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Crotamine (Ctm) is a peptide isolated from Crotalus durissus terrificus venom. This molecule has been demonstrated to diminish body weight gain and enhance browning in adipose tissue, glucose tolerance, and insulin sensitivity; hence, it has been postulated as an anti-obesogenic peptide. However, the mechanism to elicit the anti-obesogenic effects has yet to be elucidated. Thus, we investigated the possible interaction of Ctm with receptors involved in obesity-related metabolic pathways through protein-protein docking and molecular dynamics refinement. To test the anti-obesogenic mechanism of Ctm, we selected and retrieved 18 targets involved in obesity-related drug discovery from Protein Data Bank. Then, we performed protein-protein dockings. The best three Ctm-target models were selected and refined by molecular dynamics simulations. Molecular docking demonstrated that Ctm was able to interact with 13 of the 18 targets tested. Having a better docking score with glucagon-like peptide-1 receptor (GLP-1R) (-1430.2 kcal/mol), DPP-IV (dipeptidyl peptidase-IV) (-1781.7 kcal/mol) and α-glucosidase (-1232.3 kcal/mol). These three models were refined by molecular dynamics. Ctm demonstrated a higher affinity for GLP-1R (ΔG: -41.886 ± 2.289 kcal/mol). However, Ctm interaction was more stable with DPP-IV (RMSD: 0.360 ± 0.015 nm, Radius of gyration: 2.781 ± 0.009 nm). Moreover, the number of interactions and the molecular mechanics energies of Ctm residues suggest that the interaction of Ctm with these receptors is mainly mediated by basic-hydrophobic dyads Y1-K2, W31-R32, and W33-R34. Together, all these results allow elucidating a possible molecular mechanism behind the previously described anti-obesogenic effects.
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Venenos de Crotalídeos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Obesidade , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Venenos de Crotalídeos/química , Venenos de Crotalídeos/metabolismo , Animais , Humanos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/química , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/química , Redes e Vias Metabólicas , alfa-Glucosidases/metabolismo , alfa-Glucosidases/químicaRESUMO
BACKGROUND: Dipeptidyl peptidase 4 (DPP-4) plays a crucial role in breaking down various substrates. It also has effects on the insulin signaling pathway, contributing to insulin resistance, and involvement in inflammatory processes like obesity and type 2 diabetes mellitus. Emerging effects of DPP-4 on bone metabolism include an inverse relationship between DPP-4 activity levels and bone mineral density, along with an increased risk of fractures. MAIN BODY: The influence of DPP-4 on bone metabolism occurs through two axes. The entero-endocrine-osseous axis involves gastrointestinal substrates for DPP-4, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptides 1 (GLP-1) and 2 (GLP-2). Studies suggest that supraphysiological doses of exogenous GLP-2 has a significant inhibitory effect on bone resorption, however the specific mechanism by which GLP-2 influences bone metabolism remains unknown. Of these, GIP stands out for its role in bone formation. Other gastrointestinal DPP-4 substrates are pancreatic peptide YY and neuropeptide Y-both bind to the same receptors and appear to increase bone resorption and decrease bone formation. Adipokines (e.g., leptin and adiponectin) are regulated by DPP-4 and may influence bone remodeling and energy metabolism in a paracrine manner. The pancreatic-endocrine-osseous axis involves a potential link between DPP-4, bone, and energy metabolism through the receptor activator of nuclear factor kappa B ligand (RANKL), which induces DPP-4 expression in osteoclasts, leading to decreased GLP-1 levels and increased blood glucose levels. Inhibitors of DPP-4 participate in the pancreatic-endocrine-osseous axis by increasing endogenous GLP-1. In addition to their glycemic effects, DPP-4 inhibitors have the potential to decrease bone resorption, increase bone formation, and reduce the incidence of osteoporosis and fractures. Still, many questions on the interactions between DPP-4 and bone remain unanswered, particularly regarding the effects of DPP-4 inhibition on the skeleton of older individuals. CONCLUSION: The elucidation of the intricate interactions and impact of DPP-4 on bone is paramount for a proper understanding of the body's mechanisms in regulating bone homeostasis and responses to internal stimuli. This understanding bears significant implications in the investigation of conditions like osteoporosis, in which disruptions to these signaling pathways occur. Further research is essential to uncover the full extent of DPP-4's effects on bone metabolism and energy regulation, paving the way for novel therapeutic interventions targeting these pathways, particularly in older individuals.
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BACKGROUND: Type 2 diabetes mellitus is one of the most common causes of chronic kidney disease (CKD) worldwide and prevalence of 1.75 per 100 inhabitants in Colombia. The aim of this study was to describe the treatment patterns of a group of patients with type 2 diabetes mellitus and CKD in an outpatient setting from Colombia. METHODS: A cross-sectional study in adult patients with type 2 diabetes mellitus and CKD identified in the Audifarma S.A. administrative healthcare database between April 2019 and March 2020 was performed. Sociodemographic, clinical and pharmacological variables were considered and analyzed. RESULTS: A total of 14,722 patients with type 2 diabetes mellitus and CKD were identified, predominantly male (51%), with a mean age of 74.7 years. The most common treatment patterns of type 2 diabetes mellitus included the use of metformin monotherapy (20.5%), followed by the combination of metformin + dipeptidyl peptidase-4 inhibitor (13.4%). Regarding the use of drugs with nephroprotective properties, the most prescribed treatments were angiotensin receptor blockers (67.2%), angiotensin converting enzyme inhibitors (15.8%), sodium glucose cotransporter 2 inhibitors (SGLT2i) (17.0%) and glucagon-like peptide-1 analogs (GLP1a) (5.2%). CONCLUSION: In Colombia, the majority of patients with type 2 diabetes mellitus and CKD identified in this study were treated with antidiabetic and protective medications to ensure adequate metabolic, cardiovascular, and renal control. The management of type 2 diabetes mellitus and CKD may be improved if the beneficial properties of new groups of antidiabetics (SGLT2i, GLP1a), as well as novel mineralocorticoid receptor antagonists, are considered.
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Background: The nutraceutical properties of food hydrolysates rely on multiple biochemical interactions involving the modulation of enzymes and cellular receptors. Numerous bioactive peptides released from troponin and tropomyosin digestion have been identified. Their characterization has mostly been performed by hydrolysis catalyzed by proteases unrelated to the human digestive system. Objective: This study aimed to determine the bioactive profile of beef, pork, and chicken meat by analyzing the frequency and pharmacokinetics of biopeptides released from troponin and tropomyosin. Methods:In silico digestion and biopeptide release frequency were studied by three parameters; bioactive fragments release frequency (AE), frequency percentage (W), and mean occurrence (AS), all stated on the BIOPEP-UWM platform. Further on, hydrolysis end-products were screened based on gastrointestinal-absorption probability and pharmacokinetic profiling performed on SwissADME, SwissTargetPrediction, and ADME/Tlab bioinformatics web tools. Statistical analyses were performed using a one-way ANOVA test. Results: Dipeptidyl peptidase-IV (DPP-IV) and angiotensin-converting enzyme (ACE) inhibiting biopeptides exhibited the highest release frequency. Moreover, W and ASparameters showed no significant difference (p>0.05) between the myofibrillar isoforms assessed. Seven biopeptides were classified as highly absorbable and reported optimal drug-likeness compliance. Although biopeptides hold good pharmacokinetic properties, the therapeutic potency of biopeptides showed to be lower than those of DPP-IV and ACE-inhibiting drugs. Conclusions: Troponin and tropomyosin are rich dietary sources of bioactive peptides, mainly DPP-IV and ACE inhibitors. Digestion end-products are mainly dipeptides with optimal pharmacokinetic and drug-like properties, suggesting a potential therapeutic application in hypertensive and hyperglycemic disorders
Antecedentes: Las propiedades nutracéuticas de los hidrolizados de alimentos dependen de múltiples interacciones bioquímicos que involucran la modulación de enzimas y receptores celulares. Se han identificado numerosos péptidos bioactivos liberados de la digestión de troponina y tropomiosina, pero su caracterización se ha llevado a cabo principalmente por hidrólisis catalizada por proteasas ajenas al sistema digestivo humano. Objetivo: Este estudio tuvo como objetivo determinar el perfil bioactivo de la carne de res, cerdo y pollo mediante el análisis de la frecuencia y farmacocinética de los biopéptidos liberados de la troponina y la tropomiosina. Métodos: Se estudió la digestión in silico y la frecuencia de liberación de biopéptidos mediante dos parámetros; frecuencia de liberación de fragmentos bioactivos (AE), frecuencia porcentual (W) y ocurrencia media (AS), ambos indicados en la plataforma BIOPEP-UWM. Más adelante, los productos finales de la hidrólisis se examinaron en función de la probabilidad de absorción gastrointestinal y el perfil farmacocinético realizado en las herramientas bioinformáticas SwissADME, SwissTargetPrediction y ADME/Tlab. El análisis estadístico se llevó a cabo mediante una prueba ANOVA de una vía. Resultados: Los biopéptidos inhibidores de la dipeptidil peptidasa IV (DPP-IV) y la enzima convertidora de angiotensina (ECA) exhibieron la mayor frecuencia de liberación. Además, los parámetros W y ASno mostraron diferencias significativas (p> 0.05) entre las isoformas miofibrilares evaluadas. Siete biopéptidos se clasificaron como altamente absorbibles e informaron un cumplimiento óptimo de similitud con el fármaco. Aunque los biopéptidos tienen propiedades farmacocinéticas adecuadas, su potencia terapéutica demostró ser menor que la de los fármacos inhibidores de la DPP-IV y la ACE. Conclusiones: La troponina y la tropomiosina son una fuente dietética rica en péptidos bioactivos, principalmente DPP-IV e inhibidores de la ACE. Los productos finales de la digestión son principalmente dipéptidos con propiedades farmacocinéticas óptimas y similares a la de los fármacos, lo que sugiere una aplicación terapéutica factible en trastornos hipertensivos e hiperglicémicos
Assuntos
Humanos , Peptídeos , Tropomiosina , Troponina , Inibidores da Enzima Conversora de Angiotensina , Inibidores da Dipeptidil Peptidase IVRESUMO
Tuberculosis and diabetes mellitus are two global pandemics and rising public health problems. Recent studies suggest that oral antidiabetic drugs (OADs) could reduce the risk of tuberculosis and improve clinical outcomes. However, the evidence is controversial. Therefore, we aimed to assess the effect of OADs on the risk of tuberculosis and treatment outcomes. We systematically searched for six databases from inception to 31 August 2022. We followed a predefined PICO/PECO strategy and included two randomized controlled trials and sixteen observational studies. This study collects 1,109,660 participants, 908,211 diabetic patients, and at least 13,841 tuberculosis cases. Our results show that metformin decreases the risk of active tuberculosis by 40% (RR 0.60; 95% CI 0.47-0.77) in diabetic patients. In addition, metformin exhibits a dose-response gradient (medium doses reduce the risk of active tuberculosis by 45%, while high doses reduce this risk by 52%). On the other hand, DPP IV inhibitors increase the risk of active tuberculosis by 43% (RR 1.43; 95% CI 1.02-2.02). Subgroup analysis showed that study design and metformin dose accounted for the heterogeneity. We conclude that metformin significantly protects against active tuberculosis among diabetic patients. On the contrary, DPP IV inhibitors could increase the risk of developing active tuberculosis.
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Abstract Introduction and objective: In Colombia, Dipeptidyl-Peptidase IV (DPP4) inhibitors are recommended as second-best choice for type 2 diabetes mellitus treatment. However, no evaluation of the accomplishment or impact of this recommendation was performed. The objective was to determine the prescription of the DPP4 inhibitor according to the Colombian Clinicial Practice Guide regarding type 2 diabetes mellitus treatment, and its effects on glycosylated hemoglobin (HbAlc). Materials and methods: A descriptive study that included patients with type 2 diabetes mellitus who attended a first level between 2016 and 2018, had a prescription for DPP4 inhibitor and at least two control appointments. Variables included were sociodemographic, clinics, treatment and comorbidities. The unadjusted prescription was defined as the lack of accomplishment of Colombian guidelines. Descriptive statistics and X2 test were used for the comparison of categorical variables. A binary logistic regression model was applied. Results: 112 out of 207 patients accomplished inclusion criteria, of which 77 were women (68.8%). Also, 68.8% of the patients had an unadjusted prescription of the iDPP4. There was a 0.21% total reduction in HbA1c levels, with a mean of 198.2 ± 124 days between the first and second control measurement (reduction of 0.55% when the prescription was adjusted to the guidelines and 0.05% if it was unadjusted). Conclusion: There is a limited impact of DPP4 inhibitors regarding the reduction of HbA1c and metabolic control, and there is a slight follow-up to the Colombian guidelines in patients who attend a first level.
Resumen Introducción y Objetivo: En Colombia se recomiendan los inhibidores de la Dipeptidil Peptidasa-IV (iDPP4) como segunda opción para el manejo de la diabetes mellitus tipo 2. No se ha evaluado el cumplimiento e impacto de esta recomendación. Como objetivo se buscó determinar la prescripción de los iDPP4 según las recomendaciones de la Guía de Práctica Clínica colombiana, y su efecto sobre la hemoglobina glicosilada (HbA1c). Materiales y métodos: Estudio descriptivo que incluyó pacientes con diabetes mellitus tipo 2 que consultaron a un primer nivel entre 2016 y 2018, y tenían formulado un iDPP4, con al menos dos consultas de seguimiento. Se incluyeron variables sociodemográficas, clínicas, tratamiento y comorbilidades. La prescripción no ajustada se definió como la falta de cumplimento de la recomendación de la guía colombiana. Se empleó estadística descriptiva y pruebas X2 para la comparación de variables categóricas. Se aplicó un modelo de regresión logística binaria. Resultados: Hubo 207 pacientes de los cuales 112 cumplieron criterios de inclusión, 77 eran mujeres (68,8%). El 68,8% de los pacientes presentaron una prescripción no ajustada del iDPP4. Hubo una reducción total de 0,21%, con una media de 198,2±124 días entre la primera y segunda medición de HbA1c de control (reducción de 0,55% cuando la prescripción se ajustaba a la guía colombiana y 0,05% cuando no). Conclusión: Hay un limitado impacto de los iDPP4 frente a la reducción de HbA1c y poco seguimiento de la guía colombiana en pacientes de primer nivel de atención.
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Humanos , Masculino , Feminino , Hemoglobinas Glicadas , Diabetes Mellitus , Inibidores da Dipeptidil Peptidase IV , Guia de Prática Clínica , Colômbia , Prescrições , HipoglicemiantesRESUMO
In this research functional beverages based on the unprocessed and extruded sesame seeds byproduct were fabricated; phytochemical profile, antioxidant, antidiabetic, and hypoglycemic potential were evaluated. Twenty-four phytochemical compounds were identified in total in both beverages; fourteen of the phytochemical compounds were not modified by the extrusion process. Seventeen of the 24 compounds were identified in the unprocessed sesame seeds byproduct flour beverage-10% (UB10) and 21 in the extruded sesame seeds byproduct flour beverage-10% (EB10). The compounds only identified in UB10 are caffeic acid, luteolin-7-O-glucoside, and isorhamnetin; and in EB10 those compounds were vanillic acid, acteoside, luteolin, quercetin, and melanoidins. No significant difference was observed in the content of total phenolic compounds (TPC) (14.90 and 15.97 mg GAE/100 mL) and total flavonoids (TF) (5.37 and 5.85 mg QE/100 mL). An increase in the biological activity of ESFB10 (IC50: ABTS = 0.19, DPPH = 0.21, α-amylase = 1.01, α-glucosidase = 0.17, DPP4 = 0.11 mg/mL) was observed, compared to UB10 (IC50: ABTS = 0.24, DPPH = 0.31, α-amylase = 2.29, α-glucosidase = 0.47, DPP4 = 0.30 mg/mL). Therefore, the extrusion process had a positive effect, which displayed the highest efficiency inhibiting the free radicals and enzymes related to carbohydrate metabolism.
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Background: Milk-derived biopeptides have reported in vitro dipeptidyl-peptidase IV (DPP-IV) inhibition, suggesting a glycemic-regulatory effect in Type 2 Diabetes Mellitus (T2DM). Nonetheless, the therapeutic application of these nutraceuticals is limited by the scarcity of knowledge regarding their pharmacokinetic profile. Objective: This study aimed to characterize and assess the pharmacokinetics of milk-derived biopeptides. Through an in silico comparative analysis with gliptins, we expected to identify enhanced properties in food-hydrolysates and suitable DPP-IV inhibiting peptides as candidates for T2DM therapy. Methods: A comparison between gliptins and biopeptides was conducted based on in silico evaluation of drug-likeness, physicochemical properties, pharmacokinetics, and synthetic accessibility. Suitable target proteins for gastrointestinal-absorbable biopeptides were determined as well. Data collection was performed on SwissADME, ADMETlab, DrugBank, SwissTargetPrediction, ChemDes, and BIOPEP-UWM platforms. Statistical analysis was carried out using a one-way ANOVA test. Results: Drug-likeness compliance showed no significant difference between gliptins and biopeptides (p>0.05) in three out of nine assessed rules, though gastrointestinal-absorbable biopeptides exhibited no significant difference with gliptins in five drug-likeness guidelines. The physicochemical evaluation revealed a significant difference (p<0.05) between both groups, with peptides exhibiting enhanced solubility, flexibility, and polarity. Nine out of thirty-six assessed biopeptides reported being likely gastrointestinal-absorbable molecules, from which six displayed ≥30% predicted bioavailability, two reported CYP450 interactions, and all were determined to be blood confined. Biopeptides showed a slightly lower clearance than gliptins yet counteracted by a significantly lower half-life. Moreover, synthetic accessibility scores indicated higher synthetic ease for biopeptides. In addition, absorbable bioactive peptides reported a considerable binding affinity to DPP-IV and Calpain-I. Conclusions: Compared to gliptins, gastrointestinal-absorbable biopeptides exhibit superior physicochemical properties (higher solubility, flexibility, and polarity), lesser CYP450 interactions, higher synthetic ease, and some reported an important affinity for DPP-IV and Calpain-I. Only a small fraction of milk-derived biopeptides are suitable drug-like compounds and feasible candidates for T2DM therapy; yet, testing their therapeutic potency remains subject to further studies
Antecedentes: Los biopéptidos derivados de la leche han mostrado inhibir la dipeptidil-peptidasa IV (DPP-IV) en ensayos in vitro, lo que sugiere una regulación de la glicemia en la Diabetes Mellitus Tipo 2 (DM2). Sin embargo, su uso terapéutico está limitado por el escaso conocimiento de sus propiedades farmacológicas. Objetivo: Caracterizar y evaluar el perfil farmacocinético de los biopéptidos derivados de la leche. Por medio de un análisis comparativo in silico, se buscó identificar propiedades de carácter superior a las gliptinas en los biopéptidos inhibidores de DPP-IV, así como posibles candidatos a agentes terapéuticos en la DMT2. Métodos: Se llevó a cabo una comparación entre las Gliptinas y los biopéptidos basada en la evaluación in silicode las características "d r ug - li ke", propiedades fisicoquímicas, farmacocinética y accesibilidad sintética. Adicionalmente, se determinaron posibles proteínas diana para los biopéptidos de alta probabilidad de absorción gastrointestinal. Los datos se obtuvieron en SwissADME, ADMETlab, DrugBank, SwissTargetPrediction, ChemDes y BIOPEP-UWM. El análisis estadístico se basó en un análisis de varianza (one-way ANOVA test). Resultados: El cumplimiento de las reglas de "drug-likeness" no mostró diferencias significativas entre las gliptinas y los biopéptidos (p>0.05) en tres de las nueve normas evaluadas, empero, los biopéptidos absorbibles no mostraron diferencias significativas con las gliptinas en cinco de estas. La evaluación fisicoquímica reveló una diferencia significativa (p>0.05) entre ambos grupos y una mayor solubilidad, flexibilidad y polaridad para los biopéptidos. Nueve de los treinta y seis biopéptidos estudiados reportaron alta probabilidad de absorción gastrointestinal, de los cuales seis presentaron una biodisponibilidad predicha ≥30%, dos reportaron interacciones con el CYP450, y todos mostraron permanecer confinados en sangre. Los biopéptidos mostraron una tasa de aclaramiento inferior a las gliptinas, sin embargo, contrarrestado por una vida-media significativamente menor. Los valores de accesibilidad sintética indicaron una mayor facilidad de síntesis para los biopéptidos. Por último, los biopéptidos absorbibles mostraron una considerable afinidad por la DPP-IV y la Calpaína-I. Conclusiones: Frente a las gliptinas, los biopéptidos absorbibles presentan: propiedades fisicoquímicas superiores (mayor solubilidad, flexibilidad y polaridad), menores interacciones con el CYP450, mayor facilidad de síntesis y algunos una importante afinidad por la DPP-IV y la Calpaína-I. Una mínima fracción de biopéptidos derivados de la leche son candidatos viables para la terapia de DM2; sin embargo, la determinación de su efectividad terapéutica permanece sujeta a futuros estudios
Assuntos
Humanos , Farmacocinética , Peptídeos , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IVRESUMO
Phyllanthus tenellus Roxb. (Phyllanthaceae) is a plant used in Brazilian folk medicine for the treatment of intestinal infections and diabetes. Despite its use in traditional medicine, it was reported that P. tenellus extract may cause several effects in the central nervous system (CNS) of animals, such as agitation and signs of depression. The aim of this study was to determine the main constituents of P. tenellus methanol extract and to investigate whether the extract is able to inhibit the enzymes prolyl oligopeptidase (POP), acetylcholinesterase (AChE) and dipeptidyl peptidase-IV (DPP-IV). Corilagin (1) was isolated as the main constituent of the P. tenellus extract, along with rutin (2) and vitexin-2â³-O-rhamnoside (3). The extract presented the ability to inhibit mainly POP. Dichloromethane and ethyl acetate fractions showed the highest inhibitory potency against POP (IC50 values of 1.7 ± 0.4 and 11.7 ± 2 µg/mL, respectively). All fractions were inactive against AChE. Corilagin displayed selective POP inhibition in a dose-dependent manner, with IC50= 19.7 ± 2.6 µg/mL. Corilagin exhibited moderate capacity to pass through the phospholipid membrane by passive diffusion, presenting effective permeability (Pe) of 1.26 × 10-7 cm/s.
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Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Phyllanthus/química , Prolil Oligopeptidases/antagonistas & inibidores , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Brasil , Inibidores da Colinesterase/química , Glucosídeos/farmacologia , Taninos Hidrolisáveis/farmacologia , Extratos Vegetais/farmacologia , Prolil Oligopeptidases/metabolismoRESUMO
INTRODUCTION: Hepatic steatosis is a frequent condition that afflicts, especially, obese and insulin-resistant patients. Diagnosis is usually made through imaging tests. Despite the high prevalence and risk of complications, there is no specific treatment approved, though a vast number of medications have been tested. OBJECTIVE: This study aimed to determine the efficacy of dipeptidyl peptidase IV inhibitors (i DPP- IV) in the treatment of NAFLD. METHODS: We searched the electronic databases of the Cochrane Library, MEDLINE, EMBASE, and LILACS, as well as reference lists of the included studies and grey literature; 9 studies were selected for inclusion. RESULTS: 7 studies were used for metanalysis for 3 outcomes. i DPP-IV showed an ALT-reducing power of MD -10.83 (95% CI 35.23 to 13.57) at 3 months and MD -9.27 (95% CI 10.92 to -7.62) at 6 months of intervention, as well as a reduction of hepatic steatosis via MRI of SMD 0.10 (95% CI 0.31 to 0.50); the overall incidence of adverse events was very low. The studies were considered of low and very low quality by the GRADE evaluation. CONCLUSION: Because of the overall poor quality of the studies and heterogeneity of the population analyzed, i DPP-IV did not show efficacy on inflammatory markers or fibrosis in patients with NAFLD.
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Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes , Insulina , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológicoRESUMO
BACKGROUND: Glucose variability (GV) is considered an important factor for cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM). High GV causes endothelial dysfunction and increased oxidative stress. Dipeptidyl peptidase-4 (DPP-4) inhibitors may improve endothelial function and decrease GV. The aim of this study was to investigate the effects of vildagliptin, a DPP-4 inhibitor, compared with glibenclamide in GV and endothelial function in patients with T2DM and arterial hypertension. METHODS: This is a prospective, randomized, open and drug-controlled study. Fifty patients older than 35 years with T2DM and hypertension without CVD were randomized to receive vildagliptin (n=25) or glibenclamide (n=25), both in added-on metformin. Laboratory tests and analysis of endothelial function were performed before and 12 weeks after treatment. Endothelial function, defined by reactive hyperemia index (RHI), was analyzed by peripheral artery tonometry (endo-PAT2000). GV was evaluated by capillary glucose with intermittent monitoring device, six measurements per day, for three days, before and after treatment. The median of standard deviation (SD) of mean blood glucose (MBG) was used to evaluate GV. RESULTS: GV decreased in the vildagliptin group (35.2 to 30.7, P=0.037) but did not change with glibenclamide (37.6 to 37.5, P=0.765). Glycated hemoglobin was similar in both groups. MBG decreased only in glibenclamide group, without difference with vildagliptin group (P=0.374). There were no changes in the RHI in both groups and there was no correlation between GV and RHI (P=0.658). CONCLUSION: Vildagliptin reduces GV; however, the action on endothelial function was not demonstrated. In addition, there was no correlation between GV and endothelial function.
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SUMMARY After metformin failure in treatment for diabetes type 2, there is no trivial option for adjuvant medication. The last two oral class medications, gliflozins and gliptins, have different mechanisms of action but have never been compared in long run studies. The aim of the present meta-analysis is to assess the overall long-term efficacy of these drugs after metformin failure. A systematic review and meta-analysis were performed, including all trials with a duration of over 2 years, comparing gliflozins or gliptins after metformin failure in type 2 diabetes. Data Sources: Pubmed (Medline), Embase, Lilacs, and the Cochrane Library from inception through July 2016 without language restrictions. The longest study period found in the literature was 4 years. We selected 1 article on empagliflozin, 1 on dapagliflozin, and 1 on saxagliptin with missing data. After one year of treatment, over 50% of the patients presented HbA1c > 7%. Efficacy rate after 4 years of empagliflozin (23%) was better than dapagliflozin (5%) and saxagliptin (7%); however, it presented statistically non-significant values for HbA1c (7.4 and 7.3% between gliflozins), and missing data for saxaglifozin. Nonetheless, empagliflozin performed better than glimepiride in the 4-year period (standardized mean difference SMD 0.4, confidence interval CI 95% 0.23 to 0.56). The failure of the secondary treatment using gliflozins occurs in less than one year of treatment (less than 50% of the patients presenting HbA1c > 7 %). Empagliflozin offered better glycemic control compared to sulfonylureas but was similar to dapagliflozin.
RESUMO Após a falha da metformina no tratamento do diabetes tipo 2, não existe uma opção trivial para a medicação adicional. Os dois últimos medicamentos de classe oral, gliflozinas e gliptinas, têm mecanismos de ação diferentes, mas nunca foram comparados em estudos de longo prazo. O objetivo da presente meta-análise é a avaliação da eficácia global em longo prazo desses medicamentos após a falha da metformina. Uma revisão sistemática e meta-análise foram realizadas, incluindo todos os ensaios com uma duração de mais de dois anos, comparando gliflozinas ou gliptinas após a insuficiência de metformina no diabetes tipo 2. Fontes de dados: PubMed (Medline), Embase, Lilacs e a Biblioteca Cochrane desde o início até julho de 2016, sem restrições de idioma. O período mais longo de estudo encontrado na literatura foi de quatro anos. Foi selecionado um artigo sobre empagliflozina, um artigo sobre dapagliflozina e um artigo sobre saxagliptina com dados faltantes. Após um ano de tratamento, mais de 50% dos pacientes apresentavam HbA1c >7%. A taxa de eficácia em quatro anos de empagliflozina (23%) foi melhor que dapagliflozina (5%) e saxagliptina (7%), porém com valores estatisticamente não significativos para HbA1c (7,4% e 7,3% entre gliflozinas) e dados ausentes para a saxaglifozina. No entanto, a empagliflozina teve um desempenho melhor do que a glimepirida no período de quatro anos (diferença média padronizada SMD 0,4, intervalo de confiança IC 95% 0,23 a 0,56). A falha do tratamento secundário com gliflozinas ocorre em menos de um ano de tratamento (menos de 50% dos pacientes com HbA1c >7%). A empagliflozina ofereceu melhor controle glicêmico em comparação com as sulfonilureias, mas semelhante à dapagliflozina.
Assuntos
Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Metformina , Compostos Benzidrílicos , Metanálise em Rede , HipoglicemiantesRESUMO
Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.
Assuntos
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Cardiotônicos/uso terapêutico , Miocárdio/metabolismo , Fragmentos de Peptídeos/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Fosfato de Sitagliptina/uso terapêutico , Angiotensina I/sangue , Angiotensina II/sangue , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cardiotônicos/farmacologia , Diástole/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Testes de Função Renal , Masculino , Miocárdio/patologia , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
SUMMARY OBJECTIVE To investigate the clinical efficacy and the possible mechanisms of saxagliptin in the treatment of type 2 diabetes mellitus (T2DM) combined with non-alcoholic fatty liver disease (NAFLD). METHODS A total of 95 T2DM and NAFLD patients were randomly divided into group A (saxagliptin group), group B (glimepiride group), and group C (glimepiride combined with polyene phosphatidylcholine group). RESULTS After intervention treatment for 24 w, body mass index (BMI), waist-to-hip ratio (WHR), glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), fasting insulin (FINS), homeostatic model assessment of insulin resistance (HOMA-IR), interleukin-6 (IL-6), triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), and quantitative detection of liver steatosis of study subjects were observed, the action of liver steatosis in subjects of groups A and C were significantly different from those of group B; however, there were no differences between groups A and C. The FINS, HOMA-IR, and IL-6 of subjects in group A was lower than those in groups B and C; however, there were no significant differences between the latter two groups. CONCLUSION For T2DM combined with NAFLD patients, the saxagliptin treatment could not only effectively control blood glucose but also attenuate insulin resistance and inflammatory injury of the liver to improve fatty liver further.
RESUMO OBJETIVO Investigar a eficácia clínica e os possíveis mecanismos da saxagliptina no tratamento do diabetes mellitus tipo 2 (DM2) associado à doença hepática gordurosa não alcoólica (DHGNA). MÉTODOS Um total de 95 DM2 combinados com pacientes com DHGNA foram aleatoriamente divididos em grupo A (grupo saxagliptina), grupo B (grupo glimepirida) e grupo C (glimepirida combinado com grupo fosfatidilcolina polienizada). RESULTADOS Após a intervenção tratamento por 24 w, índice de massa corporal (IMC), relação cintura-quadril (RCQ), hemoglobina glicada (HbA1c), glicemia de jejum (FPG), insulina de jejum (Fins), avaliação do modelo homeostático de insulina resistência (Homa-IR), interleucina-6 (IL-6), triglicérides (TG), colesterol total (CT), alanina aminotransferase (ALT), aspartato aminotransferase (AST), γ-glutamiltransferase (γ-GT) e detecção de esteatose hepática dos sujeitos do estudo foram observados. Ação de esteatose hepática de indivíduos nos grupos A e C foram significativamente diferentes do grupo B; no entanto, não houve diferenças entre os grupos A e C. Os grupos Fins, Homa-IR e IL-6 dos participantes do grupo A foram menores que os dos grupos B e C; no entanto, não houve diferenças significativas entre os dois últimos grupos. CONCLUSÃO Para o DM2 combinado com pacientes com DHGNA, o tratamento com saxagliptina pode não apenas controlar efetivamente a glicemia, mas também atenuar a resistência à insulina e a lesão inflamatória do fígado para melhorar ainda mais o fígado gorduroso.
Assuntos
Humanos , Masculino , Feminino , Fosfatidilcolinas/administração & dosagem , Compostos de Sulfonilureia/administração & dosagem , Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Glicemia , Resistência à Insulina , Adamantano/administração & dosagem , Índice de Massa Corporal , Resultado do Tratamento , Diabetes Mellitus Tipo 2/complicações , Dipeptídeos/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/complicações , Pessoa de Meia-IdadeRESUMO
AIMS: To evaluate the glucose variability, oxidative stress, metabolic and cardiovascular responses after an aerobic exercise session in diabetic patients on treatment with metformin plus vildagliptin or glibenclamide. METHODS: Parallel clinical trial including patients with type 2 diabetes treated with metformin plus vildagliptin or glibenclamide for 12â¯weeks. Glucose variability, oxidative stress, metabolic (plasma glucose, insulin and glucagon-like-peptide-1) and cardiovascular responses were evaluated at rest, during and after a 30â¯min aerobic exercise session (70% of the peak heart rate). RESULTS: Thirteen patients were included, seven in vildagliptin group (METV) and six in glibenclamide group (METG), baseline glycated hemoglobin (HbA1c) 8.8⯱â¯0.3%. Treatment reduced HbA1c (1.2% and 1.5% for METV and METG, respectively). The aerobic exercise session did not change glucose variability in both groups. A decrease in glucose during exercise recovery was found, with area under the curve lower in the METG vs. METV (pâ¯=â¯0.04). After the intervention, systolic blood pressure (SBP) decreased in both groups. Patients treated with vildagliptin showed lower SBP variability compared to those treated with glibenclamide. CONCLUSIONS: Besides improvement in glucose control and reduction of SBP obtained by both treatments, lower blood pressure variability was observed in patients receiving vildagliptin. Glucose variability remained unaffected by both interventions and the exercise session.
Assuntos
Adamantano/análogos & derivados , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Exercício Físico/fisiologia , Glucose/metabolismo , Glibureto/uso terapêutico , Nitrilas/uso terapêutico , Pirrolidinas/uso terapêutico , Adamantano/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , VildagliptinaRESUMO
Human dipeptidyl peptidase IV (hDDP-IV) has a considerable importance in inactivation of glucagon-like peptide-1, which is related to type 2 diabetes. One approach for the treatment is the development of small hDDP-IV inhibitors. In order to design better inhibitors, we analyzed 5-(aminomethyl)-6-(2,4-dichlrophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine and a set of 24 molecules found in the BindingDB web database for model designing. The analysis of their molecular properties allowed the design of a multiple linear regression model for activity prediction. Their docking analysis allowed visualization of the interactions between the pharmacophore regions and hDDP-IV. After both analyses were performed, we proposed a set of nine molecules in order to predict their activity. Four of them displayed promising activity, and thus, had their docking performed, as well as, the pharmacokinetic and toxicological study. Two compounds from the proposed set showed suitable pharmacokinetic and toxicological characteristics, and therefore, they were considered promising for future synthesis and in vitro studies.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Hipoglicemiantes/química , Sítios de Ligação , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/química , Humanos , Hipoglicemiantes/uso terapêutico , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
Discovery of new protease inhibitors may result in potential therapeutic agents or useful biotechnological tools. Obtainment of these molecules from natural sources requires simple, economic, and highly efficient purification protocols. The aim of this work was the obtainment of affinity matrices by the covalent immobilization of dipeptidyl peptidase IV (DPP-IV) and papain onto cellulose membranes, previously activated with formyl (FCM) or glyoxyl groups (GCM). GCM showed the highest activation grade (10.2 µmol aldehyde/cm2). We implemented our strategy for the rational design of immobilized derivatives (RDID) to optimize the immobilization. pH 9.0 was the optimum for the immobilization through the terminal α-NH2, configuration predicted as catalytically competent. However, our data suggest that protein immobilization may occur via clusters of few reactive groups. DPP-IV-GCM showed the highest maximal immobilized protein load (2.1 µg/cm2), immobilization percentage (91%), and probability of multipoint covalent attachment. The four enzyme-support systems were able to bind at least 80% of the reversible competitive inhibitors bacitracin/cystatin, compared with the available active sites in the immobilized derivatives. Our results show the potentialities of the synthesized matrices for affinity purification of protease inhibitors and confirm the robustness of the RDID strategy to optimize protein immobilization processes with further practical applications.
Assuntos
Celulose/química , Dipeptidil Peptidase 4/química , Enzimas Imobilizadas/química , Membranas Artificiais , Papaína/química , Adsorção , Animais , Carica , Galinhas , Concentração de Íons de Hidrogênio , Modelos Moleculares , Oxirredução , Sefarose , SuínosRESUMO
BACKGROUND/AIM: Amaranth is a source of several bioactive compounds, among which peptides with inhibitory activity upon dipeptidyl peptidase IV (DPP-IV) have been reported. However, there is no information about the action of amaranth DPP-IV-inhibitory peptides using in vivo models. The aim of this work was to evaluate the effect of amaranth consumption on plasma and kidney DPP-IV activity as well the changes in plasma proteome profile of streptozotocin (STZ)-induced hyperglycemic rats. METHODS: Rats were fed for 12 weeks with a diet containing 20% popped amaranth grain. Kidneys and blood samples were collected for lipid profile, DPP-IV activity and expression, and proteomic analysis. RESULTS: Total cholesterol and DPP-IV activity in plasma was increased in hyperglycemic rats, but this effect was reverted by amaranth consumption. Triacylglycerols were increased in the hyperglycemic group fed amaranth, and the highest levels of high-density lipoproteins were also observed in this group. These data correlated with the accumulation of apolipoprotein A-II in plasma. Accumulation of the antioxidant protein paraoxonase/arylesterase 1 in STZ-induced hyperglycemic rats was observed when amaranth was supplied in the diet. CONCLUSION: This study provides new insights into the molecular mechanisms by which amaranth exerts its beneficial health action in a hyperglycemic state.
Assuntos
Amaranthus , Arildialquilfosfatase/sangue , Hidrolases de Éster Carboxílico/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/dietoterapia , Dipeptidil Peptidase 4/sangue , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/enzimologia , Dipeptidil Peptidase 4/metabolismo , Alimento Funcional , Rim/enzimologia , Lipídeos/sangue , Masculino , Nutrigenômica , Proteoma/metabolismo , Ratos , Ratos WistarRESUMO
OBJECTIVE: The aim of the study was to assess the influence of overweight and obesity in youth on adipocytokines levels, inflammatory and oxidative markers. DESIGN AND METHODS: Cross-sectional study of 149 young adults (54 normal weight, 27 overweight, 68 obese).Clinical and biochemical parameters, including lipid profile, fasting glucose, insulin and HOMA were determined. The levels of adipocytokines(adiponectin, retinol-binding protein 4 (RBP4), and resistin), markers of inflammation (high-sensitivity C-reactive protein (hs-CRP) adenosine deaminase (ADA), dipeptidyl peptidase-IV (DPP-IV) activities, serum IL-6 levels and oxidative stress (malondialdehyde and ferric reducing antioxidant power - FRAP) were measured. RESULTS: Obese subjects presented significantly lower levels of Sulfhydryl groups (SH groups), adiponectin, HDL-C and the highest levels of RBP4, hs-CRP, resistin, IL-6, ADA, DPP-IV activities, and oxidative markers than compared to those who were of normal weight. There was a positive correlation between hs-CRP, IL-6, DDP-IV activity, anthropometric measurements and biochemical parameters. CONCLUSIONS: This analysis shows that resistin, RBP4, IL-6, ADA and DPP-IV activities and the reduction of adiponectin can promote inflammation, impairment of insulin sensitivity, and may contribute development of the pathways involved in obesity. These findings may hold promise in identifying new inflammatory markers, benchmarks that assist in the diagnosis and monitoring of patients with overweight and obese.
Assuntos
Biomarcadores/metabolismo , Mediadores da Inflamação/metabolismo , Obesidade/fisiopatologia , Sobrepeso/fisiopatologia , Estresse Oxidativo , Adenosina Desaminase/metabolismo , Adiponectina/metabolismo , Adolescente , Adulto , Glicemia/metabolismo , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Dipeptidil Peptidase 4/metabolismo , Feminino , Seguimentos , Humanos , Imunoensaio , Insulina/metabolismo , Resistência à Insulina , Interleucina-6/metabolismo , Masculino , Prognóstico , Resistina/metabolismo , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Adulto JovemRESUMO
CONTEXT: Syzygium cumini (Myrtaceae) presents antioxidant, anti-inflammatory, hypoglycemic and antibacterial effects; however, the cellular and molecular mechanisms of action in the immune system are not yet completely elucidated. OBJECTIVE: This study evaluates the in vitro effect of gallic acid and aqueous S. cumini leaf extract (ASc) on adenosine deaminase (ADA) and dipeptidyl peptidase IV (DPP-IV) activities, cell viability and oxidative stress parameters in lymphocytes exposed to 2, 2'-azobis-2-amidinopropane dihydrochloride (AAPH). MATERIALS AND METHODS: Lymphocytes were incubated with ASc (100 and 500 µg/ml) and gallic acid (50 and 200 µM) at 37 °C for 30 min followed by incubation with AAPH (1 mM) at 37 °C for 2 h. After the incubation time, the lymphocytes were used for determinations of ADA, DPP-IV and lactate dehydrogenase (LDH) activities, lipid peroxidation, protein thiol (P-SH) group levels and cellular viability by colorimetric methods. RESULTS: (i) HPLC fingerprinting of ASc revealed the presence of catechin, epicatechin, rutin, quercitrin, isoquercitrin, quercetin, kaempferol and chlorogenic, caffeic, gallic and ellagic acids; (ii) for the first time, ASc reduced the AAPH-induced increase in ADA activity, but no effect was observed on DPP-IV activity; (iii) ASc increased P-SH groups and cellular viability and decreased LDH activity, but was not able to reduce the AAPH-induced lipid peroxidation; (iv) gallic acid showed less protective effects than ASc. DISCUSSION AND CONCLUSION: ASc affects the purinergic system and may modulate adenosine levels, indicating that the extract of this plant exhibits immunomodulatory properties. ASc also may potentially prevent the cellular injury induced by oxidative stress, highlighting its cytoprotective effects.