RESUMO
BACKGROUND: The first-line treatment for polycystic ovary syndrome (PCOS) is lifestyle modification. However, it is currently unknown whether digital medicine can assist patients with PCOS in maintaining a healthy lifestyle while alleviating PCOS symptoms. OBJECTIVE: This study aims to evaluate the efficacy of WeChat-based digital intervention versus metformin treatment in women with PCOS and insulin resistance. METHODS: A total of 80 women with PCOS and insulin resistance were recruited from an endocrinology clinic and randomly assigned to receive either a WeChat-based digital intervention (n=40, 50%) or metformin (n=40, 50%) for 12 weeks. The WeChat-based digital intervention consisted of 3 modules; a coach assisted the patients in using the intervention. The primary outcome was the change in a homeostatic model assessment for insulin resistance. At baseline and after the 12-week intervention, anthropometric parameters, menstruation frequency, sex hormone levels, metabolic factors, and body fat distribution were measured in the clinic. Furthermore, self-assessed web-based questionnaires on diet, exercise, sleep, anxiety, and depression were obtained. RESULTS: A total of 72 participants completed the follow-up (for a 90% follow-up rate), including 35 of 40 (88%) participants from the digital intervention group and 37 of 40 (93%) participants from the metformin group. The homeostatic model assessment for insulin resistance in the digital intervention group was significantly improved after 12 weeks of treatment with a mean change of -0.93 (95% CI -1.64 to -0.23), but no statistical difference was observed between the groups (least squares mean difference -0.20; 95% CI -0.98 to 0.58; P=.62). Both digital intervention and metformin treatment significantly improved menstruation frequency (digital intervention: P<.001; metformin: P<.001) and reduced body weight (digital intervention: P<.001; metformin: P<.001) and total fat mass (digital intervention: P<.001; metformin: P<.001). Furthermore, the digital intervention had a significant advantage over metformin in improving waist circumference (least squares mean difference -1.84; 95% CI -3.44 to -0.24; P=.03), waist-to-hip ratio (least squares mean difference -0.02; 95% CI -0.03 to 0.00; P=.03), total fat mass (least squares mean difference -1.59; 95% CI -2.88 to -0.30; P=.02), and dehydroepiandrosterone sulfate (least squares mean difference -69.73; 95% CI -129.70 to -9.75; P=.02). In terms of safety, the main adverse events were sensations of hunger in the digital intervention group (2/40, 5%) and gastrointestinal adverse events in the metformin group (12/40, 30%). CONCLUSIONS: Our data suggest that digital intervention is an effective treatment option for patients with PCOS, with an efficacy comparable to that of metformin, and that it can also alleviate the negative effects of medications and make it easier and more efficient to adhere to lifestyle treatments. WeChat-based digital interventions have the potential to provide a new path for the improvement and health of women with PCOS in China. TRIAL REGISTRATION: ClinicalTrials.gov NCT05386706; https://clinicaltrials.gov/study/NCT05386706.
Assuntos
Resistência à Insulina , Metformina , Síndrome do Ovário Policístico , Humanos , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/terapia , Feminino , Metformina/uso terapêutico , Adulto , Adulto Jovem , Hipoglicemiantes/uso terapêuticoRESUMO
AIMS: To examine longitudinal and dose-d ependent associations between dietary fiber intake and various clinical outcomes over 48 weeks of pharmacological treatment in T2DM patients. METHODS: In this secondary analysis, we used data from the MARCH trial, which was designed to compare the efficacy of acarbose or metformin monotherapy as the initial therapy in Chinese patients newly diagnosed with T2DM. Dietary data were obtained using a 24-h dietary recall method to evaluate the intakes of dietary fiber from different sources as well as the carbohydrate-to-fiber ratio. RESULTS: A total of 551 newly-diagnosed patients with T2DM complete dietary records (286 in the acarbose group and 265 in the metformin group) were included. Higher intake of total fiber and whole grain fiber was positively associated with better ß-cell function, insulin sensitivity and postprandial glycemic control under acarbose treatment. Higher intake of legume fiber was associated with better glycemic control under both acarbose and metformin treatment but with better weight loss only under metformin treatment. A high-carbohydrate-low-fiber diet was associated with worse glycemic control and lower HDL-C under acarbose treatment but with higher insulin sensitivity and better weight loss under metformin treatment. CONCLUSIONS: The notable effects of various dietary fibers when combined with different oral glucose-lowering medications should be considered to maximize therapeutic benefit.
Assuntos
Acarbose , Glicemia , Fatores de Risco Cardiometabólico , Diabetes Mellitus Tipo 2 , Fibras na Dieta , Hipoglicemiantes , Metformina , Redução de Peso , Humanos , Acarbose/uso terapêutico , Fibras na Dieta/administração & dosagem , Fibras na Dieta/uso terapêutico , Metformina/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Redução de Peso/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Glicemia/análise , Glicemia/metabolismo , Estudos Longitudinais , Resistência à Insulina , Idoso , Controle Glicêmico/métodos , Adulto , ChinaRESUMO
Polycystic ovary syndrome (PCOS) is a heterogeneous condition, defined by oligo-/anovulation, hyper-androgenism and/or polycystic ovaries. Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes, which severely compromise the clinical course of affected women. Yet, therapeutic options remain mostly symptomatic and of limited efficacy for the metabolic and reproductive alterations of PCOS. We report here the hormonal, metabolic and gonadal responses to the glucagon-like peptide-1 (GLP1)-based multi-agonists, GLP1/Estrogen (GLP1/E), GLP1/gastric inhibitory peptide (GLP1/GIP) and GLP1/GIP/Glucagon, in two mouse PCOS models, with variable penetrance of metabolic and reproductive traits, and their comparison with metformin. Our data illustrate the superior efficacy of GLP1/E vs. other multi-agonists and metformin in the management of metabolic complications of PCOS; GLP1/E ameliorates also ovarian cyclicity in an ovulatory model of PCOS, without direct estrogenic uterotrophic effects. In keeping with GLP1-mediated brain targeting, quantitative proteomics reveals changes in common and distinct hypothalamic pathways in response to GLP1/E between the two PCOS models, as basis for differential efficiency. Altogether, our data set the basis for the use of GLP1-based multi-agonists, and particularly GLP1/E, in the personalized management of PCOS.
Assuntos
Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon , Metformina , Síndrome do Ovário Policístico , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Feminino , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Metformina/uso terapêutico , Metformina/farmacologia , Camundongos , Humanos , Polipeptídeo Inibidor Gástrico/metabolismo , Estrogênios/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Resistência à Insulina , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Hipoglicemiantes , Metformina , Humanos , Metformina/uso terapêutico , Metformina/farmacologia , Metformina/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Masculino , Feminino , Pessoa de Meia-Idade , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Estudos Transversais , Adulto , Administração Oral , Fezes/microbiologia , Fezes/químicaRESUMO
Therapy targeting the BRAF-MEK cascade created a treatment revolution for patients with BRAF mutant advanced melanoma. Unfortunately, 80% patients treated will progress by 5 years follow-up. Thus, it is imperative we study mechanisms of melanoma progression and therapeutic resistance. We created a scRNA (single cell RNA) atlas of 128,230 cells from 18 tumors across the treatment spectrum, discovering melanoma cells clustered strongly by transcriptome profiles of patients of origins. Our cell-level investigation revealed gains of 1q and 7q as likely early clonal events in metastatic melanomas. By comparing patient tumors and their derivative cell lines, we observed that PD1 responsive tumor fraction disappears when cells are propagated in vitro. We further established three anti-BRAF-MEK treatment resistant cell lines using three BRAF mutant tumors. ALDOA and PGK1 were found to be highly expressed in treatment resistant cell populations and metformin was effective in targeting the resistant cells. Our study suggests that the investigation of patient tumors and their derivative lines is essential for understanding disease progression, treatment response and resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Melanoma , Proteínas Proto-Oncogênicas B-raf , Análise de Célula Única , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Linhagem Celular Tumoral , Fosfoglicerato Quinase/genética , Fosfoglicerato Quinase/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transcriptoma , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Mutação , Metformina/farmacologia , Metformina/uso terapêuticoAssuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Glucosídeos , Hipoglicemiantes , Metformina , Fosfato de Sitagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Glucosídeos/uso terapêutico , Glucosídeos/administração & dosagem , Metformina/uso terapêutico , Metformina/administração & dosagem , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/administração & dosagem , Fosfato de Sitagliptina/uso terapêutico , Fosfato de Sitagliptina/administração & dosagem , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Resultado do Tratamento , Masculino , Feminino , Pessoa de Meia-Idade , Glicemia/análise , Hemoglobinas Glicadas/análise , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , IdosoAssuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Glucosídeos , Hipoglicemiantes , Metformina , Fosfato de Sitagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Glucosídeos/uso terapêutico , Glucosídeos/administração & dosagem , Metformina/uso terapêutico , Metformina/administração & dosagem , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/administração & dosagem , Fosfato de Sitagliptina/uso terapêutico , Fosfato de Sitagliptina/administração & dosagem , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Resultado do Tratamento , Masculino , Feminino , Pessoa de Meia-Idade , Glicemia/análise , Hemoglobinas Glicadas/análise , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , IdosoRESUMO
Diabetic nephropathy (DN) can be prevented with early therapeutic intervention in diabetic patients. Recent investigations suggest that ß-amyrin, a pentacyclic triterpenoid, could offer significant benefits with its potential antihyperglycemic and nephroprotective effects. We investigated the protective effects of ß-amyrin alone and combined it with metformin, the cornerstone therapy for diabetes, using a hyperglycemic adult Zebrafish (ZF) model. The ZF were subjected to hyperglycemia by immersing them in 111 mM glucose solutions. Treatment efficacy was assessed by measuring serum glucose and insulin levels and antioxidant, ER stress, apoptosis, and proinflammatory markers. ZF kidneys were also studied for immunohistochemistry and histopathology. Results revealed that the combined treatment of ß-amyrin and metformin resulted in a significant decrease (p ≤ 0.05) in blood glucose levels to 104.54 ± 1.63 mg/dL, in comparison to 388.75 ± 4.32 mg/dL in the untreated diseased control group. The reduction in hyperglycemia was more pronounced than treatment with either compound alone. Moreover, treatment with the combination restored renal function in diseased ZF, leading to significantly lower (p ≤ 0.05) serum urea (SU: 19.57 ± 1.61 mg/dL) and serum creatinine (SC: 0.56 ± 0.02 mg/dL) values compared to treatment with ß-amyrin (SU:27.02 ± 0.96 mg/dL; SC: 0.7 ± 0.01 mg/dL) or metformin (SU: 24.53 ± 1.29 mg/dL; SC: 0.6 ± 0.02 mg/dL) alone. The treatment also reduced oxidative stress markers, apoptosis and ER stress markers, and proinflammatory cytokines. Histopathological analysis showed improved renal architecture with significantly lower (p ≤ 0.05) renal tubular injury scores with the combination than with individual treatment. This study provides novel insights into the combined therapeutic effects of ß-amyrin and metformin in mitigating hyperglycemia-induced renal damage through key molecular pathways, highlighting a potentially effective therapeutic strategy for diabetic nephropathy. The findings hold promising translational relevance for developing combination therapies aimed at improving clinical outcomes in diabetic nephropathy patients.
Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Hiperglicemia , Hipoglicemiantes , Rim , Metformina , Ácido Oleanólico , Estresse Oxidativo , Peixe-Zebra , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Apoptose/efeitos dos fármacos , Ácido Oleanólico/farmacologia , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Dano ao DNA/efeitos dos fármacos , Sinergismo Farmacológico , Modelos Animais de Doenças , Glicemia/efeitos dos fármacos , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Quimioterapia CombinadaRESUMO
BACKGROUND: Metformin is a hypoglycaemic medication that has been proposed to treat or prevent preeclampsia. Combining national birth data from Scotland and Sweden, we investigated whether metformin used during pregnancy was associated with an altered risk of developing a hypertensive disorder of pregnancy. METHODS: We utilised data from two population-based cohorts: Scotland (2012-2018) and Sweden (2007-2019). Nulliparous women with gestational diabetes or type 2 diabetes who had birth outcome data linked with medications prescribed during pregnancy were included. The association between metformin prescription and hypertensive disorders of pregnancy was characterised using inverse probability weighted regression analysis, adjusting for variables that predict metformin use and potential confounders. Adverse neonatal outcomes were included as secondary outcomes. Results from both countries were then combined in a meta-analysis using a random effects model. RESULTS: The Scottish cohort included 3859 women with gestational diabetes or type 2 diabetes. Of these women, 30.8% (n = 1187) received at least one metformin prescription during pregnancy. For Sweden, 7771 women with gestational diabetes were included where 19.3% (1498) used metformin during pregnancy. Metformin prescription was not associated with an altered risk of any hypertensive disorder of pregnancy (Scotland adjusted relative risk (aRR) 0.88 [95% confidence interval (CI) 0.66-1.19]; Sweden aRR 1.08 [95% CI 0.86-1.37]) or preeclampsia (Scotland aRR 1.02 [95% CI 0.66-1.60]; Sweden aRR 1.00 [95% CI 0.72-1.39]). Combining adjusted results in a meta-analysis produced similar findings, with a pooled RR of 0.98 (95% CI 0.79-1.18) for any hypertensive disorder and RR 1.01 ([95% CI 0.73-1.28]) for preeclampsia. For neonatal outcomes, metformin was associated with a reduced risk of birthweight > 4500 g in Scotland (aRR 0.39 [95% CI 0.21-0.71]) but not in Sweden. There was no association between metformin and preterm birth or birthweight < 3rd or < 10th percentiles. Pooling results from both countries, metformin was not associated with adverse neonatal outcomes, including preterm birth (RR 1.00 [95% CI 0.89-1.13]), and birthweight < 10th percentile (RR 0.82 [95% CI 0.60-1.13]) or < 3rd percentile (RR 0.78 [95% CI 0.41-1.48]). CONCLUSIONS: In this two-country analysis, metformin use in pregnancy among women with diabetes was not associated with an altered risk of developing any hypertensive disorder of pregnancy. In the combined meta-analysis, metformin was not associated with an altered risk of adverse neonatal outcomes.
Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Hipoglicemiantes , Metformina , Pré-Eclâmpsia , Humanos , Metformina/uso terapêutico , Metformina/efeitos adversos , Feminino , Gravidez , Adulto , Pré-Eclâmpsia/epidemiologia , Suécia/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/tratamento farmacológico , Escócia/epidemiologia , Estudos de Coortes , Recém-NascidoRESUMO
Metformin, a widely used anti-diabetic agent, has shown significant anti-cancer properties as reported in in various cancers, including acute myeloid leukemia. However, the detailed mechanisms by which metformin influences acute myeloid leukemia remain unrevealed. Employing a synergistic approach of network pharmacology and experimental validation, this study systematically identifies and analyzes potential metformin targets and AML-related genes. These findings are then cross-referenced with biomedical databases to construct a target-gene network, providing insights into metformin's pharmacodynamics in AML treatment. Protein-Protein Interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses are utilized. Results show metformin's effectiveness in inhibiting AML cell proliferation and inducing apoptosis through the AKT/HIF1A/PDK1 signaling pathway. This research provides insights into metformin's clinical application in AML treatment.
Assuntos
Proliferação de Células , Leucemia Mieloide Aguda , Metformina , Farmacologia em Rede , Metformina/farmacologia , Metformina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Farmacologia em Rede/métodos , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Redes Reguladoras de Genes/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genéticaRESUMO
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.
Assuntos
Terapia por Exercício , Hipoglicemiantes , Resistência à Insulina , Metformina , Estado Pré-Diabético , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Nigéria , Estado Pré-Diabético/tratamento farmacológico , Resultado do Tratamento , População da África OcidentalRESUMO
BACKGROUND: Endometrial hyperplasia (EH) is a hyperplastic endometrial lesion with irregular gland size, increased glands, and increased glandular interstitial ratio. During follow-up, some EH progressed further to endometrial cancer. It is crucial to provide timely treatment for EH and improve the overall prognosis of EH patients. METHODS: We searched the PubMed, ClinicalTrials.gov., and Embase databases for studies published from their inception to March 31, 2023. The methodological quality of each study was evaluated in accordance with the Cochrane Collaboration's tool for assessing the risk of bias. The RevMan5.3 software provided by the Cochrane Collaboration was used for direct meta-analysis statistical analysis; and the relative risk and 95% confidence interval along with the mean difference and 95% confidence interval, were used as evaluation indexes. RESULTS: We included 21 randomized controlled trials involving a total of 2276 women with EH, 6 studies were of high quality, and 15 were of moderate quality. The blinding of subjects and intervention providers was identified as the main source of potential bias. Six interventions were addressed in the network meta-analysis: medroxyprogesterone acetate (MPA), plus metformin, norethisterone (NET), levonorgestrel-releasing intrauterine system (LNG-IUD), megestrol acetate, and other drugs. In the direct meta-analysis, we found the probability of endometrial complete regression (CR) in the LNG-IUD group to be significantly higher than those in the NET. In the network meta-analysis, we found the probability of CR in the NET group to be significantly lower than those in the MPA and plus metformin groups, the probability of CR in the LNG-IUD group to be significantly higher than those in the NET, the probability of CR in the other drugs group to be significantly higher than those in the LNG-IUD. The NET group had the lowest incidences of endometrial complete regression, plus metformin could have a better outcome. CONCLUSION: According to the 21 randomized controlled trials included in this study, MPA is the most effective for EH endometrial outcome when applied as a single agent, while the combination of metformin can achieve a more significant effect.
Assuntos
Hiperplasia Endometrial , Metanálise em Rede , Humanos , Feminino , Hiperplasia Endometrial/tratamento farmacológico , Hiperplasia Endometrial/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Metformina/uso terapêutico , Acetato de Medroxiprogesterona/uso terapêutico , Acetato de Medroxiprogesterona/administração & dosagem , Levanogestrel/uso terapêutico , Levanogestrel/administração & dosagemRESUMO
Telomere dysfunction is a well-known molecular trigger of senescence and has been associated with various age-related diseases, including atherosclerosis. However, the mechanisms involved have not yet been elucidated, and the extent to which telomeres contribute to atherosclerosis is unknown. Therefore, we investigated the mechanism of metformin-induced telomere stabilization and the ability of metformin to inhibit vascular smooth muscle cell (VSMC) senescence caused by advanced atherosclerosis. The present study revealed that metformin inhibited the phenotypes of atherosclerosis and senescence in VSMCs. Metformin increased the phosphorylation of AMPK-dependent PGC-1α and thus increased telomerase activity and the protein level of TERT in OA-treated VSMCs. Mechanistically, the phosphorylation of AMPK and PGC-1α by metformin not only enhanced telomere function but also increased the protein level of TERT, whereas TERT knockdown accelerated the development of atherosclerosis and senescent phenotypes in OA-treated VSMCs regardless of metformin treatment. Furthermore, the in vivo results showed that metformin attenuated the formation of atherosclerotic plaque markers in the aortas of HFD-fed ApoE KO mice. Although metformin did not reduce plaque size, it inhibited the phosphorylation of the AMPK/PGC-1α/TERT signaling cascade, which is associated with the maintenance and progression of plaque formation, in HFD-fed ApoE KO mice. Accordingly, metformin inhibited atherosclerosis-associated phenotypes in vitro and in vivo. These observations show that the enhancement of telomere function by metformin is involved in specific signaling pathways during the progression of atherosclerosis. These findings suggest that telomere stabilization by metformin via the AMPK/p-PGC-1α pathway might provide a strategy for developing therapeutics against vascular diseases such as atherosclerosis.
Assuntos
Proteínas Quinases Ativadas por AMP , Aterosclerose , Metformina , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Transdução de Sinais , Telômero , Metformina/farmacologia , Metformina/uso terapêutico , Animais , Aterosclerose/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Aterosclerose/etiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Transdução de Sinais/efeitos dos fármacos , Telômero/metabolismo , Telômero/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Masculino , Telomerase/metabolismo , Telomerase/genética , Fosforilação/efeitos dos fármacos , Progressão da Doença , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Camundongos Knockout , Homeostase do Telômero/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
BACKGROUND: Antidiabetic therapies are effective, but could indirectly modify the inflammatory response in the ocular microenvironment; therefore, a study was developed to evaluate the inflammatory cytokine profile in the vitreous humor of diabetic patients with retinopathy under treatment with antidiabetic drugs. METHODS: Observational, comparative, retrospective, cross-sectional study. Interleukins 1ß, 6, 8, 10, and tumor necrosis factor-alpha (TNFα) were evaluated in the vitreous humor obtained from patients with type 2 diabetes mellitus, proliferative diabetic retinopathy, and concomitant retinal detachment or vitreous hemorrhage, and who were already on antidiabetic treatment with insulin or metformin + glibenclamide. The quantification analysis of each cytokine was performed by the cytometric bead array (CBA) technique; medians and interquartile ranges were obtained, and the results were compared between groups using the Mann-Whitney U test, where a p-value < 0.05 was considered significant. RESULTS: Thirty-eight samples; quantification of TNFα concentrations was higher in the group of patients administered insulin, while interleukin-8 was lower; in the metformin + glibenclamide combination therapy group, it occurred inversely. In the stratified analysis, the highest concentrations of interleukin-8 and TNFα occurred in patients with vitreous hemorrhage; however, the only statistical difference existed in patients with retinal detachment, whose TNFα concentration in the combined therapy group was the lowest value found (53.50 (33.03-86.66), p = 0.03). Interleukins 1ß, 6, and 10 were not detected. CONCLUSION: Interleukin-8 and TNFα concentrations are opposite between treatment groups; this change is more accentuated in patients with proliferative diabetic retinopathy and vitreous hemorrhage, where the highest concentrations of both cytokines are found, although only TNFα have statistical difference.
Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Hipoglicemiantes , Interleucina-8 , Fator de Necrose Tumoral alfa , Corpo Vítreo , Humanos , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Masculino , Corpo Vítreo/metabolismo , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Fator de Necrose Tumoral alfa/metabolismo , Estudos Retrospectivos , Hipoglicemiantes/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Interleucina-8/metabolismo , Insulina/uso terapêutico , Metformina/uso terapêutico , Glibureto/uso terapêutico , Quimioterapia CombinadaRESUMO
INTRODUCTION: Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. Glycaemic control decreases the risk of adverse pregnancy outcomes for the affected pregnant individual and the infant exposed in utero. One in four individuals with GDM will require pharmacotherapy to achieve glycaemic control. Injectable insulin has been the mainstay of pharmacotherapy. Oral metformin is an alternative option increasingly used in clinical practice. Both insulin and metformin reduce the risk of adverse pregnancy outcomes, but comparative effectiveness data from a well-characterised, adequately powered study of a diverse US population remain lacking. Because metformin crosses the placenta, long-term safety data, in particular, the risk of childhood obesity, from exposed children are also needed. In addition, the patient-reported experiences of individuals with GDM requiring pharmacotherapy remain to be characterised, including barriers to and facilitators of metformin versus insulin use. METHODS AND ANALYSIS: In a two-arm open-label, pragmatic comparative effectiveness randomised controlled trial, we will determine if metformin is not inferior to insulin in reducing adverse pregnancy outcomes, is comparably safe for exposed individuals and children, and if patient-reported factors, including facilitators of and barriers to use, differ between metformin and insulin. We plan to recruit 1572 pregnant individuals with GDM who need pharmacotherapy at 20 US sites using consistent diagnostic and treatment criteria for oral metformin versus injectable insulin and follow them and their children through delivery to 2 years post partum. More information is available at www.decidestudy.org. ETHICS AND DISSEMINATION: The Institutional Review Board at The Ohio State University approved this study (IRB: 2024H0193; date: 7 December 2024). We plan to submit manuscripts describing the results of each study aim, including the pregnancy outcomes, the 2-year follow-up outcomes, and mixed-methods assessment of patient experiences for publication in peer-reviewed journals and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NCT06445946.
Assuntos
Diabetes Gestacional , Hipoglicemiantes , Insulina , Metformina , Humanos , Metformina/uso terapêutico , Metformina/administração & dosagem , Diabetes Gestacional/tratamento farmacológico , Gravidez , Feminino , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Insulina/uso terapêutico , Insulina/administração & dosagem , Estados Unidos , Resultado da Gravidez , Pesquisa Comparativa da Efetividade , Estudos Multicêntricos como Assunto , AdultoRESUMO
BACKGROUND: We performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). PATIENTS AND METHODS: SPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant. RESULTS: We did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15-0.28) versus without concomitant statins (aHR: 0.31 [0.24-0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS. CONCLUSIONS: In this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS.
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Neoplasias de Próstata Resistentes à Castração , Tioidantoínas , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Tioidantoínas/uso terapêutico , Idoso , Metformina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Aspirina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pessoa de Meia-Idade , Antagonistas de Androgênios/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêuticoRESUMO
Drug repurposing in cancer taps into the capabilities of existing drugs, initially designed for other ailments, as potential cancer treatments. It offers several advantages over traditional drug discovery, including reduced costs, reduced development timelines, and a lower risk of adverse effects. However, not all drug classes align seamlessly with a patient's condition or long-term usage. Hence, repurposing of chronically used drugs presents a more attractive option. On the other hand, metabolic reprogramming being an important hallmark of cancer paves the metabolic regulators as possible cancer therapeutics. This review emphasizes the importance and offers current insights into the repurposing of antidiabetic drugs, including metformin, sulfonylureas, sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), thiazolidinediones (TZD), and α-glucosidase inhibitors, against various types of cancers. Antidiabetic drugs, regulating metabolic pathways have gained considerable attention in cancer research. The literature reveals a complex relationship between antidiabetic drugs and cancer risk. Among the antidiabetic drugs, metformin may possess anti-cancer properties, potentially reducing cancer cell proliferation, inducing apoptosis, and enhancing cancer cell sensitivity to chemotherapy. However, other antidiabetic drugs have revealed heterogeneous responses. Sulfonylureas and TZDs have not demonstrated consistent anti-cancer activity, while SGLT2 inhibitors and DPP-4 inhibitors have shown some potential benefits. GLP-1RAs have raised concerns due to possible associations with an increased risk of certain cancers. This review highlights that further research is warranted to elucidate the mechanisms underlying the potential anti-cancer effects of these drugs and to establish their efficacy and safety in clinical settings.
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Antineoplásicos , Reposicionamento de Medicamentos , Hipoglicemiantes , Neoplasias , Humanos , Reposicionamento de Medicamentos/métodos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
PURPOSE: Pancreatic cancer remains a significant public health challenge, with poor long-term outcomes due to the lack of effective treatment options. Repurposing commonly used clinical drugs, such as ACE inhibitors, ARBs, CCBs, and metformin, may enhance the efficacy of chemotherapy and offer a promising therapeutic strategy for improving patient outcomes. METHODS: A retrospective analysis of concomitant treatment with ACE-Is, ARBs, CCBs, and metformin alongside gemcitabine chemotherapy in patients with pancreatic cancer was conducted. Treatment responses were evaluated, with overall survival (OS) estimated using the Kaplan-Meier method. Additionally, the Cox proportional hazards model was employed to assess the impact of these specific agents on patient survival. RESULTS: 4628 patients with various stages of pancreatic cancer were identified in the database between 2007 and 2016. The estimated overall survival (OS) in the analyzed group was 6.9 months (95% CI 6.4-7). The use of any of the analyzed drugs was associated with a significant improvement in mOS of 7.5 months (95% CI 6.8-7.8) vs. 6.7 months (95% CI 6.4-7.0) for patients who did not have additional treatment (p < 0.0001). ARBs, ACE-Is, CCBs, and metformin varied in their effectiveness in prolonging mOS among patients. The longest mOS of 8.9 months (95% CI 7.7-11.6) was observed in patients receiving additional therapy with ARBs, while the shortest mOS of 7.7 months (95% CI 6.5-8.9) was achieved by patients receiving metformin. In the adjusted Cox analysis, metformin was associated with a significantly weaker effect on mOS (p = 0.029). A particularly interesting trend in prolonging 5-year survival was demonstrated by ARBs and CCBs with 14.1% (95% CI 9-22%) and 14.8% (95% CI 11.1-19.6%), respectively, compared to patients not taking these drugs, who achieved a 5-year OS of 3.8% (95% CI 3.2-4.4%). CONCLUSION: Our results demonstrate a significant positive impact of ARBs, ACE inhibitors, and CCBs on survival in patients with pancreatic cancer treated with gemcitabine. The addition of these inexpensive and relatively safe drugs in patients with additional comorbidities may represent a potential therapeutic option in this indication. However, prospective clinical trials to evaluate the optimal patient population and further studies to determine the potential impact of these agents on chemotherapy are necessary.
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Antagonistas de Receptores de Angiotensina , Protocolos de Quimioterapia Combinada Antineoplásica , Bloqueadores dos Canais de Cálcio , Desoxicitidina , Gencitabina , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Masculino , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Bloqueadores dos Canais de Cálcio/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Sinergismo Farmacológico , Metformina/uso terapêutico , Idoso de 80 Anos ou mais , AdultoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , Metformina , Polimorfismo de Nucleotídeo Único , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Locos de Características Quantitativas , Biologia Computacional/métodos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regiões Promotoras Genéticas , MultiômicaRESUMO
As the most common and aggressive primary malignant brain tumor, glioblastoma is still lacking a satisfactory curative approach. The standard management consisting of gross total resection followed by radiotherapy and chemotherapy with temozolomide only prolongs patients' life moderately. In recent years, many therapeutics have failed to give a breakthrough in GBM treatment. In the search for new treatment solutions, we became interested in the repurposing of existing medicines, which have established safety profiles. We focused on the possible implementation of well-known drugs, metformin, and arginine. Metformin is widely used in diabetes treatment, but arginine is mainly a cardiovascular protective drug. We evaluated the effects of metformin and arginine on total DNA methylation, as well as the oxidative stress evoked by treatment with those agents. In glioblastoma cell lines, a decrease in 5-methylcytosine contents was observed with increasing drug concentration. When combined with temozolomide, both guanidines parallelly increased DNA methylation and decreased 8-oxo-deoxyguanosine contents. These effects can be explained by specific interactions of the guanidine group with m5CpG dinucleotide. We showed that metformin and arginine act on the epigenetic level, influencing the foreground and potent DNA regulatory mechanisms. Therefore, they can be used separately or in combination with temozolomide, in various stages of disease, depending on desired treatment effects.