometric mean ratio of test to reference drug fell within predefined margins of 80% -125% for AUC0-τ, ss. The pharmacodynamics parameters evaluated were percent dipeptidyl-peptidase-4 (DPP-4) inhibition and weighted average percent DPP-4 inhibition. The safety assessment was based on clinical laboratory evaluation, chest, ECG recordings, clinical examination, blood glucose monitoring, and post-study clinical laboratory safety evaluation. Results: Forty healthy adult males completed the study. There was no significant difference between the pharmacokinetic and pharmacodynamic profiles in reference and test products. The mean ± standard deviation (SD) values of AUC0-τ, ss for test and reference product was 2689.06 ± 835.47 2875.57 ± 703.85 ng. hr/mL, respectively. The 90% CIs of geometric least-square means of test/reference ratio for AUC0-τ, ss with vildagliptin SR 100 mg tablet was 86.32-97.26% within the bioequivalence acceptance range. The test and reference product showed over 90% inhibition of DPP-4 activity with multiple doses. The weighted average percent of DPP-4 inhibition (0-24 hrs) was 92.66% with the test product and 93.26% with the reference product. Both products were well tolerated during the entire study period. No serious adverse events (AEs) were reported during the study. Conclusion: The two formulations of vildagliptin, i.e., vildagliptin SR 100 mg once daily and vildagliptin 50 mg twice daily, demonstrated similar pharmacokinetic and pharmacodynamic profiles under fed conditions in healthy adult males. Both formulations were bioequivalent and well tolerated. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related death worldwide, and the survival rate of metastatic lung cancer is exceedingly low. Helminthostatchys Zeylanica (H. Zeylanica) is a Chinese herbal medicine renowned for its anti-inflammatory, immunomodulatory, and anti-cancer activities in various cellular and animal studies. The current study evaluated the effects of H. Zeylanica derivatives on lung cancer cells. We determined that dipeptidyl peptidase-4 (DPP-4) expression levels were higher in lung cancer tissues than in normal tissues. We also determined that DPP-4 expression levels were higher in the metastatic stage and strongly correlated with lung cancer survival rates. An H. Zeylanica derivative (ugonin P) was shown to inhibit DPP-4 mRNA and protein expression in two lung cancer cell lines in a dose-dependent manner. Ugonin P was shown to decrease migration and invasion activities in lung cancer cells while promoting the synthesis of miR-130b-5p, which was found to negatively regulate DPP-4 protein expression and cell motility in lung cancer. We determined that ugonin P suppresses the DPP-4-dependent migration and invasion of lung cancer cells by downregulating the RAF/MEK/ERK signalling pathway and enhancing the expression of miR-130b-5p. This study provides compelling evidence that ugonin P could be used to develop novel therapeutic agents for the treatment of lung cancer.

Current oral medications for type 2 diabetes target a single main physiological mechanism. They either activate or inhibit receptors to enhance insulin sensitivity, increase insulin secretion, inhibit glucose absorption, or inhibit glucose production. In advanced stages, combination therapy may be required because of the limited efficacy of single-target drugs; however, medications are becoming more costly, and there is also the risk of developing the combined side effects of each drug. Thus, identifying a multi-target drug may be the best strategy to improve treatment efficacy. This study sees the potential of 2657 Filipino phytochemicals as a source of natural inhibitors against four targets of diabetes: PTP1B, DPP-4, SGLT-2, and FBPase. Different computer-aided drug discovery techniques, including ADMET profiling, DFT optimization, molecular docking, MD simulations, and MM/PBSA energy calculations, were employed to elucidate the stability and determine the binding affinity of the candidate ligands. Through in silico methods, we have identified seven potential natural inhibitors against PTP1B, DPP-4, and FBPase, and ten against SGLT-2. Eight plants containing at least one natural inhibitor of each protein target were also identified. It is recommended to further investigate the plants' potential to be transformed into a safe and scientifically validated multi-target drug for diabetes therapies. [ABSTRACT FROM AUTHOR]

The synthesis of some novel 1,2,3-triazole-based linagliptin derivatives from the CuI catalyzed 1,3-dipolar cycloaddition reaction between N-propargyl purines and several aryl azides as described herein. All these new compounds were further evaluated for their in vitro dipeptidyl peptidase-4 (DPP-4) activity and the compounds 8-bromo-1,3-dimethyl-7-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-purine-2,6(3H,7H)-dione, 7-(but-2-yn-1-yl)-1,3-dimethyl-8-(4-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl) piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione and 7-(but-2-yn-1-yl)-8-(4-((1-(3,5-dichloro phenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione have shown good inhibitory activity against DPP-4. Molecular docking studies were performed for the promising compounds for their binding interactions with the receptor dipeptidyl peptidase IV (PDB ID-3G0B). The most potent compound was deliberated optimal structure, and data were calculated using the density functional theory (DFT) B3LYP method on a 6-311++G (d,p) basis set. The structural parameters were derived from geometry optimization. The HOMO and LUMO energies are calculated for the molecule. [ABSTRACT FROM AUTHOR]

Introduction: Microvascular and endothelial disorders play a significant role in the pathophysiology of coronary slow flow phenomenon (CSFP). However, according to previous studies, the etiology of CSFP is not completely understood. As CD40 and dipeptidyl peptidase-4 (DPP-4) are reported to play an important role in atherosclerosis process as well as microvascular and the endothelial dysfunction, this study evaluated the role of these two biomarkers in the pathophysiology of CSFP. Methods: One-hundred twenty-nine volunteers who were candidates for angiography and fulfilled the inclusion criteria were selected, including 29 patients with coronary artery diseases (CADs) which had less than 50% stenosis (CAD+,

Context Edible mushrooms have a long history of use in traditional Chinese or Japanese medicine. Coprinus comatus (O.F. Müll.) Pers. (Agaricaceae) contains antioxidant and antidiabetic agents.Objective To identify the benefits of ethanol extracts of the C. comatus fruit body in streptozotocin-induced hyperglycaemic rats by evaluating their blood glucose, glycosylated haemoglobin (HbA1c), insulin, glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4), and glutathione (GSH) levels, with and without extract administration.Materials and methods Wistar rats were either left untreated or were administered 45 mg/kg body weight (BW) streptozotocin; 45 mg/kg BW metformin; or 250, 500, or 750 mg/kg BW extract for 14 days. The blood glucose, GLP-1, DPP-4, GSH, insulin, and HbA1c levels were determined. Data were analysed using analysis of variance and Duncan’s multiple range tests.Results Preliminary data showed that administration of C. comatus ethanol extract dose of 250, 500, and 750 mg orally has no toxicity effects after 24 h administration. The ethanolic extract of fruiting body of C. comatus considerably reduced the rat’s fasting blood glucose levels 26.69%, and DPP-4 6.97% at dose of 750 mg. The extract reduced HbA1c 4–4.30%, increased GLP-1 71.09%, GSH 11.19% at dose of 500 mg, and increased insulin levels 13.83%. Extracts contain bioactive compounds such as flavonoid, alkaloid, terpenoids, vitamins C and E, rutin, and saponin.Conclusions The C. comatus extract can be used as herbal medicine that reduces diabetic symptoms. Further investigation on C. comatus extracts should be conducted with gas chromatography-mass spectrometry to characterise the bioactive compounds.

Gestational diabetes mellitus (GDM) is considered one of the most common diseases that occur during pregnancy. In addition to increasing the risk of numerous complications throughout gestation, it is also believed to have a long-term potential to impact the risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease for the mother and her offspring. While there are clear guidelines for healthy weight gain in pregnancy depending on pre-pregnancy BMI, as well as dietary and training recommendations to achieve this, an increasing number of women are experiencing excessive gestational weight gain (EGWG). Such patients have a higher risk of developing GDM and gestational hypertension, as well as requiring caesarian delivery. Dipeptidyl peptidase-4 (DPP-4) is a glycoprotein that seems to play an important role in glucose metabolism, and inhibition of its activity positively affects glucose regulation. The aim of our study was to compare DPP-4 concentrations in patients with GDM and EGWG with healthy women. DPP-4 levels were assessed in serum and urine samples collected on the day of delivery. The bioelectrical impedance analysis (BIA) method was also used to analyze the body composition of patients on the second day of the postpartum period. DPP-4 serum concentrations were significantly higher in patients in the GDM and EGWG groups compared to healthy women. Urinary DPP-4 concentrations were significantly higher in the control and GDM groups than in the EGWG group. Serum DPP-4 levels were positively correlated with BMI measured before pregnancy, on the delivery day, and in the early postpartum period, among other factors. According to our knowledge, this is the first study to determine DPP-4 levels in EGWG patients. DPP-4 may be related to the occurrence of GDM and EGWG; however, this requires further research.

Abstract Background Biomarkers are needed to diagnose kidney rejection in transplant recipients. We evaluated whether dipeptidyl peptidase-4 (DPP-4) could serve as a biomarker of rejection. Methods We determined DPP-4 concentrations and enzymatic activities in serum and urine, as well as DPP-4 expression in 49 kidney biopsy samples from 28 kidney transplant recipients. This study was approved by the ethical standards of the institutional research committee and comply with Helsinki declaration. All patients provided their informed consent. Donors were not from prisoners and were not paid or coerced. Results Serum and urinary DPP-4 activities closely correlated with DPP-4 concentrations, but were suppressed by DPP-4 inhibitors. Urinary DPP-4 concentrations increased with acute T cell-mediated rejection (ATCMR; p = 0.030) and higher Banff t and i scores (p

Ashwani Sharma,1 Tarun Virmani,1 Anjali Sharma,2 Vaishnavi Chhabra,1 Girish Kumar,1 Kamla Pathak,3 Abdulsalam Alhalmi4 1School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India; 2Freelancer, Pharmacovigilance Expert, Uttar Pradesh, India; 3Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Uttar Pradesh, 206130, India; 4Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, YemenCorrespondence: Abdulsalam Alhalmi, Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen, Email aa.abdulla@pharm.adenuniv.comAbstract: Dipeptidyl-peptidase-4 (DPP-4) is an enzyme having various properties and physiological roles in lipid accumulation, resistance to anticancer agents, and immune stimulation. DPP-4 includes membrane-bound peptidases and is a kind of enzyme that cleaves alanine or proline-containing peptides such as incretins, chemokines, and appetite-suppressing hormones (neuropeptide) at their N-terminal dipeptides. DPP-4 plays a role in the final breakdown of peptides produced by other endo and exo-peptidases from nutritious proteins and their absorption in these tissues. DPP-4 enzyme activity has different modes of action on glucose metabolism, hunger regulation, gastrointestinal motility, immune system function, inflammation, and pain regulation. According to the literature survey, as DPP-4 levels increase in individuals with liver conditions, up-regulation of hepatic DPP-4 expression is likely to be the cause of glucose intolerance or insulin resistance. This review majorly focuses on the cleavage of alanine or proline-containing peptides such as incretins by the DPP-4 and its resulting conditions like glucose intolerance and cause of DPP-4 level elevation due to some liver conditions. Thus, we have discussed the various effects of DPP-4 on the liver diseases like hepatitis C, non-alcoholic fatty liver, hepatic regeneration and stem cell, hepatocellular carcinoma, and the impact of elevated DPP-4 levels in association with liver diseases as a cause of glucose intolerance and their treatment drug of choices. In addition, the effect of DPP-4 inhibitors on obesity and their negative aspects are also discussed in brief.Keywords: DPP-4, insulin, incretins, glucose intolerance, liver diseases, sitagliptin, DPP-4 inhibitors

OBJECTIVE: Genetic relationship with biochemical, hormones and markers of inflammation. METHODOLOGY: This collaborative study was cross-sectional and carried out by the Department of Biochemistry, Karachi University, Baqai Diabetology and Endocrinology Institute (BIDE), Karachi-Pakistan and Kansai Electric Power Institute of Medical Research (KEPIIMR), Osaka-Japan. The duration of the research was from March 2019 to May 2020. Both genders aged 30-70 (years) visiting the outpatient department of BIDE and fulfilling the inclusion criteria were recruited. An oral glucose tolerance test as diagnostic criteria was used. Subjects were categorized into healthy (glucose levels of fasting glucose (FPG) less than 100 (mg/dL), a two-hour glucose post level (2-hr PGL) below 140mg/dL). Newly diagnosed diabetics (NDD) (FPG =126mg/dL or 2-hr PGL =200mg/dL or both without any antidiabetic medicines use). Subjects with any complications were excluded. SPSS (Social Science Package for Statistical) Version 20 was used to analyze data. RESULTS: Of 34 subjects, 17 were NDD and 17 were healthy. The mean age was 49.65±1.95, and the mean BMI was 28.12±0.93. DPP-4 C/T exhibited significant findings (p<0.05) compared with GLP-1R C/A among healthy and NDD subjects. Polymorphism of GLP1R C/A is associated significantly with fasting triacylglycerides and GLP1. In Comparison, polymorphism of DPP4 C/T was associated significantly in fasting with GLP1, GIP, HDL and IL-1ß when compared to NDD with healthy participants. CONCLUSION: We found significantly more association of DPP4 C/T polymorphism rs2970932 with biochemical parameters than GLP1R C/A polymorphisms rs1042044 in NDD individuals. [ABSTRACT FROM AUTHOR]

A series of new 1,2,3-triazole derivatives of tolbutamide analogues have been synthesized in a simple and effective way in high yields to explore the possibilities of some altered biological actions such as antibacterial, antioxidant and DPP-4 activities. Structure of the newly synthesized compounds is well characterized by various spectroscopic methods. Among all the synthesized compounds N-({[1-((2-fluoroethyl)sulfonyl)-1H-1,2,3-triazol-4-yl]methyl}carbamoyl)-4-methylbenzenesulfonamide and N-({[1-((4-chlorophenyl)-sulfonyl)-1H-1,2,3-triazol-4-yl]methyl}carbamoyl)-4-methylbenzenesulfonamide shows potent antibacterial and antioxidant activity as compared to standard drugs. Compound N-({[1-((4-chlorophenyl) sulfonyl)-1H-1,2,3-triazol-4-yl]methyl}carbamoyl)-4-methylbenzenesulfonamide has shown good DPP-4 inhibitory activity. Molecular docking and ADME studies have also been conducted to complement the experimental results. [ABSTRACT FROM AUTHOR]

Context: Edible mushrooms have a long history of use in traditional Chinese or Japanese medicine. Coprinus comatus (O.F. Müll.) Pers. (Agaricaceae) contains antioxidant and antidiabetic agents. Objective: To identify the benefits of ethanol extracts of the C. comatus fruit body in streptozotocininduced hyperglycaemic rats by evaluating their blood glucose, glycosylated haemoglobin (HbA1c), insulin, glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4), and glutathione (GSH) levels, with and without extract administration. Materials and methods: Wistar rats were either left untreated or were administered 45mg/kg body weight (BW) streptozotocin; 45mg/kg BW metformin; or 250, 500, or 750mg/kg BW extract for 14 days. The blood glucose, GLP-1, DPP-4, GSH, insulin, and HbA1c levels were determined. Data were analysed using analysis of variance and Duncan's multiple range tests. Results: Preliminary data showed that administration of C. comatus ethanol extract dose of 250, 500, and 750mg orally has no toxicity effects after 24 h administration. The ethanolic extract of fruiting body of C. comatus considerably reduced the rat's fasting blood glucose levels 26.69%, and DPP-4 6.97% at dose of 750mg. The extract reduced HbA1c 4-4.30%, increased GLP-1 71.09%, GSH 11.19% at dose of 500mg, and increased insulin levels 13.83%. Extracts contain bioactive compounds such as flavonoid, alkaloid, terpenoids, vitamins C and E, rutin, and saponin. Conclusions: The C. comatus extract can be used as herbal medicine that reduces diabetic symptoms. Further investigation on C. comatus extracts should be conducted with gas chromatography-mass spectrometry to characterise the bioactive compounds. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated levels of blood glucose due to insulin resistance or insulin-secretion defects. The development of diabetes is mainly attributed to the interaction of several complex pathogenic, genetic, environmental and metabolic processes. Dipeptidyl peptidase-4 (DPP-4) is a serine protease that cleaves X-proline dipeptides from the N-terminus of several polypeptides, including natural hypoglycemic incretin hormones. Inhibition of this enzyme restores and maintains glucose homeostasis, making it an attractive drug target for the management of T2DM. Natural products are important sources of bioactive agents for anti-T2DM drug discovery. Marine ecosystems are a rich source of bioactive products and have inspired the development of drugs for various human disorders, including diabetes. Here, structure-based virtual screening and molecular docking were performed to identify antidiabetic compounds from the Comprehensive Marine Natural Products Database (CMNPD). The binding characteristics of two shortlisted compounds, CMNPD13046 and CMNPD17868, were assessed using molecular dynamics simulations. Thus, this study provides insights into the potential antidiabetic activity and the underlying molecular mechanism of two compounds of marine origin. These compounds could be investigated further for the development of potent DPP-4 inhibitors. [ABSTRACT FROM AUTHOR]

• Inhibition of DPP4 as a medication for women with type 2 diabetes and specific cancer could have various consequences. • In the case of breast cancer (BC), DPP4 inhibition induces EMT, invasion, metastasis, and chemotherapy resistance. • In ovarian cancer (OV), DPP4 inhibition induces EMT, invasion, and metastasis, while there is no supporting evidence for chemo-resistance. • For endometrial cancer (EC), inhibition of DPP4 decreased invasion and migration but no synergistic effects were found for chemo-resistance. • Concerning cervical cancer (CC), DPP4 inhibition by sitagliptin increases invasion and migration. The inhibition of dipeptidyl- peptidase 4 (DPP-4) is an essential therapy for controlling hyperglycemia in patients with type 2 diabetes (T2DM). However, the role of DPP-4 in cancer is not yet clear, with some studies suggesting that it may either promote or suppress tumors. This makes it crucial to have personalized treatment for diabetic women with cancer to effectively manage their diabetes whilst and preventing cancer mortality. To address this issue, we conducted an integrative in-silico analysis and systematic review of the literature to comprehensively examine the relationship between DPP-4 expression and the effects of its inhibitors on prevalent female malignancies. We specifically chose studies that examined the effects of DPP-4 expression and DPP-4 inhibition (DPP-4i) on prevalent cancers in women, such as breast cancer (BC), ovarian cancer (OV), cervical cancer (CC), and endometrial cancer (EC). These studies comprised those conducted both in vivo and in vitro. The review of the literature indicated that DPP-4i may worsen aggressive traits such as metastasis, Epithelial-to-mesenchymal transition (EMT), and chemotherapy resistance in BC cells. However, cohort studies on diabetic and BC patients did not confirm these findings. In vitro studies indicate that on OV, DPP-4 upregulation has been shown to prevent metastasis, while CCappears to be influenced by DPP-4 expression in terms of cell migration. sitagliptin, a pharmaceutical inhibitor of DPP-4, had a significant impact on reducing adhesion in CC cells in vitro. Overexpression of DPP-4 increased cell migration and proliferation in CC and EC cells, and hence the application of sitagliptin is expected to prevent this effect. On the other hand, the result of in-silico data confirmed that a significant correlation exists between DPP-4 expression and immune cell infiltration in breast, ovarian, cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) as well as downregulated in these cancers compared to their normal tissue samples. Furthermore, a significant (p < 0.05) effect on OS of BC and CESC patients has been reported due to the elevation of DPP-4 methylation on a specific CPG Island. These findings could aid in creating specialized treatments for diabetic women with specific malignancies, but caution should be exercised when considering the patient's medical history and cancer type. [ABSTRACT FROM AUTHOR]

Andrographolide (ADG) is contained in bitter plants, and its effects are widely thought to be associated with taste receptors. The current study used animal studies and cell lines to investigate the role of ADG in diabetic models. The Takeda G-protein-coupled receptor (TGR5) was directly influenced by ADG, and this boosted GLP-1 synthesis in CHO-K1 cells transfected with the TGR5 gene. However, this was not seen in TGR5-mutant cells. The human intestinal L-cell line NCI-H716 showed an increase in GLP-1 production in response to ADG. In NCI-H716 cells, the TGR5 inhibitor triamterene reduced the effects of ADG, including the rise in TGR5 mRNA levels that ADG caused. Additionally, as with the antihyperglycemic impact in type-1 diabetic rats, the increase in plasma-active GLP-1 level caused by ADG was enhanced by a DPP-4 inhibitor. The recovery of the hypoglycemic effect in diabetic rats and the increase in plasma GLP-1 caused by ADG were both suppressed by TGR5 blockers. As a result, after activating TGR5, ADG may boost GLP-1 synthesis in diabetic rats, enhancing glucose homeostasis. In Min-6 cells, a pancreatic cell line grown in culture, ADG-induced insulin secretion was also examined. Blocking GLP-1 receptors had little impact, suggesting that ADG directly affects TGR5 activity in Min-6 cells. A TGR5 mRNA level experiment in Min-6 cells further confirmed that TGR5 is activated by ADG. The current study revealed a novel finding suggesting that ADG may activate TGR5 in diabetic rats in a way that results in enhanced insulin and GLP-1 production, which may be helpful for future research and therapies.

Purpose of reviewThe purpose of this review is to correlate predictions based on pre-clinical data with outcomes from clinical trials that examine the effects of incretin-based diabetes treatments on the kidney. The incretin-based treatments include agonists of the glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of the enzyme, dipeptidyl peptidase-4 (DPP-4). In addition, what is known about the incretin-based therapies will be compared to what is known about the renal effects of SGLT2 inhibitors.Recent findingsLarge-scale clinical trials have shown that SGLT2 inhibitors reduce albuminuria and preserve estimated glomerular filtration rate (eGFR) in patients with diabetic nephropathy. A concise and plausible hemodynamic mechanism is supported by pre-clinical research on the physiology and pharmacology of SGLT2. Large-scale clinical trials have shown that incretin-based therapies mitigate albuminuria but have not shown beneficial effects on eGFR. Research on the incretin-based therapies has yielded a diverse array of direct effects throughout the body, which fuels speculation as to how these drugs might benefit the diabetic kidney and affect its function(s). But in vivo experiments have yet to confirm that the proposed mechanisms underlying emergent phenomena, such as proximal tubular fluid reabsorption, are the ones predicted by cell and molecular experiments. There may be salutary effects of incretin-based treatments on the diabetic kidney, but the system is complex and not amenable to simple explanation or prior prediction. This contrasts with the renal effects of SGLT2 inhibitors, which can be explained concisely.

The purpose of this study was to examine whether endogenous GLP-1 (glucagon-like peptide-1) could respond to exercise training in mice, as well as whether dihydromyricetin (DHM) supplementation could enhance GLP-1 levels in response to exercise training. After 2 weeks of exercise intervention, we found that GLP-1 levels were significantly elevated. A reshaped gut microbiota was identified following exercise, as evidenced by the increased abundance of Bifidobacterium, Lactococcus, and Alistipes genus, which are involved in the production of short-chain fatty acids (SCFAs). Antibiotic treatment negated exercise-induced GLP-1 secretion, which could be reversed with gut microbiota transplantation. Additionally, the combined intervention (DHM and exercise) was modeled in mice. Surprisingly, the combined intervention resulted in higher GLP-1 levels than the exercise intervention alone. In exercised mice supplemented with DHM, the gut microbiota composition changed as well, while the amount of SCFAs was unchanged in the stools. Additionally, DHM treatment induced intracellular cAMP in vitro and down-regulated the gene and protein expression of dipeptidyl peptidase-4 (DPP-4) both in vivo and in vitro. Collectively, the auxo-action of exercise on GLP-1 secretion is associated with the gut-microbiota-SCFAs axis. Moreover, our findings suggest that DHM interacts synergistically with exercise to enhance GLP-1 levels by stimulating cAMP and inhibiting DPP-4. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2D) is associated with an increased fracture risk. There is little evidence for the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA) on fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) for treatment with GLP-1RA compared to dipeptidyl peptidase 4 inhibitors (DPP-4i) as add-on therapies to metformin. Methods: We conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either GLP-1RA or DPP-4i were enrolled from 2007 to 2018. Subjects were propensity-score matched 1:1 based on age, sex, and index date. MOF were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. In addition, Aalen’s Additive Hazards model was applied to examine additive rather than relative hazard effects while allowing time-varying effects. Results: In total, 42,816 individuals treated with either combination were identified and included. After matching, 32,266 individuals were included in the main analysis (16,133 in each group). Median follow-up times were 642 days and 529 days in the GLP-1RA and DPP-4i group, respectively. We found a crude HR of 0.89 [0.76–1.05] for MOF with GLP-1RA compared to DPP-4i. In the fully adjusted model, we obtained an unaltered HR of 0.86 [0.73–1.03]. For the case of hip fracture, we found a crude HR of 0.68 [0.49–0.96] and a similar adjusted HR. Fracture risk was lower in the GLP-1RA group when examining higher daily doses of the medications, when allowing follow-up to continue after medication change, and when examining hip fractures, specifically. Additional subgroup- and sensitivity analyses yielded results similar to the main analysis. Conclusion: In our primary analysis, we did not observe a significantly different risk of MOF between treatment with GLP-1RA and DPP-4i. We conclude that GLP-1RA are safe in terms of fracture. [ABSTRACT FROM AUTHOR]

Patients with acute myocardial infarction are at high risk for developing heart failure due to scar development. Although regenerative approaches are evolving, consistent clinical benefits have not yet been reported. Treatment with dutogliptin, a second-generation DPP-4 inhibitor, in co-administration with filgrastim (G-CSF) has been shown to enhance endogenous repair mechanisms in experimental models. The REC-DUT-002 trial was a phase 2, multicenter, double-blind placebo-controlled trial which explored the safety, tolerability, and efficacy of dutogliptin and filgrastim in patients with ST-elevation Myocardial Infarction (STEMI). Patients (n = 47, 56.1 ± 10.7 years, 29% female) with STEMI, reduced left ventricular ejection fraction (EF ≤ 45%) and successful revascularization following primary PCI were randomized to receive either study treatment or matching placebo. Cardiac magnetic resonance imaging (cMRI) was performed within 72 h post-PCI and repeated after 3 months. The study was closed out early due to the SARS-CoV-2 pandemic. There was no statistically significant difference between the groups with respect to serious adverse events (SAE). Predefined mean changes within cMRI-derived functional and structural parameters from baseline to 90 days did not differ between placebo and treatment (left ventricular end-diastolic volume: +13.7 mL vs. +15.7 mL; LV-EF: +5.7% vs. +5.9%). Improvement in cardiac tissue health over time was noted in both groups: full-width at half-maximum late gadolinium enhancement (FWHM LGE) mass (placebo: −12.7 g, treatment: −19.9 g; p = 0.23). Concomitant treatment was well tolerated, and no safety issues were detected. Based on the results, the FDA and EMA have already approved an adequately powered large outcome trial. [ABSTRACT FROM AUTHOR]

Inhibition of DPP-4 and stimulation of GLP-1 secretion are therapeutic strategies for controlling glycaemia in type 2 diabetes. The present study assessed the DPP-4 inhibitory activity and GLP-1 secretory action of pigmented and non-pigmented rice (Oryza sativa L.), along with an extruded food product. Cereal-based extruded food products, with or without passion fruit powder, were prepared from red rice using a twin extruder. Optimal extrusion conditions were determined using a CCD of response surface methodology resulting in optimal conditions to be 97.5 °C, a screw speed of 250 rpm, feed moisture of 25.2% and addition of 11.25% passion fruit powder. Samples were sequentially extracted in n-hexane, ethanol (50%) and water. Ethanol/water (50:50) extracts of rice bran significantly inhibited DPP-4 activity by 70.48 ± 1.06%, comparing favourably with RR (42.55 ± 0.84%), PRR (35.91 ± 1.27%) and PA (29.14 ± 1.23%). DPP-4 inhibitory activity was retained in both extruded products albeit at reduced levels. GLP-1 secretion was stimulated mostly by extruded products extracted with n-hexane or ethanol which upregulated basal secretion by 6.1-fold and 4.2-fold, respectively. ICP-MS results showed that extruded food items have a lower arsenic content. In conclusion, there are potential opportunities for the nutraceuticals and functional food products using pigmented red rice. [ABSTRACT FROM AUTHOR]

BackgroundType 2 diabetes mellitus (T2D) is associated with an increased fracture risk. There is little evidence for the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA) on fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) for treatment with GLP-1RA compared to dipeptidyl peptidase 4 inhibitors (DPP-4i) as add-on therapies to metformin.MethodsWe conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either GLP-1RA or DPP-4i were enrolled from 2007 to 2018. Subjects were propensity-score matched 1:1 based on age, sex, and index date. MOF were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. In addition, Aalen’s Additive Hazards model was applied to examine additive rather than relative hazard effects while allowing time-varying effects.ResultsIn total, 42,816 individuals treated with either combination were identified and included. After matching, 32,266 individuals were included in the main analysis (16,133 in each group). Median follow-up times were 642 days and 529 days in the GLP-1RA and DPP-4i group, respectively. We found a crude HR of 0.89 [0.76–1.05] for MOF with GLP-1RA compared to DPP-4i. In the fully adjusted model, we obtained an unaltered HR of 0.86 [0.73–1.03]. For the case of hip fracture, we found a crude HR of 0.68 [0.49–0.96] and a similar adjusted HR. Fracture risk was lower in the GLP-1RA group when examining higher daily doses of the medications, when allowing follow-up to continue after medication change, and when examining hip fractures, specifically. Additional subgroup- and sensitivity analyses yielded results similar to the main analysis.ConclusionIn our primary analysis, we did not observe a significantly different risk of MOF between treatment with GLP-1RA and DPP-4i. We conclude that GLP-1RA are safe in terms of fracture.

Current oral medications for type 2 diabetes target a single main physiological mechanism. They either activate or inhibit receptors to enhance insulin sensitivity, increase insulin secretion, inhibit glucose absorption, or inhibit glucose production. In advanced stages, combination therapy may be required because of the limited efficacy of single-target drugs; however, medications are becoming more costly, and there is also the risk of developing the combined side effects of each drug. Thus, identifying a multi-target drug may be the best strategy to improve treatment efficacy. This study sees the potential of 2657 Filipino phytochemicals as a source of natural inhibitors against four targets of diabetes: PTP1B, DPP-4, SGLT-2, and FBPase. Different computer-aided drug discovery techniques, including ADMET profiling, DFT optimization, molecular docking, MD simulations, and MM/PBSA energy calculations, were employed to elucidate the stability and determine the binding affinity of the candidate ligands. Through in silico methods, we have identified seven potential natural inhibitors against PTP1B, DPP-4, and FBPase, and ten against SGLT-2. Eight plants containing at least one natural inhibitor of each protein target were also identified. It is recommended to further investigate the plants’ potential to be transformed into a safe and scientifically validated multi-target drug for diabetes therapies.

There was no association of plasma DPP-4 activity levels with bone mineral density (BMD), body composition, or incident hip fractures in a cohort of elderly community-dwelling adults.IntroductionDipeptidyl peptidase IV (DPP-4) inactivates several key hormones including those that stimulate postprandial insulin secretion, and DPP-4 inhibitors (gliptins) are approved to treat diabetes. While DPP-4 is known to modulate osteogenesis, the relationship between DPP-4 activity and skeletal health is uncertain. The purpose of the present study was to examine possible associations between DPP-4 activity in elderly subjects enrolled in the Cardiovascular Health Study (CHS) and BMD, body composition measurements, and incident hip fractures.MethodsAll 1536 male and female CHS participants who had evaluable DXA scans and plasma for DPP-4 activity were included in the analyses. The association between (1) BMD of the total hip, femoral neck, lumbar spine, and total body; (2) body composition measurements (% lean, % fat, and total body mass); and (3) incident hip fractures and plasma levels of DPP-4 activity were determined.ResultsMean plasma levels of DPP-4 activity were significantly higher in blacks (227 ± 78) compared with whites (216 ± 89) (p = 0.04). However, there was no significant association of DPP-4 activity with age or gender (p ≥ 0.14 for both). In multivariable adjusted models, there was no association of plasma DPP-4 activity with BMD overall (p ≥ 0.55 for all) or in gender stratified analyses (p ≥ 0.23). There was also no association of DPP-4 levels and incident hip fractures overall (p ≥ 0.24) or in gender stratified analyses (p ≥ 0.39).ConclusionPlasma DPP-4 activity, within the endogenous physiological range, was significantly associated with race, but not with BMD, body composition, or incident hip fractures in elderly community-dwelling subjects.

Wound healing is a complex and long-term process consisting of hemostasis, inflammation, proliferation, and maturation/remodeling. These four stages overlap and influence each other; they affect wound healing in different ways, and if they do not function perfectly, they may cause scarring, proliferative scarring and keloid formation. A therapeutic target affecting wound healing in multiple ways will help the healing process proceed more effectively. DPP-4/CD26 is a multifunctional dimorphic glycoprotein widely distributed on the surface of a variety of cells, including fibroblasts and keratin-forming cells. It has been found to affect periwound inflammation, re-epithelialization, extracellular matrix secretion and skin fibrosis and is a potential target for promoting wound healing and inhibiting scar formation. After presenting a brief introduction of the wound healing process and DPP-4/CD26, this paper summarizes the effects of DPP-4/CD26 on cells involved in different stages of wound healing and discusses the feasibility of DPP-4/CD26 as a multifunctional target for the treatment of wound healing and inhibition of scar formation.

Abstract Context Withania coagulans (Stocks) Dunal fruits are used in the therapeutics of several ailments due to possessing of potent phytoconstituents which is also used traditionally for curing the diabetes. Objective The present study was assessing the amelioration potential of the phytochemicals of an ethanol fruit extract of W. coagulans (Stocks) Dunal in the HOMA (Homeostatic model assessment) indices and pancreatic endocrinal tissues by inhibition of DPP-4 and antioxidants activities. Material and methods The identification of phytoconstituents of the test extract was performed by LCMS. Further, assessments of in-vitro, in-vivo and in-silico were achieved by following standard methods. In-vivo studies were conducted on type-2 diabetic rats. Results The chosen extract inhibited DPP-4 activity by 63.2% in an in vitro assay as well as significantly inhibit serum DPP-4 levels. Accordingly, the administration of the ethanol fruit extract resulted in a significant (P ≤ 0.001) alterations in the lipid profile, antioxidant levels, and HOMA indices. Moreover, pancreatic endocrinal tissues (islet of Langerhans) appeared to have the restoration of normal histoarchitecture as evidenced by increased cellular mass. Molecular docking (Protein-ligands) of identified phytoconstituents with DPP-4 (target enzyme) shown incredibly low binding energy (Kcal/mol) as required for ideal interactions. ADMET analysis of the pharmacokinetics of the identified phytoconstituents indicated an ideal profile as per Lipinski laws. Conclusion It can be concluded that the phytoconstituents of an ethanol fruit extract of W. coagulans have the potential to inhibit DPP-4 which result in improved glucose homeostasis and restoration of pancreatic endocrinal tissues in type-2 diabetic rats.

Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels, which can cause many diseases, including osteoporosis, fractures, arthritis, and foot complications. The inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme involved in glucose metabolism regulation, are essential for managing Type 2 Diabetes Mellitus (T2DM). The inhibition of DPP-4 has become a promising treatment approach for T2DM because it can increase levels of active glucagon-like peptide-1 (GLP-1), leading to improved insulin secretion in response to glucose and reduced release of glucagon. The review commences by elucidating the role of DPP-4 in glucose homeostasis and its significance in T2DM pathophysiology. Furthermore, it presents the mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity profiles of small-molecule DPP-4 inhibitors across various clinical stages. This comprehensive review provides valuable insights into the synthesis and clinical application of DPP-4 inhibitors, serving as an invaluable resource for researchers, clinicians, and pharmaceutical professionals interested in diabetes therapeutics and drug development. [Display omitted] • An overview of small-molecule DPP-4 inhibitors in the clinic are timely organized. • Synthesis and clinical application of representative DPP-4 inhibitors are highlighted. • A brief summary and prospect are also provided to guide future design of DPP-4 inhibitors. [ABSTRACT FROM AUTHOR]

The present investigation was conducted to elucidate the antidiabetic activity and mechanism of lignan Matairesinol (MAT) in Streptozotocin (STZ)-induced diabetes in Wistar Rats. The MAT was administered to diabetic rats (5, 10, and 15 mg/kg), and various biochemical parameters were studied to ascertain its pharmacological effect. Results suggest that MAT, in a dose-dependent manner, improves the level of plasma blood glucose, blood insulin, body weight, and hepatic enzymes, e.g., hexokinase (HK), Glucose 6-phosphatase (G6Pase), and Fructose 1,6-bisphosphatase (FBPase) in Wistar rats. In flow cytometry analysis, MAT significantly prevented apoptosis of hepatocytes compared to STZ rats. In docking analysis, MAT showed excellent interaction with DPP-4 via the formation of hydrophobic interaction of both phenyl rings with Tyr628 and Phe319 of S1 pocket lined with a lipophilic cavity by residues such as Tyr631, Val656, Trp659, Tyr662, Tyr666. It also showed the formation of H-bonds with Glu167, Arg87, Ser171, and His88. The present study showed a significant antidiabetic and hepatoprotective effect of matairesinol. [ABSTRACT FROM AUTHOR]