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AIMS: The present study investigated the vasorelaxant mechanisms of an oral antidiabetic drug, anagliptin, using phenylephrine (Phe)-induced pre-contracted rabbit aortic rings. METHODS: Arterial tone measurement was performed in rabbit thoracic aortic rings. RESULTS: Anagliptin induced vasorelaxation in a dose-dependent manner. Pre-treatment with the classical voltagedependent K+ (Kv) channel inhibitors 4-aminopyridine and tetraethylammonium significantly decreased the vasorelaxant effect of anagliptin, whereas pre-treatment with the inwardly rectifying K+ (Kir) channel inhibitor Ba2+, the ATP-sensitive K+ (KATP) channel inhibitor glibenclamide, and the large-conductance Ca2+-activated K+ (BKCa) channel inhibitor paxilline did not attenuate the vasorelaxant effect. Furthermore, the vasorelaxant response of anagliptin was effectively inhibited by pre-treatment with the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid. Neither cAMP/protein kinase A (PKA)-related signaling pathway inhibitors (adenylyl cyclase inhibitor SQ 22536 and PKA inhibitor KT 5720) nor cGMP/protein kinase G (PKG)-related signaling pathway inhibitors (guanylyl cyclase inhibitor ODQ and PKG inhibitor KT 5823) reduced the vasorelaxant effect of anagliptin. Similarly, the anagliptin-induced vasorelaxation was independent of the endothelium. CONCLUSIONS: Based on these results, we suggest that anagliptin-induced vasorelaxation in rabbit aortic smooth muscle occurs by activating Kv channels and the SERCA pump, independent of other vascular K+ channels, cAMP/PKA- or cGMP/PKG-related signaling pathways, and the endothelium.
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Purpose: In people with type 2 diabetes mellitus (T2DM), both glucose metabolism abnormalities and atherosclerosis risk are significant concerns. This study aims to investigate the effects of the sodium-glucose cotransporter 2 inhibitor tofogliflozin (TOFO) and the dipeptidyl peptidase-4 inhibitor anagliptin (ANA) on markers of glucose metabolism and atherosclerosis when administered individually or in combination. Methods: Fifty T2DM patients were divided into two groups (receiving either TOFO or ANA monotherapy) and observed for 12 weeks (observation points: 0 and 12 weeks). The TOFO and ANA groups were then further treated with ANA and TOFO, respectively, and the patients were observed for an additional 36 weeks (observation points: 24 and 48 weeks). Therapeutic effects and various biomarkers were compared between the two groups at the observation points. Results: Combination therapy led to significant improvements in HbA1c levels and atherosclerosis markers. Additionally, the TOFO pretreatment group exhibited significant reductions in sLOX-1 and IL-6 levels. Conclusion: The increase in sLOX-1 and IL-6 levels, which indicates the response of scavenger receptors to oxidized low-density lipoproteins in people with T2DM, is mitigated following TOFO and ANA combination therapy. TOFO alone or in combination with ANA may be beneficial for preventing atherosclerosis development in people with T2DM, in addition to its effect on improving HbA1c levels.
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INTRODUCTION: The effects of switching DPP-4 inhibitors in type 2 diabetes mellitus (T2DM) patients are being widely studied. However, information of which factors affect the therapeutic response is limited. We evaluated the difference in HbA1c lowering effect by comorbidity and other variables after switching to anagliptin in patients with T2DM inadequately controlled by other DPP-4 inhibitors. METHODS: In a multicenter, open-label, single-arm, prospective observational study, patients with T2DM, HbA1c ≥ 7.0% who have taken DPP-4 inhibitors other than anagliptin, either alone or in combination (DPP-4 inhibitors + metformin/sulfonylurea (SU)/thiazolidinedione (TZD)/insulin), for at least 8 weeks were enrolled. After the switch to anagliptin, HbA1c and available clinical characteristics were determined. RESULTS: The change in HbA1c levels from baseline to week 12 and 24 was - 0.40% and - 0.42% in all patients. However, comparing the subgroups without and with comorbidities, the change in HbA1c levels at weeks 12 and 24 was - 0.68% and - 0.89% vs. - 0.27% and 0.22%, respectively. In addition, the proportion of patients achieving HbA1c < 7% from baseline to week 12 and 24 was increased to 70% and 70% vs. 20% and 24%, respectively. Duration of T2DM and different subtype classes of DPP-4 inhibitor did not significantly contribute to the change in HbA1c. CONCLUSION: In patients with T2DM poorly controlled by other DPP-4 inhibitors, HbA1c levels were significantly decreased after switching to anagliptin. Given that the change in HbA1c was greater in patients without comorbidities than in patients with comorbidities, switching to anagliptin before adding other oral hypoglycemic agents (OHAs) may be an option in patients without comorbidities.
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INTRODUCTION: The combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin are used for both once-daily and twice-daily agents in Japan. If there is no difference in effectiveness between the once-daily and twice-daily DPP-4 inhibitor/metformin combination tablets, the once-daily agent is advantageous in terms of frequency of administration. The aim of this study was to compare the effectiveness of once-daily alogliptin/metformin combination tablet (alogliptin 25 mg/metformin 500 mg) and twice-daily anagliptin/metformin combination tablet low dose (LD) (anagliptin 100 mg/metformin 250 mg). METHODS: Forty-eight Japanese patients with type 2 diabetes whose metformin administration of 250 mg twice daily had remained unchanged for at least 8 weeks, except when using DPP-4 inhibitors, glucagon-like peptide-1 receptor agonists, or insulin, were randomized to either the once-daily alogliptin/metformin combination tablet group or the twice-daily anagliptin/metformin combination tablet LD group. The primary endpoint was the difference in glycosylated hemoglobin (HbA1c) levels from baseline to week 12 of administration, whereas the secondary endpoints were fasting blood glucose, body mass index (BMI), and adherence. RESULTS: Forty-four patients completed the study, and intention-to-treat analyses were performed. The adjusted mean value (standard error) for the change in HbA1c from week 0 to 12, was - 0.75 (0.109)% for the once-daily alogliptin/metformin combination tablet group and - 0.65 (0.109)% for the twice-daily anagliptin/metformin combination tablet LD group, with an intergroup difference of - 0.10% (95% confidence interval, CI - 0.407, 0.215). The upper limit of the bilateral 95% CI was 0.215%, below the 0.40% pre-defined as the non-inferiority margin. Fasting blood glucose, BMI, and adherence were not significantly different between the groups. CONCLUSIONS: The once-daily alogliptin/metformin combination tablet was non-inferior to the twice-daily anagliptin/metformin combination tablet LD in Japanese patients with type 2 diabetes. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) (registration number: UMIN000034951).
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Cancer cells frequently exhibit an acidic extracellular microenvironment, where inversion of the transmembrane pH gradient is associated with tumor proliferation and metastasis. To elucidate a new therapeutic target against cancer, the current study aimed to determine the mechanism by which the dipeptidyl peptidase-4 inhibitor anagliptin regulates the cellular pH gradient and concomitant extracellular acidosis during cancer progression. A total of 5x105 CT-26 cells (resuspended in phosphate buffer saline) were injected subcutaneously in the right flank of male BALB/c mice (weighing 25-28 g). The tumor samples were harvested, and lactate was detected using a lactate assay kit. Immunohistochemistry was used to detect the Ki67 and PCNA. MTT assay and flow cytometric were used to detect cell viability. Intracellular pH was detected by fluorescence pH indicator. The results revealed that anagliptin effectively reduced tumor growth, but did not affect the body weight of treated mice. Anagliptin reduced the accumulation of lactate in tumor sample. Treatment with anagliptin stimulated the apoptosis of CT-26 cells. And lactate excretion inhibition is accompanied by an increase in extracellular pH (pHe) after treatment with anagliptin. Furthermore, anagliptin induced intracellular acidification and reversed the low pHe gradient via monocarboxylate transporter-4 (MCT-4)-mediated lactate excretion. Additionally, anagliptin reversed the aberrant transmembrane extracellular/intracellular pH gradient by suppressing MCT-4-mediated lactate excretion, while also reducing mitochondrial membrane potential and inducing apoptosis. These data revealed a novel function of anagliptin in regulating lactate excretion from cancer cells, suggesting that anagliptin may be used as a potential treatment for cancer.
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Sepsis is a multiple organ dysfunction syndrome (MODS) induced by infection, which significantly threatens public health. The overactivation of inflammatory reactions and oxidative stress participate in the pathogenesis of sepsis. Anagliptin, a novel anti-diabetic agent widely applied for the treatment of type II diabetes, has been recently claimed to possess anti-inflammatory properties. Here, the protective effects of anagliptin on lipopolysaccharide (LPS)- stimulated macrophages will be checked to explore the possible pharmacological property of anagliptin on sepsis. The state of oxidative stress was dramatically activated by LPS, accompanied by the upregulation of toll-like receptor 4 (TLR4) and high mobility group box-1 (HMGB-1), as well as the elevated expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO). After treatment with anagliptin, the state of oxidative stress in macrophages was alleviated, with the downregulation of TLR4, HMGB-1, iNOS, and the declined release of NO. The excessive secretion of inflammatory factors, activation of the NF-κB pathway, and promoted expression level of receptor-interacting protein 1 (RIP1) were observed in LPS- stimulated macrophages, all of which were greatly reversed by the introduction of anagliptin. Lastly, the protective properties of anagliptin on LPS- treated macrophages, including the inhibitory effects on inflammation and the NF-κB pathway, were dramatically abolished by the overexpression of RIP1 in macrophages. Collectively, anagliptin prevented LPS-induced inflammation and activation of P338D1 macrophages by repressing the expression level of RIP1.
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Antiinflamatorios/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Macrófagos/efectos de los fármacos , Pirimidinas/farmacología , Animales , Línea Celular , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolisacáridos , Macrófagos/metabolismo , Ratones , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial. METHODS: PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin (n=122) or sitagliptin (n=128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization. RESULTS: Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P=0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P=0.07). CONCLUSIONS: PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.
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Diabetes Mellitus Tipo 2/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Proproteína Convertasa 9/sangre , Pirimidinas/uso terapéutico , Fosfato de Sitagliptina/uso terapéutico , Anciano , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/complicaciones , Hipercolesterolemia/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Triglicéridos/sangreRESUMEN
BACKGROUND: Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been shown to decrease plasma low-density lipoprotein cholesterol (LDL-C) levels. The objective of our study was to elucidate the mechanisms responsible for the anagliptin-mediated improvements in high LDL-C levels (hyper-LDL cholesterolemia). METHODS: We prospectively examined the effects of anagliptin monotherapy on fasting plasma lathosterol, sitosterol, and campesterol levels in patients with type 2 diabetes mellitus and hyper-LDL cholesterolemia for 6 months. We examined 14 patients who did not use hypoglycemic or lipid-lowering drugs for 4 months before initiating the study. Plasma variables related to glucose and lipid metabolism were measured before and after 6 months of treatment and pre- and postprandially using the cookie-loading test. RESULTS: After treatment, anagliptin monotherapy (n = 14) significantly decreased fasting LDL-C (175.6 to 148.5 mg/dL, mean values before and after the treatment, respectively) and plasma lathosterol levels (3.56 to 2.49 mg/dL), whereas it did not lower fasting sitosterol or campesterol levels. Furthermore, fasting plasma lathosterol levels were negatively correlated with preprandial glucagon-like peptide-1 (GLP-1) levels after anagliptin treatment. CONCLUSIONS: Anagliptin monotherapy may have a beneficial effect on lipid metabolism, which could be mediated by the inhibition of hepatic cholesterol synthesis rather than the inhibition of intestinal lipid transport.
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It has been reported that dipeptidyl peptidase-4 (DPP4) inhibition protects against acute lung injury (ALI). Anagliptin is a novel selective inhibitor of DPP4 but its role in ALI has not been studied. The present study aimed to investigate the effects of anagliptin on lipopolysaccharide (LPS)-induced human pulmonary microvascular endothelial cell (HPMVEC) injury, as well as its underlying mechanism. HPMVECs were exposed to LPS in the presence or absence of anagliptin co-treatment. MTT assay was used to evaluate cell viability and nitric oxide (NO) production was detected using a commercial kit. DPP4 and pro-inflammatory cytokine expression levels, apoptosis and migration were assessed via reverse transcription-quantitative PCR, western blotting, TUNEL staining and wound healing assay, respectively. Western blot analysis was performed to assess expression levels of proteins involved in NF-κB signaling, cell apoptosis and migration, as well as high mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE). LPS decreased cell viability and NO production, but elevated expression of DPP4 in HPMVECs. LPS promoted pro-inflammatory cytokine expression, NF-κB activation and cell apoptosis, but inhibited cell migration and phosphorylated-AKT/endothelial NO synthase expression. Anagliptin co-treatment significantly restored all of these effects. Mechanistically, the upregulation of HMGB1/RAGE expression induced by LPS was markedly blocked by anagliptin. In conclusion, anagliptin alleviated inflammation, apoptosis and endothelial dysfunction in LPS-induced HPMVECs via modulating HMGB1/RAGE expression. These data provide a basis for use of anagliptin in ALI treatment.
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Vascular smooth muscle cell senescence plays a pivotal role in the pathogenesis of atherosclerosis. Anagliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of hyperglycemia. Recent progress indicates that DPP-4 inhibitors show a wide range of cardiovascular benefits. We hypothesize that Anagliptin plays a role in vascular smooth muscle cell senescence and this may imply its modulation of atherosclerosis. Here, the beneficial effect of Anagliptin against interleukin 1ß (IL-1ß)-induced cell senescence in vascular smooth muscle cells was studied to learn the promising therapeutic capacity of Anagliptin on atherosclerosis. Firstly, we found that Anagliptin treatment ameliorated the elevated secretions of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and macrophage chemoattractant protein-1 (MCP-1). Secondly, our findings indicate that exposure to IL-1ß reduced telomerase activity from 26.7 IU/L to 15.8 IU/L, which was increased to 20.3 and 24.6 IU/L by 2.5 and 5 µM Anagliptin, respectively. In contrast, IL-1ß stimulation increased senescence- associated ß-galactosidase (SA-ß-gal) staining to 3.1- fold compared to the control group, it was then reduced to 2.3- and 1.6- fold by Anagliptin dose-dependently. Thirdly, Anagliptin dramatically reversed the upregulated p16, p21, and downregulated sirtuin1 (SIRT1) in IL-1ß-treated vascular smooth muscle cells. Lastly, the protective effect of Anagliptin against cellular senescence in vascular smooth muscle cells was abolished by silencing of SIRT1. In conclusion, Anagliptin protects vascular smooth muscle cells from cytokine-induced senescence, and the action of Anagliptin in vascular smooth muscle cells requires SIRT1 expression.
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Senescencia Celular , Regulación de la Expresión Génica , Interleucina-1beta/toxicidad , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Pirimidinas/farmacología , Sirtuina 1/genética , Supervivencia Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Citocinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Mediadores de Inflamación/metabolismo , Sustancias Protectoras/farmacología , Pirimidinas/química , Sirtuina 1/metabolismoRESUMEN
BACKGROUND: Dipeptidyl peptidase 4 (DPP-4) inhibitors have been used to treat type 2 diabetes mellitus (T2DM) via inhibition of the enzymatic activity of DPP-4 in degrading active circulating glucagon-like peptide-1. In addition to their glucose-lowering effect, DPP-4 inhibitors have pleiotropic effects. Cellular senescence regarded as important pathophysiological mechanism underlying many degenerative diseases, including atherosclerosis. This study was performed to examine whether the DPP-4 inhibitor, anagliptin, can directly protect against stress-induced accelerated senescence (SIAS) of vascular endothelial cells, regardless of changes in ambient glucose level. METHODS: Cultured human umbilical vein endothelial cells (HUVECs) were exposed to various concentrations of H2O2, and a fixed high concentration of glucose (25 mM) with varying concentrations of palmitate. Changes in cell viability, senescence-associated beta-galactosidase (SA-ß-Gal), p16 protein, markers of endoplasmic reticulum (ER) stress, NOX4, NLRP inflammasome, lactate dehydrogenase (LDH) release and interleukin (IL) 1ß levels were measured by Cell Counting Kit-8 assay, immunofluorescent staining, Western blotting, and enzyme-linked immunosorbent assay, respectively before and after application of anagliptin. RESULTS: The application of oxidative and glucolipotoxic stresses markedly increased the degree of SIAS of HUVECs, represented by increased SA-ß-Gal immunopositivity and p16 protein expression. Aggravation of ER stress and inflammatory response were also observed through increased levels of ATF4, CHOP, peIF2α, NOX4, NLRP inflammasome, LDH, and IL1ß. These changes were markedly reversed by the administration of anagliptin. CONCLUSIONS: The DPP-4 inhibitor anagliptin effectively protects HUVECs against SIAS, suggesting its potential use in the development of new treatment strategies for aging.
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Platelet-derived growth factor-B (PDGF-B) is a main factor to promote adipose tissue angiogenesis, which is responsible for the tissue expansion in obesity. In this process, PDGF-B induces the dissociation of pericytes from blood vessels; however, its regulatory mechanism remains unclear. In the present study, we found that stromal cell-derived factor 1 (SDF1) plays an essential role in this regulatory mechanism. SDF1 mRNA was increased in epididymal white adipose tissue (eWAT) of obese mice. Ex vivo pharmacological analyses using cultured adipose tissue demonstrated that physiological concentrations (1-100 pg/mL) of SDF1 inhibited the PDGF-B-induced pericyte dissociation from vessels via two cognate SDF1 receptors, CXCR4 and CXCR7. In contrast, higher concentrations (> 1 ng/mL) of SDF1 alone caused the dissociation of pericytes via CXCR4, and this effect disappeared in the cultured tissues from PDGF receptor ß (PDGFRß) knockout mice. To investigate the role of SDF1 in angiogenesis in vivo, the effects of anagliptin, an inhibitor of dipeptidyl peptidase 4 (DPP4) that degrades SDF1, were examined in mice fed a high-fat diet. Anagliptin increased the SDF1 levels in the serum and eWAT. These changes were associated with a reduction of pericyte dissociation and fat accumulation in eWAT. AMD3100, a CXCR4 antagonist, cancelled these anagliptin effects. In flow-cytometry analysis, anagliptin increased and decreased the PDGF-B expression in endothelial cells and macrophages, respectively, whereas anagliptin reduced the PDGFRß expression in pericytes of eWAT. These results suggest that SDF1 negatively regulates the adipose tissue angiogenesis in obesity by altering the reactivity of pericytes to PDGF-B.
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Tejido Adiposo Blanco/patología , Tejido Adiposo Blanco/fisiopatología , Quimiocina CXCL12/metabolismo , Obesidad/patología , Obesidad/fisiopatología , Proteínas Proto-Oncogénicas c-sis/metabolismo , Remodelación Vascular , Tejido Adiposo Blanco/irrigación sanguínea , Inductores de la Angiogénesis/metabolismo , Animales , Vasos Sanguíneos/patología , Quimiocina CXCL12/sangre , Dieta Alta en Grasa , Epidídimo/patología , Conducta Alimentaria , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Obesos , Modelos Biológicos , Neovascularización Fisiológica/efectos de los fármacos , Pericitos/efectos de los fármacos , Pericitos/metabolismo , Pericitos/patología , Pirimidinas/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores CXCR/metabolismo , Receptores CXCR4/metabolismo , Delgadez/patologíaRESUMEN
AIMS: To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase-4 (DPP-4) inhibitor, on acute ischemia-induced bladder dysfunction in rats. METHODS: Eight-week-old female Wistar-ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE-2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP-4) activity, GLP-1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery. RESULTS: No differences in blood glucose levels among the groups were observed. DPP-4 activity decreased in the Lig + Ana group (P < .01). GLP-1 levels in the Lig + Ana and Lig + Lira groups were higher than those in the sham and Lig groups (P < .01). Intercontraction intervals (ICIs) were longer in the Lig and Lig + Lira groups than in the sham group (P < .05), but similar to those observed in the Lig + Ana and sham groups. The Lig group exhibited reduced bladder blood flow relative to the sham group (P < .01); however, this measure improved in the Lig + Ana group (P < .01). CONCLUSIONS: Ana administration improved ICIs and bladder blood flow after acute bladder ischemia through a GLP-1 receptor-independent signaling pathway, without altering the blood glucose levels. Therefore, Ana dosing might be useful to prevent ischemia-induced bladder dysfunctions.
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Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hemodinámica/efectos de los fármacos , Arteria Ilíaca , Pirimidinas/uso terapéutico , Enfermedades de la Vejiga Urinaria/tratamiento farmacológico , Animales , Glucemia/metabolismo , Dieta , Dipeptidil Peptidasa 4/sangre , Femenino , Receptor del Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Isquemia , Ligadura , Liraglutida/uso terapéutico , Ratas , Ratas Wistar , Enfermedades de la Vejiga Urinaria/fisiopatologíaRESUMEN
Osteoporosis is a common debilitating bone disease characterized by loss of bone mass and degradation of the bone architecture, which is primarily driven by dysregulated differentiation of mesenchymal stem cells into bone-producing osteoblasts. Osteoblasts contribute to bone formation by secreting various proteins that guide the deposition of bone extracellular matrix, such as alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). The Wnt/ß-catenin pathway is widely recognized as a regulator of bone mass and is required to maintain bone homeostasis. Hormones have long been recognized as playing a key role in bone metabolism, and in recent years, growing evidence has shown that diabetes is a risk factor for osteoporosis. In the present study, we investigated the effects of the antidiabetic drug anagliptin on the differentiation and mineralization of osteoblasts induced by osteogenic medium. Anagliptin promotes insulin production via inhibition of dipeptidyl peptidase IV (DPP-4), an enzyme that targets the incretin hormone glucagon-like peptide 1 (GLP-1) for degradation. Our findings show that anagliptin significantly increases the differentiation of MSCs into osteoblasts via activation of RUNX2. Anagliptin significantly increased matrix deposition and mineralization by osteoblasts, as evidenced by elevated levels of ALP, OCN, OPN, and BMP-2. We further demonstrate that anagliptin activates the canonical and noncannonical Wnt signaling pathways and that silencing of Wnt/ß-catenin signaling completely abolished the effects of anagliptin. Thus, anagliptin might be a safe, effective therapy for type II diabetes that might show promise as a therapy against osteoporosis.
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Conservadores de la Densidad Ósea/farmacología , Calcificación Fisiológica/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Pirimidinas/farmacología , Células 3T3 , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Proteína Morfogenética Ósea 2/genética , Proteína Morfogenética Ósea 2/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Regulación de la Expresión Génica , Ratones , Osteoblastos/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Vía de Señalización WntRESUMEN
BACKGROUND: Fatty acid-binding protein 4 (FABP4) acts as a novel adipokine, and elevated FABP4 concentration is associated with obesity, insulin resistance and atherosclerosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of antidiabetic drugs, have distinct structures among the drugs, possibly leading to a drug class effect and each drug effect. Sitagliptin, a DPP-4 inhibitor, has been reported to decrease FABP4 concentration in drug-naïve and sulfonylurea-treated patients with type 2 diabetes mellitus. Anagliptin, another DPP-4 inhibitor, was shown to decrease low-density lipoprotein cholesterol (LDL-C) level to a greater extent than that by sitagliptin in the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. AIM AND METHODS: As a sub-analysis study using data obtained from the REASON trial, we investigated the effects of treatment with anagliptin (n = 148, male/female: 89/59) and treatment with sitagliptin (n = 159, male/female: 93/66) for 52 weeks on FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular events who were receiving statin therapy. RESULTS: The DPP-4 inhibitor had been administered in 82% of the patients in the anagliptin group and 81% of the patients in sitagliptin group prior to randomization. Serum FABP4 level was significantly decreased by 7.9% by treatment with anagliptin (P = 0.049) and was not significantly decreased by treatment with sitagliptin (P = 0.660). Change in FABP4 level was independently associated with basal FABP4 level and changes in waist circumference and creatinine after adjustment of age, sex and the treatment group. CONCLUSION: Anagliptin decreases serum FABP4 concentration independent of change in hemoglobin A1c or LDL-C in patients with type 2 diabetes mellitus and dyslipidemia who are on statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. Registered January 5, 2015, https://clinicaltrials.gov/ct2/show/NCT02330406.
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Glucemia/efectos de los fármacos , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Dislipidemias/tratamiento farmacológico , Proteínas de Unión a Ácidos Grasos/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pirimidinas/uso terapéutico , Anciano , Biomarcadores/sangre , Glucemia/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Regulación hacia Abajo , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/epidemiología , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Masculino , Persona de Mediana Edad , Pirimidinas/efectos adversos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
A simple, accurate, precise and economical Q- Absorption Ratio spectrophotometric method was developed and validated for estimation of Anagliptin and Metformin HCl in synthetic mixture. Anagliptin and Metformin HCl showed an iso-absorptive point at 238 nm in distilled water. The second wavelength used was 233 nm which is λmax of Metformin HCl in distilled water. The concentration of the drugs was determined by using ratio of absorbance at iso-absorptive point (λ1 = 238 nm) and at the λmax of Metformin HCl (λ2 = 233 nm). This method is linear for both drugs; in range of 2-12 µg/mL at λ1 (R2 = 0.999) and at λ2 (R2 = 0.9998) for Anagliptin, and in the range of 5-30 µg/mL for Metformin HCl found at λ1 (R2 = 0.9995) and at λ2 (R2 = 0.9997). The % Recovery was 100.42-101.83 % of Anagliptin and 99.94-101.63 % of Metformin HCl by standard addition method. The LOD was found to be 0.201 µg/mL and 0.262 µg/mL for Anagliptin at λ1 and λ2 respectively. The LOD was found to be 0.320 µg/mL and 0.167 µg/mL for Metformin HCl at λ1 and λ2 respectively. The LOQ was found to be 0.610 µg/mL and 0.794 µg/mL for Anagliptin at λ1 and λ2 respectively. The LOQ was found to be 0.972 µg/mL and 0.506 µg/mL for Metformin HCl at λ1 and λ2 respectively. The method was found to be precise as % RSD was less than 2.00 in Repeatability, Interday and Intraday precision for Anagliptin and Metformin HCl. The % assay of analyte drugs in synthetic mixture was found to be 100.601% of Anagliptin and 100.206 % of Metformin HCl which showed good applicability of the developed method.
RESUMEN
BACKGROUND: Recently, we reported that the level of lathosterol, a cholesterol synthesis marker, was suppressed after 1 month of treatment with anagliptin, a dipeptidyl peptidase-4 inhibitor. In this study, we administered either anagliptin or miglitol, an alpha-glucosidase inhibitor, for 3 months in patients with type 2 diabetes and compared the lipid-lowering effects of anagliptin with those of miglitol. METHODS: This study was a 12-week, open-label, prospective, randomized, parallel-group comparison trial. Fifty-two patients with type 2 diabetes who aged 20 - 70 years with a low-density lipoprotein cholesterol (LDL-C) level of over 120 mg/dL, and with no history of treatment with antihyperlipidemic drugs were enrolled. Patients were randomly assigned to either the anagliptin group or miglitol group. The 100 mg of anagliptin was administered twice a day for the anagliptin group and 50 mg of miglitol was administered thrice a day for miglitol group. The changes in lipids, cholesterol synthesis, and absorption markers were evaluated after 12 weeks. RESULTS: Fifty-two participants were initially enrolled in the trial, and 47 of them completed the protocol. There was no significant difference in LDL-C, cholesterol synthesis, and the absorption markers between anagliptin and miglitol groups. CONCLUSIONS: Anagliptin and miglitol are similarly effective on lipid and glycemic control.
RESUMEN
Obesity is a major risk factors for type 2 diabetes, and weight loss is beneficial to diabetic patients who are obese or overweight. Dipeptidyl peptidase-4 (DPP-4) inhibitors are anti-diabetic drugs. Although it has been known that the effect of most of the DPP-4 inhibitors on body weight is neutral, several studies suggested that some DPP-4 inhibitors suppressed body weight. Nonetheless, the mechanisms underlying DPP-4 inhibitor-induced weight loss are not fully understood. In this study, the mice fed high-fat high sucrose diet (HFHSD) containing a DPP4 inhibitor, anagliptin, showed reduced food intake and body weight compared to the mice fed non-treated HFHSD, but oxygen consumption and respiratory exchange ratio (RER) were not altered. Sequential administration of leptin suppressed food intake and body weight more apparently in anagliptin treated HFHSD fed mice than non-treated HFHSD fed mice. Oxygen consumption and RER were comparable between anagliptin treated and non-treated mice after leptin administration. The number of phospho STAT3 expressed cells in the arcuate nucleus after leptin administration was increased in anagliptin treated mice compared to non-treated mice. These data suggested that anagliptin ameliorated leptin resistance induced by HFHSD and thereby decreased food intake and body weight. These effects of anagliptin could be beneficial to the treatment of obese diabetic patients.
Asunto(s)
Peso Corporal/efectos de los fármacos , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Ingestión de Alimentos/efectos de los fármacos , Hiperfagia/tratamiento farmacológico , Leptina/farmacología , Obesidad/tratamiento farmacológico , Pirimidinas/uso terapéutico , Animales , Dieta Alta en Grasa/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hiperfagia/sangre , Leptina/sangre , Ratones , Actividad Motora/efectos de los fármacos , Obesidad/sangre , Obesidad/etiología , Consumo de Oxígeno/efectos de los fármacos , Pirimidinas/farmacologíaRESUMEN
To investigate the regulatory effects of anagliptin, a DPP-IV inhibitor used to treat type 2 diabetes mellitus (T2DM), on myoblast differentiation and mitochondrial biogenesis in C2C12 mouse skeletal muscle cells. C2C12 myoblasts were differentiated into myotubes and then treated with anagliptin (10, 25, and 50 µmol/L) for 24 hours. In C2C12 myotubes, anagliptin treatment was significantly increased the expression of MHC, PGC1α, Sirt-1, NRF-1, and TFAM and the phosphorylation of AMPK and ACC in a concentration-dependent manner. Anagliptin also significantly increased the total ATP levels in the myotubes. These results suggest that anagliptin can help prevent skeletal muscle dysfunction in T2DM by promotion of myoblast differentiation and enhancement of energy production via upregulation of mitochondrial biogenetic factors and activation of the AMPK/ACC signalling pathway.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Metabolismo Energético/efectos de los fármacos , Mitocondrias Musculares/efectos de los fármacos , Mioblastos Esqueléticos/efectos de los fármacos , Biogénesis de Organelos , Pirimidinas/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Animales , Línea Celular , Ratones , Mitocondrias Musculares/metabolismo , Mioblastos Esqueléticos/metabolismo , Fosforilación , Transducción de Señal , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain. AIM AND METHODS: We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353). RESULTS: There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 µg/mL vs. 52 weeks, 1.4 ± 1.0 µg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 µg/mL vs. 52 weeks, 1.3 ± 0.7 µg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06). CONCLUSION: These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015.