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Journal of Hematology & Oncology Dec 2023In retrospective studies, metformin use has been associated with better clinical outcomes in diabetic patients with advanced, well-differentiated neuroendocrine tumors...
In retrospective studies, metformin use has been associated with better clinical outcomes in diabetic patients with advanced, well-differentiated neuroendocrine tumors (WDNETs). However, prospective evidence of metformin safety and activity is lacking. Here, we conducted the first-in-human phase Ib MetNET2 trial to investigate the safety and antitumor activity of metformin in combination with the somatostatin analog lanreotide autogel (ATG) in both diabetic and non-diabetic patients with advanced WDNETs of the gastrointestinal (GI) or thoracic tract. Enrolled patients received lanreotide ATG 120 mg plus oral metformin, up to a maximum dosage of 2550 mg/day. We enrolled 20 patients, of whom 18 (90%) and 2 (10%) had WDNETs of the GI and thoracic tract, respectively. Fourteen patients (70%) were non-diabetic. With a 5% incidence of SAEs, the study met its primary objective of demonstrating treatment safety. With a median follow-up of 39 months (95% CI 28-NE), median PFS was 24 months (95% CI 16-NE), with 12-month and 24-month PFS probability of 75% (95% CI 58-97) and 49% (95% CI 31-77), respectively. We found no statistically significant PFS differences between diabetic and non-diabetic patients. Among exploratory analyses, the presence of tumor genomic alterations in DNA damage pathways was associated with trend towards worse PFS, whereas a precocious reduction of HOMA-IR index and plasma cholesterol concentration showed a trend towards an association with better PFS. In conclusion, metformin plus lanreotide ATG is a safe and well tolerated combination treatment that is associated with promising antitumor activity in both non-diabetic and diabetic patients with WDNETs, and that warrants further investigation in larger clinical trials.
Topics: Humans; Metformin; Neuroendocrine Tumors; Pancreatic Neoplasms; Retrospective Studies; Prospective Studies; Somatostatin; Diabetes Mellitus; Lung
PubMed: 38098114
DOI: 10.1186/s13045-023-01510-9 -
European Review For Medical and... Sep 2023Metformin is a medication used to treat type 2 diabetes by inhibiting hepatic glucose production through adenosine monophosphate-activated protein kinase (AMPK)...
OBJECTIVE
Metformin is a medication used to treat type 2 diabetes by inhibiting hepatic glucose production through adenosine monophosphate-activated protein kinase (AMPK) activation. Autophagy is closely related to the homeostasis and stress mechanisms of the body. In recent years, much research has arisen on therapeutic methods utilizing autophagy mechanisms to treat diagnoses such as metabolic diseases, tumors, and Alzheimer's disease. This study thus aimed to investigate the effects of metformin treatment on the differentiation of osteoclasts and changes in AMPK mechanisms, which play an important role in regulating energy homeostasis, and mTOR, a highly conserved kinase that regulates autophagy.
MATERIALS AND METHODS
Experimentation, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, tartrate-resistant acid phosphate (TRAP) staining, pit formation assay, immunofluorescence, western blotting, and real-time polymerase chain reaction (PCR) was performed to investigate the effects of metformin on osteoclast differentiation. Additionally, to investigate its association with AMPK and pathways, the AMPK inhibitor compound C and mammalian targets of rapamycin (mTOR) activator leucine were used to examine the expression of osteoclast- or autophagy-related proteins, genes, and TRAP-positive cells.
RESULTS
Metformin showed no cytotoxic effects on mouse osteoblastic cell lines (MC3T3-E1) and murine macrophage cell lines (RAW264.7) but did inhibit osteoclast differentiation. Furthermore, metformin was found to inhibit osteoclast differentiation through AMPK activation and mTOR inhibition. In turn, AMPK inhibition using compound C promoted osteoclast differentiation, and mTOR activation using leucine inhibited autophagy and osteoclast differentiation.
CONCLUSIONS
Metformin activates the AMPK pathway while functioning as an activator of mTOR, thereby leading to the inhibition of autophagy and osteoclast differentiation.
Topics: Animals; Mice; AMP-Activated Protein Kinases; Diabetes Mellitus, Type 2; Leucine; Metformin; Osteoclasts; TOR Serine-Threonine Kinases
PubMed: 37782190
DOI: 10.26355/eurrev_202309_33801 -
Respiratory Research Jul 2023Chronic lung allograft dysfunction (CLAD) directly causes an abysmal long-term prognosis after lung transplantation (LTx), but effective and safe drugs are not...
BACKGROUND
Chronic lung allograft dysfunction (CLAD) directly causes an abysmal long-term prognosis after lung transplantation (LTx), but effective and safe drugs are not available. Metformin exhibits high therapeutic potential due to its antifibrotic and immunomodulatory effects; however, it is unclear whether metformin exerts a therapeutic effect in CLAD. We sought to investigate the effect of metformin on CLAD based on rat models.
METHODS
Allogeneic LTx rats were treated with Cyclosporin A (CsA) in the first week, followed by metformin, CsA, or vehicle treatment. Syngeneic LTx rats received only vehicles. All rats were sacrificed on post-transplant week 4. Pathology of lung graft, spleen, and thymus, extent of lung fibrosis, activity of profibrotic cytokines and signaling pathway, adaptive immunity, and AMPK activity were then studied.
RESULTS
Allogeneic recipients without maintenance CsA treatment manifested CLAD pathological characteristics, but these changes were not observed in rats treated with metformin. For the antifibrotic effect, metformin suppressed the fibrosis extent and profibrotic cytokine expression in lung grafts. Regarding immunomodulatory effect, metformin reduced T- and B-cell infiltration in lung grafts, spleen and thymus weights, the T- and B-cell zone areas in the spleen, and the thymic medullary area. In addition, metformin activated AMPK in lung allografts and in α-SMA cells and T cells in the lung grafts.
CONCLUSIONS
Metformin attenuates CLAD in rat models, which could be attributed to the antifibrotic and immunomodulatory effects. AMPK activation suggests the potential molecular mechanism. Our study provides an experimental rationale for further clinical trials.
Topics: Animals; Rats; Metformin; AMP-Activated Protein Kinases; Thorax; Cytokines; Lung; Allografts
PubMed: 37516880
DOI: 10.1186/s12931-023-02492-5 -
Acta Bio-medica : Atenei Parmensis Aug 2023the COVID-19 infection, caused by severe Coronavirus 2 syndrome (Sars-Cov-2), immediately appeared to be the most tragic global pandemic event of the twentieth century.... (Meta-Analysis)
Meta-Analysis
the COVID-19 infection, caused by severe Coronavirus 2 syndrome (Sars-Cov-2), immediately appeared to be the most tragic global pandemic event of the twentieth century. Right from the start of the pandemic, diabetic patients treated with metformin experienced a reduction in mortality and complications from COVID-19 compared to those with different treatments or no treatment. Objective The main objective of the study was to observe the effects of metformin in hospitalized subjects infected with COVID-19. Specifically, the outcomes of hospitalization in Intensive Care Units or death were examined. Materials and Methods A specific research PICOS was developed and the Pubmed, Embase and Scopus databases were consulted down to April 30, 2022. To estimate the extent of the metformin effect and risk of severity in SARS-CoV-2 infection, the Odd Ratio (OR) with 95% Confidence Interval (CI) published by the authors of the selected systematic reviews was used. Results from five systematic reviews 36 studies were selected. The final meta-analysis showed that thanks to treatment with metformin, DM2 patients affected by COVID-19 had protection against risk of disease severity, complications (ES 0.80; 95% CI) and mortality (ES 0.69; 95% CI). Conclusions More in-depth studies on the use of metformin, compared to other molecules, may be required to understand the real protective potential of the drug against negative outcomes caused by COVID-19 infection in DM2 patients.
Topics: Humans; COVID-19; SARS-CoV-2; Systematic Reviews as Topic; Databases, Factual; Metformin
PubMed: 37695186
DOI: 10.23750/abm.v94iS3.14405 -
Redox Biology Aug 2023Diabetic retinopathy (DR) is a major cause of blindness in adult, and the accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR....
Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1.
Diabetic retinopathy (DR) is a major cause of blindness in adult, and the accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a precursor of AGEs. Although the therapeutic potential of metformin for retinopathy disorders has recently been elucidated, possibly through AMPK activation, it remains unknown how metformin directly affects the MGO-induced stress response in retinal pigment epithelial cells. Therefore, in this study, we compared the effects of metformin and the AMPK activator A769662 on MGO-induced DR in mice, as well as evaluated cytotoxicity, mitochondrial dynamic changes and dysfunction in ARPE-19 cells. We found MGO can induce mitochondrial ROS production and mitochondrial membrane potential loss, but reduce cytosolic ROS level in ARPE-19 cells. Although these effects of MGO can be reversed by both metformin and A769662, we demonstrated that reduction of mitochondrial ROS production rather than restoration of cytosolic ROS level contributes to cell protective effects of metformin and A769662. Moreover, MGO inhibits AMPK activity, reduces LC3II accumulation, and suppresses protein and gene expressions of MFN1, PGC-1α and TFAM, leading to mitochondrial fission, inhibition of mitochondrial biogenesis and autophagy. In contrast, these events of MGO were reversed by metformin in an AMPK-dependent manner as evidenced by the effects of compound C and AMPK silencing. In addition, we observed an AMPK-dependent upregulation of glyoxalase 1, a ubiquitous cellular enzyme that participates in the detoxification of MGO. In intravitreal drug-treated mice, we found that AMPK activators can reverse the MGO-induced cotton wool spots, macular edema and retinal damage. Functional, histological and optical coherence tomography analysis support the protective actions of both agents against MGO-elicited retinal damage. Metformin and A769662 via AMPK activation exert a strong protection against MGO-induced retinal pigment epithelial cell death and retinopathy. Therefore, metformin and AMPK activator can be therapeutic agents for DR.
Topics: Mice; Animals; Metformin; AMP-Activated Protein Kinases; Pyruvaldehyde; Reactive Oxygen Species; Magnesium Oxide; Lactoylglutathione Lyase; Mitochondria; Retinal Diseases; Glycation End Products, Advanced; Epithelial Cells; Retinal Pigments
PubMed: 37348156
DOI: 10.1016/j.redox.2023.102786 -
Journal of Clinical Oncology : Official... Dec 2023JCO Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin (... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer.
JCO Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin ( placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; = .13. These included 48 contralateral invasive breast cancers (27 metformin 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; = .40 and 136 new nonbreast primary cancers (75 metformin 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.
Topics: Female; Humans; Breast Neoplasms; Canada; Double-Blind Method; Metformin
PubMed: 37695982
DOI: 10.1200/JCO.23.00296 -
Journal of Medicine and Life Nov 2023Polycystic ovary syndrome (PCOS) is one of the most prevalent metabolic diseases during female reproductive life, often associated with insulin resistance and... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of combined metformin and cabergoline versus metformin alone on ovarian and hormonal activities in Iraqi patients with PCOS and hyperprolactinemia: a randomized clinical trial.
Polycystic ovary syndrome (PCOS) is one of the most prevalent metabolic diseases during female reproductive life, often associated with insulin resistance and hyperprolactinemia. The efficacy of metformin and cabergoline for managing PCOS remains debated in the literature. This three-arm interventional study in Iraq assessed the effects of these drugs on body mass index (BMI), hormonal balance, and uterine artery blood flow in 75 women with PCOS and hyperprolactinemia. Participants were randomized into three groups: metformin (500 mg twice daily), cabergoline (0.5 mg weekly), and a combination of both, with 25 patients in each group. Baseline and 90-day follow-up characteristics included BMI, serum hormonal levels, and ultrasound features. Metformin resulted in significant weight reduction (p=0.038); however, the addition of cabergoline caused a more significant reduction in body mass index (p=0.001). The combined treatment significantly lowered testosterone levels (p=0.008). In addition, this combination significantly reduced the level of LH (p=0.043) and increased the level of FSH (p=0.047). The results suggest that metformin and cabergoline when used together, act synergistically and safely to reduce BMI, testosterone, and LH levels while increasing FSH levels. Furthermore, this combination improved endometrial blood flow and ovulation in women with PCOS.
Topics: Female; Humans; Polycystic Ovary Syndrome; Metformin; Cabergoline; Luteinizing Hormone; Iraq; Hyperprolactinemia; Follicle Stimulating Hormone; Testosterone
PubMed: 38406771
DOI: 10.25122/jml-2023-0317 -
International Immunopharmacology Nov 2023Metformin, a first-line drug for type-2 diabetes, displays pleiotropic effects on inflammation, aging, and cancer. Obesity triggers a low-grade chronic inflammation...
Metformin, a first-line drug for type-2 diabetes, displays pleiotropic effects on inflammation, aging, and cancer. Obesity triggers a low-grade chronic inflammation leading to insulin resistance, characterized by increased pro-inflammatory cytokines produced by adipocytes and infiltrated immune cells, which contributes to metabolic syndrome. We investigated metformin's differentiation and immunoregulatory properties of human umbilical cord-mesenchymal stem cells (UC-MSC), as cellular basis of its beneficial role in metabolic dysfunctions. Isolation, characterization and multilineage differentiation of UC-MSC were performed using standard protocols and flow-cytometry. Metformin effects on UC-MSC growth was assessed by colony formation and MTT assay, gene and protein expression by qRT-PCR, and western blot analysis. Proliferation of peripheral blood mononuclear cells (PBMCs) co-cultured with metformin-treated UC-MSC-conditioned media was evaluated by dye dilution assay. We show that metformin decreases proliferation and colony formation of UC-MSCs and enhances their adipogenic lineage commitment. Metformin (3 mM) increases PPARγ and downregulates FABP4 mRNA both in basal and in adipogenic culture conditions; however, the modulation of PPARγ expression is unrelated to the antiproliferative effects. Moreover, metformin inhibits UC-MSC inflammatory activity reducing the expression of IL-6, MCP-1, and COX-2. Conditioned media, collected from metformin-treated UC-MSCs, down-regulate CD3 T lymphocyte growth in stimulated PBMCs and, in particular, reduce the CD8 T cell population. These results indicate that metformin may favor new adipocyte formation and potentiate immune suppressive properties of UC-MSCs. Thus, adipose tissue regeneration and anti-inflammatory activity may represent possible mechanisms by which metformin exerts its positive effect on lipid metabolism.
Topics: Humans; Culture Media, Conditioned; Immunosuppressive Agents; Leukocytes, Mononuclear; Metformin; PPAR gamma; Cell Differentiation; Umbilical Cord; Inflammation; Mesenchymal Stem Cells; Cells, Cultured
PubMed: 37844465
DOI: 10.1016/j.intimp.2023.111078 -
The Journal of Maternal-fetal &... Dec 2024The use of metformin for treating gestational diabetes mellitus (GDM) remains controversial because it can pass through the placenta. This meta-analysis aimed to compare... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The use of metformin for treating gestational diabetes mellitus (GDM) remains controversial because it can pass through the placenta. This meta-analysis aimed to compare the effects of metformin and insulin on maternal and neonatal outcomes in patients with GDM.
METHODS
We conducted a comprehensive search of the PubMed, Embase, and Cochrane Library databases, focusing on randomized controlled trials (RCTs) that evaluated the impacts of metformin and insulin on both maternal and neonatal outcomes in patients with GDM.
RESULTS
Twenty-four RCTs involving 4934 patients with GDM were included in this meta-analysis. Compared with insulin, metformin demonstrated a significant reduction in the risks of preeclampsia (RR 0.61, 95% CI 0.48 to 0.78, < .0001), induction of labor (RR 0.90, 95% CI 0.82 to 0.98, = .02), cesarean delivery (RR 0.91, 95% CI 0.85 to 0.98, = .01), macrosomia (RR 0.67, 95% CI 0.53 to 0.83, = .0004), neonatal intensive care unit (NICU) admission (RR 0.75, 95% CI 0.66 to 0.86, < .0001), neonatal hypoglycemia (RR 0.55, 95% CI 0.48 to 0.63, < .00001), and large for gestational age (LGA) (RR 0.80, 95% CI 0.68 to 0.94, = .007). Conversely, metformin showed no significant impact on gestational hypertension (RR 0.84, 95% CI 0.67 to 1.06, = .15), spontaneous vaginal delivery (RR 1.13, 95% CI 1.00 to 1.08, = .05), emergency cesarean section (RR 0.94, 95% CI 0.77 to 1.16, = .58), shoulder dystocia (RR 0.65, 95% CI 0.31 to 1.39, = .27), premature birth (RR 0. 92, 95% CI 0.61 to 1.39, = .69), polyhydramnios (RR 1.11, 95% CI 0.54 to 2.30, = .77), birth trauma (RR 0.87, 95% CI 0.54 to 1.39, = .56), 5-min Apgar score < 7 (RR 1.13, 95% CI 0.76 to 1.68, = .55), small for gestational age (SGA) (RR 0.93, 95% CI 0.71 to 1.22, = .62), respiratory distress syndrome (RDS) (RR 0.74, 95% CI 0.50 to 1.08, = .11), jaundice (RR 1.09, 95% CI 0.95 to 1.25, = .24) or birth defects (RR 0.80, 95% CI 0.37 to 1.74, = .57).
CONCLUSIONS
The findings suggest that metformin can reduce the risk of certain maternal and neonatal outcomes compared with insulin therapy for GDM. However, long-term follow-up studies of patients with GDM taking metformin and their offspring are warranted to provide further evidence.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Diabetes, Gestational; Fetal Macrosomia; Hypoglycemia; Insulin; Metformin; Weight Gain
PubMed: 38124287
DOI: 10.1080/14767058.2023.2295809 -
Journal of Ethnopharmacology Apr 2024Jiawei Buzhong Yiqi Decoction (JWBZYQ), from records of FuqingzhuNvke, is a classical formula for treating obese women related infertility. JWBZYQ has been shown to be...
ETHNOPHARMACOLOGICAL RELEVANCE
Jiawei Buzhong Yiqi Decoction (JWBZYQ), from records of FuqingzhuNvke, is a classical formula for treating obese women related infertility. JWBZYQ has been shown to be effective in treating polycystic ovary syndrome (PCOS) in both clinical studies and practical practice, with the pharmacological mechanism remaining unknown.
AIM OF THE STUDY
To explore the potential therapeutic effects and mechanistic insights of JWBZYQ in PCOS.
MATERIALS AND METHODS
An overweight PCOS rat model was established via testosterone propionate (TP) injection and 45% high-fat diet (HFD). Then they were categorized into five distinct groups: Control group, Model group, low-dose of JWBZYQ (JWBZYQ1) group, high-dose of JWBZYQ (JWBZYQ2) group, and metformin (Met) group. Body weight, estrous cycle, and sex hormone levels were observed. Hematoxylin-Eosin staining was employed to investigate the histological characteristics of the ovaries. To identify the pathways that changed significantly, transcriptome analysis was performed. The protein and mRNA levels of key molecules in ovarian zona pellucida (ZP) organization, transzonal projections (TZPs) assembly, steroid hormone receptors, and steroidogenesis were assessed using phalloidin staining, immunohistochemistry, Western blot, and polymerase chain reaction.
RESULTS
RNA-seq analysis demonstrated that regulation of hormone secretion, cilium assembly, cell projection assembly, and ZP production may all have crucial impact on the etiology of PCOS and therapeutic effect of JWBZYQ. In particular, PCOS rats exhibited elevated expressions of ZP1-3, which can be reversed by JWBZYQ2 particularly. Simultaneously, TZPs assembly was totally disrupted in PCOS rats, evidenced by the phalloidin staining, upregulated calcium-/calmodulin-dependent protein kinase II beta (CaMKIIβ), and deficient p-CaMKIIβ, myosin X (MYO10), proline-rich tyrosine kinase 2 (PTK2), and Fascin. Nonetheless, JWBZYQ or metformin treatment revived the disturbance, repairing the oocyte-granulosa cell communication, regulating steroidogenesis in PCOS rats. In this way, JWBZYQ and metformin exerted remarkable effects in alleviating altered ovarian morphology and function in PCOS rats, with JWBZYQ2 revealing the best effect.
CONCLUSIONS
JWBZYQ restored the altered ovarian morphology and function by regulating the oocyte-granulosa cell communication, which was related with ZP organization and TZPs assembly in the ovary.
Topics: Humans; Rats; Female; Animals; Polycystic Ovary Syndrome; Phalloidine; Oocytes; Metformin; Cell Communication; Hormones
PubMed: 38158097
DOI: 10.1016/j.jep.2023.117654