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ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Persian medicine (TPM), people often use herbal infusions as a dosage form to treat diseases related to hyperglycemia, known as 'dam-kardeh'. Traditionally, herbal preparations of Eryngium bungei Boiss. (E. b), Tragopogon buphthalmoides (DC.) Boiss. (T. b), Salvia hydrangea DC. ex Benth. (S. h), and Juniperus polycarpos K. Koch. (J. p) are used to manage diabetes in Iran. However, there is no evidence of their effectiveness in controlling glucose levels and their mechanisms remain unclear. AIM OF THE STUDY: This study aimed to investigate whether traditional doses of plant infusions can have hypoglycemic and/or anti-hyperglycemic effects during fasting and/or postprandial states and establish the basis for future research on their potential mechanisms of action. MATERIALS AND METHODS: The effects of traditional doses of herbal extracts on blood glucose levels in STZ-NA-induced hyperglycemic rats were investigated in 2-h acute tests during fasting and postprandial states (with a glucose load). In addition, the potential inhibitory effect in vitro of enzymes involved in relevant pathways, such as gluconeogenesis (fructose-1,6-bisphosphatase, FBPase and glucose-6-phosphatase, G6Pase), carbohydrate breakdown (intestinal α-glucosidases), and insulin sensitivity (protein tyrosine phosphatase 1B, PTP-1B) was evaluated. Acute toxicity tests were carried out and HPLC-SQ-TOF was used to analyze the chemical profiles of the plant extracts. RESULTS: In the fasting state, T. b, S. h, and E. b were as effective as glibenclamide in lowering blood glucose levels in hyperglycemic rats. Moreover, all three suppressed G6Pase and FBPase enzymatic activity by 90-97% and 80-91%, respectively. On the other hand, significant postprandial hypoglycemic efficacy was observed for E. b, S. h, and T. b. Based on the AUC values, T. b caused a reduction comparable to the therapeutic efficacy of repaglinide. When investigating the possible mechanisms of action involved in this activity, E. b, S. h, and T. b showed significant inhibition of PTP-1B in vitro (>70%). Finally, all plant extracts showed no signs of acute toxicity. Several compounds that may contribute to biological activities were identified, including phenolic acids and flavonoid glycosides. CONCLUSIONS: The present study supports the traditional use of T. b, E. b and S. h for the control of diabetes in the fasting and postprandial state. Moreover, these plants were found to be rich in bioactive compounds with hypoglycemic and antihyperglycemic activities. On the other hand, J. p, showed a modest effect only in the fasting state and after 90 min. Further studies are needed to expand these results by analyzing the chemical composition and using complementary experimental models.
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Glucemia , Diabetes Mellitus Experimental , Ayuno , Hipoglucemiantes , Extractos Vegetales , Periodo Posprandial , Animales , Hipoglucemiantes/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/sangre , Masculino , Irán , Ratas , Medicina Persa , Ratas Wistar , Hiperglucemia/tratamiento farmacológico , Plantas Medicinales/química , Estreptozocina , Juniperus/químicaRESUMEN
Ripened pu-erh tea is known to have beneficial hypoglycemic properties. However, it remains unclear whether the bioactive peptides produced during fermentation are also related to hypoglycemic potential. This study aimed to identify hypoglycemic peptides in ripened pu-erh tea and to elucidate their bioactive mechanisms using physicochemical property prediction, molecular docking, molecular dynamics simulations, and cell experiments. Thirteen peptides were identified by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Among them, AADTDYRFS (AS-9) and AGDGTPYVR (AR-9) exhibited high α-glucosidase inhibitory activity, with half-maximal inhibitory concentration (IC50) values of 0.820 and 3.942 mg/mL, respectively. Molecular docking and dynamics simulations revealed that hydrogen bonding, hydrophobic interactions, and van der Waals forces assist peptides AS-9 and AR-9 in forming stable and tight complexes with α-glucosidase. An insulin-resistance (IR)-HepG2 cell model was established. AS-9 was non-toxic to IR-HepG2 cells and significantly increased the glucose consumption capacity, hexokinase, and pyruvate kinase activities of IR-HepG2 cells (p < 0.05). AS-9 alleviated glucose metabolism disorders and ameliorated IR by activating the IRS-1/PI3K/Akt signaling pathway and increasing the expression levels of MDM2, IRS-1, Akt, PI3K, GLUT4, and GSK3ß genes. In addition, no hemolysis of mice red blood cells red blood cells occurred at concentrations below 1 mg/mL. This work first explored hypoglycemic peptides in ripened pu-erh tea, providing novel insights for enhancing its functional value.
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Inhibidores de Glicósido Hidrolasas , Hipoglucemiantes , Simulación del Acoplamiento Molecular , Péptidos , Té , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Animales , Té/química , Humanos , Células Hep G2 , Péptidos/química , Péptidos/farmacología , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Ratones , Simulación de Dinámica Molecular , Resistencia a la Insulina , Transducción de Señal/efectos de los fármacos , Proteínas Sustrato del Receptor de Insulina/metabolismo , Espectrometría de Masas en Tándem , alfa-Glucosidasas/metabolismo , FermentaciónRESUMEN
Cardiovascular-kidney-metabolic health reflects the interactions between metabolic risk factors, chronic kidney disease, and the cardiovascular system. A growing body of literature suggests that metabolic syndrome (MetS) in individuals of normal weight is associated with a high prevalence of cardiovascular diseases and an increased mortality. The aim of this study was to establish a non-invasive preclinical model of MetS in support of future research focusing on the effects of novel antidiabetic therapies beyond glucose reduction, independent of obesity. Eighteen healthy adult Beagle dogs were fed an isocaloric Western diet (WD) for ten weeks. Biospecimens were collected at baseline (BAS1) and after ten weeks of WD feeding (BAS2) for measurement of blood pressure (BP), serum chemistry, lipoprotein profiling, blood glucose, glucagon, insulin secretion, NT-proBNP, angiotensins, oxidative stress biomarkers, serum, urine, and fecal metabolomics. Differences between BAS1 and BAS2 were analyzed using non-parametric Wilcoxon signed-rank testing. The isocaloric WD model induced significant variations in several markers of MetS, including elevated BP, increased glucose concentrations, and reduced HDL-cholesterol. It also caused an increase in circulating NT-proBNP levels, a decrease in serum bicarbonate, and significant changes in general metabolism, lipids, and biogenic amines. Short-term, isocaloric feeding with a WD in dogs replicated key biological features of MetS while also causing low-grade metabolic acidosis and elevating natriuretic peptides. These findings support the use of the WD canine model for studying the metabolic effects of new antidiabetic therapies independent of obesity.
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Modelos Animales de Enfermedad , Hipoglucemiantes , Síndrome Metabólico , Obesidad , Animales , Perros , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/metabolismo , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Masculino , Glucemia/metabolismo , Biomarcadores/sangre , Presión Sanguínea/efectos de los fármacos , Péptido Natriurético Encefálico/sangre , Péptido Natriurético Encefálico/metabolismo , Estrés Oxidativo/efectos de los fármacos , FemeninoRESUMEN
BACKGROUND: Pre-diabetes is an important risk factor for the development of type 2 diabetes and is common in Nigeria. Effective intervention can reverse the underlying pathogenesis of insulin resistance in pre-diabetes. This study aimed to determine and compare the impact of moderate exercise and metformin interventions on insulin resistance among participants with pre-diabetes. MATERIALS AND METHODS: Using a randomised placebo-controlled design, 54 Nigerians with pre-diabetes were selected using simple random sampling. They were offered metformin, moderate exercise or placebo treatment and followed up for 12 weeks. Insulin resistance was assessed before and after the interventions and the outcome was compared. RESULTS: Forty-nine participants with pre-diabetes completed the study. Participants in both the exercise and metformin groups had significantly decreased insulin resistance compared to placebo after 12 weeks of intervention. However, there was a decrease in insulin resistance by 77.3% (homeostasis model assessment-insulin resistance [HOMA-IR]) and an increase in insulin sensitivity by 81.2% (quantitative insulin sensitivity check index [QUICKI]) in the exercise group. In comparison, participants in the metformin group had a decrease in insulin resistance by 66.3% (HOMA-IR) and an increase in insulin sensitivity by 76.2% (QUICKI). CONCLUSION: Amongst Nigerians with pre-diabetes, both moderate exercise and metformin have significantly higher efficacy than placebo in improving insulin resistance. However, moderate exercise improved insulin resistance more than the metformin intervention. Participants in this study need to be followed up for a longer period to assess the long-term effects of these interventions.
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Hipoglucemiantes , Resistencia a la Insulina , Metformina , Estado Prediabético , Humanos , Metformina/uso terapéutico , Femenino , Masculino , Estado Prediabético/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Nigeria , Adulto , Persona de Mediana Edad , Ejercicio Físico/fisiología , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Terapia por Ejercicio/métodos , Resultado del Tratamiento , Pueblo de África OccidentalRESUMEN
There are numerous uses for the pharmacological effects of thiazolo-pyridine and its derivatives. The main objective of the study was to synthesis 10 novel derivatives of thiazolo[3,2-a] pyridine-6,8-dicarbonitrile with a 22-78% yield, with a focus on their potential anti-diabetic properties. We investigated the interactions between these compounds and the enzyme α-amylase through an in silico study involving molecular docking. According to the docking analysis results, the resulting compounds had advantageous inhibitory properties. With a docking score of -7.43 kcal/mol against the target protein, compound 4e performed best. The stability root-mean-square deviation (RMSD) showed that the complex stabilizes after 25 ns and with minor perturbation at 80. The RMSF values of the ligand-protein complex indicate that the following residues have interacted with compound 4e during the MD simulation: Trp58, Trp59, Tyr62, Gln63, His101, Val107, lle148, Asn152, Leu162, Thr163, Gly164, Leu165, Asp197, Ala198, Asp 236, Leu237, His299, Asp300, and His305. Moreover, the pharmacokinetic and drug-like properties of the synthesized derivatives of 2-arylamino-dihydroindeno[1,2-b] pyrrol-4(1H)-one suggest that they have the potential to be effective inhibitors of α-amylase and should be considered for further research. Nevertheless, it is crucial to ascertain the in vivo and in vitro effectiveness of these compounds through biochemical and structural investigations.
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Hipoglucemiantes , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Piridinas , alfa-Amilasas , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Piridinas/química , Piridinas/farmacología , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/metabolismo , alfa-Amilasas/química , Tiazoles/química , Tiazoles/farmacología , Tiazoles/síntesis química , Nitrilos/química , Nitrilos/farmacología , HumanosRESUMEN
Purpose: Effective mucosal delivery of drugs continues to pose a significant challenge owing to the formidable barrier presented by the respiratory tract mucus, which efficiently traps and clears foreign particulates. The surface characteristics of micelles dictate their ability to penetrate the respiratory tract mucus. In this study, polymeric micelles loaded with insulin (INS) were modified using mucus-penetrative polymers. Methods: We prepared and compared polyethylene glycol (PEG)-coated micelles with micelles where cell-penetrating peptide (CPP) is conjugated to PEG. Systematic investigations of the physicochemical and aerosolization properties, performance, in vitro release, mucus and cell penetration, lung function, and pharmacokinetics/pharmacodynamics (PK/PD) of polymeric micelles were performed to evaluate their interaction with the respiratory tract. Results: The nano-micelles, with a particle size of <100 nm, exhibited a sustained-release profile. Interestingly, PEG-coated micelles exhibited higher diffusion and deeper penetration across the mucus layer. In addition, CPP-modified micelles showed enhanced in vitro cell penetration. Finally, in the PK/PD studies, the micellar solution demonstrated higher maximum concentration (Cmax) and AUC0-8h values than subcutaneously administered INS solution, along with a sustained blood glucose-lowering effect that lasted for more than 8 h. Conclusion: This study proposes the use of mucus-penetrating micelle formulations as prospective inhalation nano-carriers capable of efficiently transporting peptides to the respiratory tract.
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Péptidos de Penetración Celular , Insulina , Micelas , Polietilenglicoles , Insulina/administración & dosificación , Insulina/farmacocinética , Insulina/química , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Animales , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacocinética , Humanos , Tamaño de la Partícula , Administración por Inhalación , Masculino , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Ratas Sprague-Dawley , Moco/química , Moco/metabolismo , Moco/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Glucemia/efectos de los fármacos , Glucemia/análisisRESUMEN
Metformin is the most commonly prescribed medication for treating type 2 diabetes (T2D). It is known that metformin can alter the gut microbiome, which influences the effectiveness of metformin treatment. We posited that if the gut microbiome, a reservoir of the resistome, is altered, then the resistome should change as well. To test this hypothesis, we reanalyzed microbiome data generated by Wu et al. (Nat Med 23(7):850-858, 2017), identifying antibiotic resistance genes (ARGs) and bacterial species. Through read-based analysis, we observed that the abundance of ARGs indeed changed in many samples treated with metformin. Moreover, the altered pattern was sufficiently heterogeneous across individual samples to allow subcategorization. We also found a strong correlation between the abundance of multidrug-resistant ARGs (MDR-ARGs) and the presence of E. coli. The contig-based analysis led to the same conclusion: an increase in MDR-ARGs due to metformin was associated with an increase in E. coli. In relation to this, we were able to confirm that the majority of MDR-ARGs are likely to originate from E. coli. These results suggest that metformin may have the potential side effect of increasing E. coli carrying ARGs, particularly MDR-ARGs, which could be a concern in T2D therapy that relies on metformin.
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Diabetes Mellitus Tipo 2 , Escherichia coli , Microbioma Gastrointestinal , Metformina , Metformina/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/microbiología , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Humanos , Hipoglucemiantes/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Antibacterianos/farmacologíaRESUMEN
Limonoids are important constituents of citrus that have a significant impact on promoting human health. Therefore, the primary focus of this research was to assess the overall limonoid content and isolate limonoids from Adalia lemon (Citrus limon L.) peels for their potential use as antioxidants and anti-diabetic agents. The levels of limonoid aglycones in the C. limon peel extract were quantified through a colorimetric assay, revealing a concentration of 16.53 ± 0.93 mg/L limonin equivalent. Furthermore, the total concentration of limonoid glucosides was determined to be 54.38 ± 1.02 mg/L. The study successfully identified five isolated limonoids, namely limonin, deacetylnomilin, nomilin, obacunone 17-O-ß-D-glucopyranoside, and limonin 17-O-ß-D-glucopyranoside, along with their respective yields. The efficacy of the limonoids-rich extract and the five isolated compounds was evaluated at three different concentrations (50, 100, and 200 µg/mL). It was found that both obacunone 17-O-ß-D-glucopyranoside and limonin 17-O-ß-D-glucopyranoside possessed the highest antioxidant, free radical scavenging, and anti-diabetic activities, followed by deacetylnomilin, and then the limonoids-rich extract. The molecular dynamic simulations were conducted to predict the behavior of the isolated compounds upon binding to the protein's active site, as well as their interaction and stability. The results revealed that limonin 17-O-ß-D-glucopyranoside bound to the protein complex system exhibited a relatively more stable conformation than the Apo system. The analysis of Solvent Accessible Surface Area (SASA), in conjunction with the data obtained from Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), and Radius of Gyration (ROG) computations, provided further evidence that the limonin 17-O-ß-D-glucopyranoside complex system remained stable within the catalytic domain binding site of the human pancreatic alpha-amylase (HPA)-receptor. The research findings suggest that the limonoids found in Adalia lemon peels have the potential to be used as effective natural substances in creating innovative therapeutic treatments for conditions related to oxidative stress and disorders in carbohydrate metabolism.
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Antioxidantes , Citrus , Hipoglucemiantes , Limoninas , Simulación de Dinámica Molecular , Extractos Vegetales , Limoninas/farmacología , Limoninas/química , Citrus/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Antioxidantes/farmacología , Antioxidantes/química , Simulación del Acoplamiento Molecular , Humanos , Frutas/química , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/metabolismo , BenzoxepinasRESUMEN
INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a healthcare issue of growing concern. Its development is multifactorial, and it is more commonly seen in obese patients. In those circumstances, intracellular lipid overload ensues, resulting in oxidative stress that might be responsible for progression toward steatohepatitis. Novel therapeutic approaches that are effective in weight management are expected to improve the course of MASLD. One of the potential mechanisms involved in such protective properties may relate to the reduction in oxidative stress. MATERIAL AND METHODS: The induction of steatosis and the assessment of oxidative stress level and expression of antioxidant enzymes (superoxide dismutase - SOD, glutathione peroxidase - GPx and catalase - Cat) in HepG2 hepatoma cell line subjected to glucagon and exenatide treatment. RESULTS: Exenatide monotherapy successfully reduced lipid accumulation by 25%. Significant reductions in markers of oxidative stress (reactive oxygen species and malondialdehyde) were obtained in cells subjected to combined treatment with glucagon and exenatide (by 24 and 21%, respectively). Reduced burden of oxidative stress was associated with elevated expression of SOD and GPx but not Cat. CONCLUSIONS: Combined activation of glucagon-like peptide-1 (GLP-1) and glucagon receptors reduces oxidative stress in HepG2 steatotic cell cultures. This observation may stem from increased antioxidative potential.
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Catalasa , Exenatida , Glucagón , Glutatión Peroxidasa , Estrés Oxidativo , Superóxido Dismutasa , Humanos , Exenatida/farmacología , Estrés Oxidativo/efectos de los fármacos , Células Hep G2 , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/efectos de los fármacos , Catalasa/metabolismo , Glucagón/metabolismo , Glucagón/farmacología , Superóxido Dismutasa/metabolismo , Antioxidantes/farmacología , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Ponzoñas/farmacología , Péptidos/farmacología , Hipoglucemiantes/farmacología , Especies Reactivas de Oxígeno/metabolismoAsunto(s)
Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Vildagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metformina/uso terapéutico , Metformina/farmacología , Vildagliptina/farmacología , Vildagliptina/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Glucósidos/uso terapéutico , Glucósidos/farmacología , Glucósidos/efectos adversos , Pirrolidinas/uso terapéutico , Pirrolidinas/farmacología , Pirrolidinas/efectos adversos , Quimioterapia Combinada/métodos , Nitrilos/uso terapéutico , Nitrilos/efectos adversos , Adamantano/análogos & derivados , Adamantano/uso terapéutico , Adamantano/efectos adversos , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacologíaRESUMEN
Background: The twigs and roots of Erythrina subumbrans (Hassk). Merr. Was reported to possess antidiabetic activity by reducing the activity of α-glucosidase and α-amylase. TNF-α is a pro-inflammatory cytokine in obesity and diabetes mellitus (DM). It inhibits the action of insulin, causing insulin resistance. Adiponectin is an anti-inflammatory peptide synthesized in white adipose tissue (WAT) and its high levels are linked with a decreased risk of DM. However, information about the effect of Erythrina subumbrans (Hassk). Merr. on insulin resistance are still lacking. Purpose: To obtain the effects of the ethanol extract of E. subumbrans (Hassk) Merr. leaves (EES) in improving insulin resistance conditions. Methods: The leaves were collected at Ciamis, West Java, Indonesia, and were extracted using ethanol 96%. The effects of EES were studied in fructose-induced adult male Wistar rats by performing the insulin tolerance test (ITT) and assessing blood glucose, TNF-α, adiponectin, and FFA levels. The number of WAT and BAT of the adipose tissues was also studied. The total phenols and flavonoids in EES were determined by the spectrophotometric method and the presence of quercetin in EES was analyzed using the LC-MS method. Results: EES significantly reduced % weight gain, TNF-α levels, and increased adiponectin levels in fructose-induced Wistar rats. EES significantly reduced the FFA levels of fructose-induced Wistar rats and significantly affected the formation of BAT similar to that of metformin. All rats in EES and metformin groups improved insulin resistance as proven by higher ITT values (3.01 ± 0.91 for EES 100 mg/kg BW; 3.01 ± 1.22 for EES 200 mg/kg BW; 5.86 ± 3.13 for EES 400 mg/kg BW; and 6.44 ± 2.58 for metformin) compared with the fructose-induced group without treatment (ITT = 2.62 ± 1.38). EES contains polyphenol compounds (2.7638 ± 0.0430 mg GAE/g extract), flavonoids (1.9626 ± 0.0152 mg QE/g extract), and quercetin 0.246 µg/mL at m/z 301.4744. Conclusion: Erythrina subumbrans (Hassk). Merr. extract may have the potential to be further explored for its activity in improving insulin resistance conditions. However, further studies are needed to confirm its role in alleviating metabolic disorders.
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Erythrina , Fructosa , Resistencia a la Insulina , Extractos Vegetales , Ratas Wistar , Animales , Ratas , Masculino , Erythrina/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Fructosa/farmacología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/aislamiento & purificación , Hojas de la Planta/química , Relación Dosis-Respuesta a DrogaRESUMEN
Exceeding a healthy weight significantly elevates the likelihood of developing type 2 diabetes (T2DM). A commercially available singular constituent, available as either purified vitexin or iso-vitexin, has been associated with a decreased risk of T2DM, but its synergistic effect has not been reported yet. Vitexin and iso-vitexin were extracted using an ethanol-based solvent from mung bean seed coat (MBCE) and subsequently purified using preparative liquid chromatography (Prep-LC). Eleven mixture ratios of vitexin and/or iso-vitexin were determined for their antioxidant and antihyperglycemic activities. The 1:1.5 ratio of vitexin to iso-vitexin from MBCE demonstrated the most synergistic effects for enzyme inhibition and glucose uptake in HepG2 cells within an insulin-resistant system, while these ratios exhibited a significantly lower antioxidant capacity than that of each individual component. In a gut model system, the ratio of 1:1.5 (vitexin and iso-vitexin) regulated the gut microbiota composition in overweight individuals by decreasing the growth of Enterobacteriaceae and Enterococcaceae, while increasing in Ruminococcaceae and Lachnospiraceae. The application of vitexin/iso-vitexin for 24 h fermentation enhanced a high variety of abundances of 21 genera resulting in five genera of Parabacteroides, Ruminococcus, Roseburia, Enterocloster, and Peptacetobacter, which belonged to the phylum Firmicutes, exhibiting high abundant changes of more than 5%. Only two genera of Proteus and Butyricicoccus belonging to Proteobacteria and Firmicutes decreased. The findings suggest that these phytochemicals interactions could have synergistic effects in regulating glycemia, through changes in antihyperglycemic activity and in the gut microbiota in overweight individuals. This optimal ratio can be utilized by industries to formulate more potent functional ingredients for functional foods and to create nutraceutical supplements aimed at reducing the risk of T2DM in overweight individuals.
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Apigenina , Microbioma Gastrointestinal , Hipoglucemiantes , Sobrepeso , Semillas , Vigna , Apigenina/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Hipoglucemiantes/farmacología , Semillas/química , Masculino , Células Hep G2 , Diabetes Mellitus Tipo 2 , Antioxidantes/farmacología , Extractos Vegetales/farmacología , FemeninoRESUMEN
The goal of our study was to identify and assess the functionally significant SNPs with potentially important roles in the development of type 2 diabetes mellitus (T2DM) and/or their effect on individual response to antihyperglycemic medication with metformin. We applied a bioinformatics approach to identify the regulatory SNPs (rSNPs) associated with allele-asymmetric binding and expression events in our paired ChIP-seq and RNA-seq data for peripheral blood mononuclear cells (PBMCs) of nine healthy individuals. The rSNP outcomes were analyzed using public data from the GWAS (Genome-Wide Association Studies) and Genotype-Tissue Expression (GTEx). The differentially expressed genes (DEGs) between healthy and T2DM individuals (GSE221521), including metformin responders and non-responders (GSE153315), were searched for in GEO RNA-seq data. The DEGs harboring rSNPs were analyzed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We identified 14,796 rSNPs in the promoters of 5132 genes of human PBMCs. We found 4280 rSNPs to associate with both phenotypic traits (GWAS) and expression quantitative trait loci (eQTLs) from GTEx. Between T2DM patients and controls, 3810 rSNPs were detected in the promoters of 1284 DEGs. Based on the protein-protein interaction (PPI) network, we identified 31 upregulated hub genes, including the genes involved in inflammation, obesity, and insulin resistance. The top-ranked 10 enriched KEGG pathways for these hubs included insulin, AMPK, and FoxO signaling pathways. Between metformin responders and non-responders, 367 rSNPs were found in the promoters of 131 DEGs. Genes encoding transcription factors and transcription regulators were the most widely represented group and many were shown to be involved in the T2DM pathogenesis. We have formed a list of human rSNPs that add functional interpretation to the T2DM-association signals identified in GWAS. The results suggest candidate causal regulatory variants for T2DM, with strong enrichment in the pathways related to glucose metabolism, inflammation, and the effects of metformin.
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Diabetes Mellitus Tipo 2 , Estudio de Asociación del Genoma Completo , Metformina , Polimorfismo de Nucleótido Simple , Humanos , Metformina/farmacología , Metformina/uso terapéutico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Sitios de Carácter Cuantitativo , Biología Computacional/métodos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Regiones Promotoras Genéticas , MultiómicaRESUMEN
GLP-1 receptor agonists, which were initially intended to treat type 2 diabetes patients, have demonstrated promise as an adjuvant therapy for type 1 diabetes (T1D). These medications can manage T1D by improving ß-cell function, reducing glucose fluctuation, and providing cardioprotective effects. Recent research suggests that boosting cell proliferation and lowering apoptosis can help maintain the bulk of ß-cells. Furthermore, GLP-1 receptor agonists have potent anti-inflammatory characteristics, improving immunological control and lowering systemic inflammation, both of which are critical for reducing autoimmune damage in T1D. Beyond glucose control, these agonists have neuroprotective qualities and aid in weight management. Combining these medications with insulin could significantly change how T1D is managed. The clinical data and biological mechanisms discussed in this review support the potential use of GLP-1 receptor agonists in T1D.
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Diabetes Mellitus Tipo 1 , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Animales , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Insulina/uso terapéutico , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
Chalcones have been utilized for centuries as foods and medicines across various cultures and traditions worldwide. This paper concisely overviews their biosynthesis as specialized metabolites in plants and their significance, potential, efficacy, and possibility as future medicines. This is followed by a more in-depth exploration of naturally occurring chalcones and their corresponding mechanisms of action in human bodies. Based on their mechanisms of action, chalcones exhibit many pharmacological properties, including antioxidant, anti-inflammatory, anticancer, antimalarial, antiviral, and antibacterial properties. Novel naturally occurring chalcones are also recognized as potential antidiabetic drugs, and their effect on the GLUT-4 transporter is investigated. In addition, they are examined for their anti-inflammatory effects, focusing on chalcones used for future pharmaceutical utilization. Chalcones also bind to specific receptors and toxins that prevent bacterial and viral infections. Chalcones exhibit physiological protective effects on the biological degradation of different systems, including demyelinating neurodegenerative diseases and preventing hypertension or hyperlipidemia. Chalcones that are/were in clinical trials have been included as a separate section. By revealing the many biological roles of chalcones and their impact on medicine, this paper underlines the significance of naturally occurring chalcones and their extension to patient care, providing the audience with an index of topic-relevant information.
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Chalconas , Chalconas/farmacología , Chalconas/química , Humanos , Ensayos Clínicos como Asunto , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/uso terapéuticoAsunto(s)
Receptor del Péptido 1 Similar al Glucagón , Hipolipemiantes , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipolipemiantes/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & controlRESUMEN
Background and aims: To analyze the effect of oral metformin on changes in gut microbiota characteristics and metabolite composition in normal weight type 2 diabetic patients. Methods: T2DM patients in the cross-sectional study were given metformin for 12 weeks. Patients with unmedicated T2DM were used as a control group to observe the metrics of T2DM patients treated with metformin regimen. 16S rDNA high-throughput gene sequencing of fecal gut microbiota of the study subjects was performed by llumina NovaSeq6000 platform. Targeted macro-metabolomics was performed on 14 cases of each of the gut microbiota metabolites of the study subjects using UPLC-MS/MS technology. Correlations between the characteristics of the gut microbiota and its metabolites, basic human parameters, glycolipid metabolism indicators, and inflammatory factors were analyzed using spearman analysis. Results: Glycolipid metabolism indexes and inflammatory factors were higher in normal-weight T2DM patients than in the healthy population (P<0.05), but body weight, BMI, waist circumference, and inflammatory factor concentrations were lower in normal-weight T2DM patients than in obese T2DM patients (P<0.05). Treatment with metformin in T2DM patients improved glycolipid metabolism, but the recovery of glycolipid metabolism was more pronounced in obese T2DM patients. None of the differences in α-diversity indexes were statistically significant (P>0.05), and the differences in ß-diversity were statistically significant (P <0.05). Community diversity and species richness recovered after metformin intervention compared to before, and were closer to the healthy population. We found that Anaerostipes/Xylose/Ribulose/Xylulose may play an important role in the treatment of normal-weight T2DM with metformin by improving glycemic lipids and reducing inflammation. And Metformin may play a role in obese T2DM through Romboutsia, medium-chain fatty acids (octanoic acid, decanoic acid, and dodecanoic acid). Conclusion: Gut microbial dysbiosis and metabolic disorders were closely related to glucose-lipid metabolism and systemic inflammatory response in normal-weight T2DM patients. Metformin treatment improved glucose metabolism levels, systemic inflammation levels in T2DM patients, closer to the state of healthy population. This effect may be mediated by influencing the gut microbiota and microbial host co-metabolites, mainly associated with Anaerostipes and xylose/Ribulose/Xylulose. Metformin may exert its effects through different pathways in normal-weight versus obese T2DM patients.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Hipoglucemiantes , Metformina , Humanos , Metformina/uso terapéutico , Metformina/farmacología , Metformina/administración & dosificación , Microbioma Gastrointestinal/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiología , Masculino , Femenino , Persona de Mediana Edad , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Estudios Transversales , Adulto , Administración Oral , Heces/microbiología , Heces/químicaRESUMEN
Incretin gut hormones, especially glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), raise a huge interest in diabetology. GLP-1 receptor agonists have gained a privileged role in the management of type 2 diabetes (T2D). They improve glucose control without inducing hypoglycaemia, while promoting weight loss. Furthermore, they protect people with T2D against atherosclerotic cardiovascular disease and contribute to reduce the risk of heart failure and chronic kidney disease, two other common complications of T2D. A recent innovation consists in the development of co-agonists that target both GIP and GLP-1 receptors. Whereas the co-infusion of GIP and GLP-1 failed to further reduce hyperglycaemia of T2D compared to GLP-1 single infusion, tirzepatide, an original dual unimolecular biaised GIP/GLP-1 agonist, showed a remarkable improvement of glucose control in the SURPASS programme in patients with T2D. Consequently, it is now commercialized in many countries for the management of T2D. GLP-1/glucagon (GCG) co-agonists and GIP/GLP-1/GCG poly-agonists are currently in development, aiming to benefit from the favourable effects of GCG on energy expenditure and liver lipid metabolism, while mitigating the hyperglycaemic effects of this hormone thanks to balanced effects of GLP-1 and/or GIP. They might occupy in the future an interesting place in the management of obesity and its metabolic complications among which T2D and liver steatosis.
Les hormones digestives à effet incrétine, en particulier le «glucagon-like peptide-1¼ (GLP-1) et le «glucose-dependent insulinotropic polypeptide¼ (GIP) suscitent un intérêt considérable en diabétologie. Les agonistes des récepteurs du GLP-1 ont acquis une place de choix dans la prise en charge des patients avec un diabète de type 2 (DT2). Ils améliorent le contrôle glycémique, sans provoquer des hypoglycémies, tout en faisant perdre du poids. De plus, ils protègent contre les maladies cardiovasculaires athéromateuses. Enfin, ils contribuent à réduire le risque d'insuffisance cardiaque et de maladie rénale chronique, deux autres complications fréquentes du DT2. Une innovation récente consiste dans le développement de co-agonistes ciblant à la fois les récepteurs du GLP-1 et du GIP. Alors que la co-infusion de GIP et de GLP-1 ne réduit pas davantage l'hyperglycémie du DT2 qu'une perfusion isolée de GLP-1, le tirzépatide, un agoniste biaisé unimoléculaire original à effet double sur les récepteurs GIP/GLP-1, a montré une amélioration remarquable du contrôle glycémique, tout en favorisant l'amaigrissement, dans le programme SURPASS chez le patient avec DT2. Ce médicament est maintenant commercialisé dans de nombreux pays. Des co-agonistes GLP-1/glucagon (GCG) et des poly-agonistes GIP/GLP-1/GCG sont actuellement développés, profitant des effets favorables du glucagon sur les dépenses énergétiques et le métabolisme lipidique hépatique, tout en maîtrisant les effets hyperglycémiants de cette hormone grâce aux actions balancées du GLP-1 et/ou du GIP. Ils pourraient occuper à l'avenir une place intéressante dans le traitement de l'obésité et ses complications métaboliques dont le DT2 et la stéatopathie hépatique.
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Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Incretinas , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Incretinas/uso terapéutico , Incretinas/farmacología , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Polipéptido Inhibidor Gástrico/uso terapéutico , Polipéptido Inhibidor Gástrico/agonistas , Polipéptido Inhibidor Gástrico/farmacología , Péptido 1 Similar al Glucagón/agonistas , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
The Target-Based Virtual Screening approach is widely employed in drug development, with docking or molecular dynamics techniques commonly utilized for this purpose. This systematic review (SR) aimed to identify in silico therapeutic targets for treating Diabetes mellitus (DM) and answer the question: What therapeutic targets have been used in in silico analyses for the treatment of DM? The SR was developed following the guidelines of the Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis, in accordance with the protocol registered in PROSPERO (CRD42022353808). Studies that met the PECo strategy (Problem, Exposure, Context) were included using the following databases: Medline (PubMed), Web of Science, Scopus, Embase, ScienceDirect, and Virtual Health Library. A total of 20 articles were included, which not only identified therapeutic targets in silico but also conducted in vivo analyses to validate the obtained results. The therapeutic targets most frequently indicated in in silico studies were GLUT4, DPP-IV, and PPARγ. In conclusion, a diversity of targets for the treatment of DM was verified through both in silico and in vivo reassessment. This contributes to the discovery of potential new allies for the treatment of DM.