Efficacy of WeChat-Based Digital Intervention Versus Metformin in Women With Polycystic Ovary Syndrome: Randomized Controlled Trial.

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.

Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with meta-regression of observational studies.

INTRODUCTION: Metformin is the most prescribed medication for type 2 diabetes mellitus (T2DM); there is a well-established link with the elevated incidence of gastrointestinal (GI) adverse events (AE) limiting its administration or intensification. OBJECTIVES: The objective of this systematic review and meta-analysis of observational studies was to evaluate the pooled incidence of GI AE related to metformin use in patients with T2DM. MATERIALS AND METHODS: PUB MED/CINAHL/Web of Science/Scopus were searched from database inception until 29.07.2024 for observational studies in English describing the frequency of GI AE in patients with T2DM treated with metformin. Random-effects meta-analyses were used to derive effect sizes: event rates. RESULTS: From 7019 publications, we identified 211 potentially eligible full-text articles. Ultimately, 21 observational studies were included in the meta-analysis. The prevalence of GI AE was as follows: diarrhea 6.9% (95% CI: 0.038-0.123), bloating 6,2% (95% CI: 0.020-0.177), abdominal pain 5,3% (95% CI: 0.003-0.529), vomiting 2.4% (95%: CI 0.007-0.075), constipation 1.1% (95%: CI 0.001-0.100). The incidence of bloating (coefficient -4.46; p < 0.001), diarrhea (coefficient -1.17; p = 0.0951) abdominal pain (coefficient -2.80; p = 0.001), constipation (coefficient -5.78; p = 0.0014) and vomiting (coefficient -2.47; p < 0.001) were lower for extended release (XR) metformin than metformin immediate release (IR) formulation. CONCLUSIONS: This study highlights the prevalence of GI AE in patients receiving metformin, with a diarrhea predominance, followed by bloating, diarrhea, abdominal pain, constipation, and vomiting. The incidence is lower in patients administered with XR metformin. TRIAL REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289975 , identifier CRD42021289975.

Metformin represses the carcinogenesis potentially induced by 50 Hz magnetic fields in aged mouse fibroblasts via inhibition of NF-kB.

Aging is a risk factor for various human disorders, including cancer. Current literature advocates that the primary principles of aging depend on the endogenous stress-induced DNA damage caused by reactive oxygen species 50 Hz low-frequency magnetic field was suggested to induce DNA damage and chromosomal instability. NF-kB, activated by DNA damage, is upregulated in age-related cancers and inhibition of NF-kB results in aging-related delayed pathologies. Metformin (Met), an NF-kB inhibitor, significantly reduces both NF-kB activation and expression in aging and cancer. This in vitro study, therefore, was set out to assess the effects of 5mT MF in 50 Hz frequency and Met treatment on the viability and proliferation of aged mouse NIH/3T3 fibroblasts and expression of RELA/p65, matrix metalloproteinases MMP2 and MMP9, and E-cadherin (CDH1) genes. The trypan blue exclusion assay was used to determine cell viability and the BrdU incorporation assay to determine cell proliferation. The MMP-2/9 protein analysis was carried out by immunocytochemistry, NF-kB activity by ELISA and the expressions of targeted genes by qRT-PCR methods. Four doses of Met (500 uM, 1 mM, 2 mM and 10 mM) suppressed both the proliferation and viability of fibroblasts exposed to the MF in a dose-dependent pattern, and the peak inhibition was recorded at the 10 mM dose. Met reduced the expression of NF-kB, and MMP2/9, elevated CDH1 expression and suppressed NF-kB activity. These findings suggest that Met treatment suppresses the carcinogenic potential of 50 Hz MFs in aged mouse fibroblasts, possibly through modulation of NF-kB activation and epithelial-mesenchymal transition modulation.

Evaluation the efficacy of microneedling with topical metformin solution compared with microneedling with topical vitamin C solution in treatment of melasma.

Several treatment modalities have been used for the treatment of melasma. Topical metformin is an anti-diabetic drug, which has melanopenic action. Vitamin C acts on melanin by inhibiting the tyrosinase enzyme, thus inhibiting melanogenesis. To compare the efficacy and safety of microneedling combined with topical metformin solution versus microneedling combined with topical vitamin C in the treatment of melasma. A spitted-face interventional comparative on 30 female patients suffering from melasma. The right side of the face was treated with microneedling and topical metformin, while the left side was treated with microneedling and topical vitamin C solution. Hemi-MASI score decreased significantly after treatment from before treatment in both groups P-value < 0.001. The percentage of improvement of Hemi-MASI score metformin group was 48.29%, While with vitamin C group was 37.19%. There was a significant improvement in dermoscopic findings in microneedling with topical metformin than with topical vitamin C group. Microneedling with topical metformin or topical vitamin C solution can be an effective and safe therapeutic option for treating melasma with no significant side effects.

Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome.

With aging, the body's ability to maintain regular functions declines, increasing susceptibility to age-related diseases. Therapeutic interventions targeting the underlying biological changes of aging hold promise for preventing or delaying multiple age-related diseases. Metformin, a drug commonly used for diabetes treatment, has emerged as a potential gerotherapeutic agent due to its established safety record and preclinical and clinical data on its anti-aging effects. Glycosylation, one of the most common and complex co- and post-translational protein modifications, plays a crucial role in regulating protein function and has been linked to aging and various diseases. Changes in immunoglobulin G (IgG) glycosylation patterns have been observed with age, and these alterations may serve as valuable biomarkers for disease predisposition, diagnosis, treatment monitoring, and overall health assessment. In this study, we analyzed the IgG glycosylation patterns of white men from Europe, aged 29-45 years, under treatment with metformin, testosterone, metformin plus testosterone, and placebo (trial registration number NCT02514629, 2013/07/04), and investigated the longitudinal changes in glycosylation over time. We observed statistically significant differences in the IgG glycome composition between participants on testosterone therapy and placebo, with decreased agalactosylation and increased galactosylation and sialylation. However, metformin therapy did not result in statistically significant changes in glycosylation patterns. These findings contribute to our understanding of the impact of therapeutic interventions on IgG glycosylation and confirm the value of IgG glycosylation as a significant biomarker, capable of assessing biological age using the GlycanAge index and providing insight into overall health compared to chronological age.

Subclinical Hyperthyroidism Enhances Gonadotropin-Lowering Effects of Metformin in Postmenopausal Women.

Metformin treatment decreases elevated concentrations of anterior pituitary hormones. The aim of this prospective, cohort study was to investigate whether hyperthyroidism modulates the impact of metformin on gonadotroph secretory function. The study population included 48 postmenopausal women with untreated type 2 diabetes or prediabetes, 24 of whom had coexisting grade 1 subclinical hyperthyroidism. Both groups were matched for age, insulin sensitivity, and gonadotropin levels. Over the entire study period, all participants were treated with metformin (2.55-3 g daily). Plasma glucose, insulin, thyroid-stimulating hormone (TSH), total and free thyroid hormones, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin, adrenocorticotropic hormone (ACTH), and insulin-like growth factor-1 (IGF-1) were assayed at entry and 6 months later. At baseline, the study groups differed in levels of TSH and thyroid hormones but not in body mass index, blood pressure, glucose homeostasis markers (fasting glucose, homeostatic model assessment 1 of insulin resistance ratio [HOMA1-IR], and glycated hemoglobin [HbA1c]), and the remaining hormones. There were no differences between both groups in the degree of reduction in plasma glucose and HbA1c in response to metformin treatment. Although metformin decreased HOMA1-IR in both groups, this effect was stronger in women with hyperthyroidism than with normal thyroid function (-50 ± 20% vs -30 ± 15%). Similar relationships were observed for FSH (-43 ± 21% vs -21 ± 12%). Only in hyperthyroid women did the drug reduce LH concentration (by 35 ± 17%). Metformin did not affect circulating levels of TSH, total and free thyroxine, total and free triiodothyronine, estradiol, prolactin, ACTH, and IGF-1. The obtained results indicate that hyperthyroidism enhances the gonadotropin-lowering effects of metformin, as well as the fact that this agent has a neutral effect on the hypothalamic-pituitary-thyroid axis in case of its overactivity.

Non-coding RNAs as potential targets in metformin therapy for cancer.

Metformin, a widely used oral hypoglycemic drug, has emerged as a potential therapeutic agent for cancer treatment. While initially known for its role in managing diabetes, accumulating evidence suggests that metformin exhibits anticancer properties through various mechanisms. Several cellular or animal experiments have attempted to elucidate the role of non-coding RNA molecules, including microRNAs and long non-coding RNAs, in mediating the anticancer effects of metformin. The present review summarized the current understanding of the mechanisms by which non-coding RNAs modulate the response to metformin in cancer cells. The regulatory roles of non-coding RNAs, particularly miRNAs, in key cellular processes such as cell proliferation, cell death, angiogenesis, metabolism and epigenetics, and how metformin affects these processes are discussed. This review also highlights the role of lncRNAs in cancer types such as lung adenocarcinoma, breast cancer, and renal cancer, and points out the need for further exploration of the mechanisms by which metformin regulates lncRNAs. In addition, the present review explores the potential advantages of metformin-based therapies over direct delivery of ncRNAs, and this review highlights the mechanisms of non-coding RNA regulation when metformin is combined with other therapies. Overall, the present review provides insights into the molecular mechanisms underlying the anticancer effects of metformin mediated by non-coding RNAs, offering novel opportunities for the development of personalized treatment strategies in cancer patients.

Comparing psilocybin to metformin as neuroprotective agents against Parkinson's dementia: A systematic review of evidence and efficacy.

BACKGROUND & AIM: Treatment of Parkinson's disease (PD) has remained largely unchanged and focuses primarily on symptomatic relief through activation of dopaminergic pathways. Currently, there are no proven prophylactic approaches to the prevention of PD. This systematic review seeks to compare two separate compounds, metformin (MTF) and psilocybin, as potential prophylactic therapeutics against the development of PD. METHODS: The authors conducted a systematic review focusing on primary studies that test these compounds on cell and animal models to determine if they might have any neuroprotective or neuroplastic effects. RESULTS: The results of this review found that MTF may halt the progression of diseases such as PD through multiple mechanisms including reduced oxidative stress at the level of the mitochondria, thereby reducing α-synuclein related damage. Psilocybin, on the other hand, may increase repair of damaged neurons through psychoplastogenic activation of serotonergic pathways, particularly 5-HT2A receptor activation, ultimately increasing the release of brain derived neurotropic factor (BDNF) and the reduction of α-synuclein accumulation. CONCLUSION: Implications of this study include a need for further research in off-label use of MTF as well as further research into serotonergic compounds such as psilocybin for the treatment and prevention of neurodegenerative diseases.

Characterising the expression of the organic cation transporter OCT3 in cutaneous papillomas of dogs.

BACKGROUND: The identification of the activation of the mammalian target of rapamycin (mTOR) signalling pathway as a frequent molecular event in canine cutaneous papillomas (CPs) has provided the rational foundation to explore novel molecular-targeted therapies. Recent evidence indicates that metformin reduces the size of CPs in mice by inhibiting the mTOR signalling pathway. These effects require the expression of the organic cation transporter 3 (OCT3/SLC22A3), a well-known metformin uptake transporter. HYPOTHESIS/OBJECTIVES: The aim of the present study was to characterise the expression pattern of the metformin uptake transporter OCT3 in canine samples of CP that have shown activation of the mTOR signalling pathway in order to predict if this hyperplastic epidermal lesion is potentially sensitive to metformin. METHODS: The expression of OCT3 was evaluated by immunohistochemical investigation in sections of a previously constructed tissue microarray containing 28 samples of canine CP and compared with that previously evaluated for the mTOR activation marker pS6. RESULTS: OCT3 was highly expressed in the membrane and cytoplasm of the basal and suprabasal epidermal cells in all samples of canine CP. This OCT3 expression was localised at similar epidermal compartments to those observed for pS6. CONCLUSIONS AND CLINICAL RELEVANCE: These results show that canine CPs exhibit the expression of surrogate markers that suggest sensitivity to metformin, such as upregulated OCT3 and pS6 expression. Taken together, these findings provide the rationale for the early assessment of the use of metformin as a mechanism-based therapeutic approach for treating canine patients with persistent or multiple CPs.

Sex differences in the orofacial antinociceptive effect of metformin and the role of transient receptor potential channels.

Metformin is classified as a biguanide and is used in the treatment of type 2 diabetes. It is used worldwide and has been investigated in drug repositioning. The present study aims to investigate whether there is sexual dimorphism in the orofacial antinociceptive effect of metformin and the participation of TRP channels. Acute nociceptive behavior was induced by administering cinnamaldehyde or capsaicin to the upper lip. Nociceptive behavior was assessed through orofacial rubbing, and the effects of pre-treatment with metformin (125 or 250 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint. The chronic pain model involved infraorbital nerve transection (IONX) was evaluated using Von Frey electronic filaments. Trpv1 gene expression was analyzed in the nerve ganglion. Docking experiments were performed. Metformin, but not the vehicle, produced antinociception (p < 0.0001) in all acute nociceptive behaviors in both sexes, and these effects were attenuated by the TRPV1 antagonist capsazepine and the TRPA1 antagonist HC-030031. In IONX with better (**p < 0.01, ****p < 0.0001 vs. control) results in females. TRPV1 gene expression was observed in the metformin treated group (*p < 0.05 vs. control). Docking experiments revealed that metformin may interact with TRPV1 and TRPA1 channels. Metformin promotes orofacial antinociception in both sexes in acute pain and is more effective in chronic pain in females than in males, through the modulation of TRPV1 and TRPA1 channels. These preclinical findings suggest a potential repositioning of metformin as an analgesic agent in acute and chronic orofacial pain states.

Hypoglycemic drugs, circulating inflammatory proteins, and gallbladder diseases: A mediation mendelian randomization study.

BACKGROUND: The relationship of hypoglycemic drugs, inflammatory proteins and gallbladder diseases remain unknown. METHODS: Four hypoglycemic drugs were selected as exposure: glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and metformin. The outcome were two gallbladder diseases: cholecystitis and cholelithiasis. Mendelian Randomization (MR) was employed to determine the association between hypoglycemic drugs and gallbladder diseases. RESULTS: DPP-4i and SGLT-2i had no effect on cholecystitis and cholelithiasis. However, a causal relationship was found between inhibition of ETFDH gene, a target of metformin expressed in cultured fibroblasts, and cholelithiasis (OR: 0.84, 95 %CI: (0.72,0.97), p = 0.021), as well as between GLP1R expression in the brain caudate basal ganglia and cholecystitis (OR: 1.29, 95 %CI: (1.11,1.49), p = 0.001). The effect of ETFDH inhibition on cholelithiasis through Interleukin-10 receptor subunit beta (IL-10RB) levels and Neurotrophin-3 (NT-3) levels, with a mediated proportion of 8 % and 8 %, respectively. CONCLUSION: Metformin plays a protective role in cholelithiasis, while GLP-1RA have a harmful effect on the risk of cholecystitis. Metformin may reduce the risk of cholelithiasis by modulating the levels of Neurotrophin-3 (NT-3) and Interleukin-10 receptor subunit beta (IL-10RB). Further clinical and mechanistic studies are required to confirm these findings.

Metformin continuation post-metabolic bariatric surgery and relapse of diabetes.

AIM: To evaluate the association of metformin continuation with relapse of diabetes after metabolic bariatric surgery (MBS) in patients with type 2 diabetes and obesity who achieved an HbA1c level of less than 6.5%. MATERIALS AND METHODS: This observational, retrospective cohort study included Clalit Health Service members aged 24 years or older with obesity and diabetes, who were treated with metformin, underwent MBS during 2005-2020 and achieved an HbA1c level of less than 6.5% up to 6 months after surgery (index date). Patients who continued metformin treatment (> 2 prescriptions filled, n = 122) after the index date were matched (1:2) on age, sex and HbA1c level at index date and compared with those who stopped treatment (no filled prescriptions, n = 244). The outcome was relapse of diabetes as measured by an HbA1c level of 6.5% or higher (yes/no). RESULTS: The two matched groups maintained a mean HbA1c level of less than 6.5% during the follow-up (mean ~ 5 years). An adjusted Cox proportional hazards model revealed no significant association of metformin continuation after MBS with relapse of diabetes (adjusted hazard ratio = 1.70, 95% confidence interval: 0.98-2.94). No significant differences were observed between the two groups in weight loss and filled prescriptions for other diabetes medications during the follow-up period. CONCLUSIONS: Among individuals living with obesity and diabetes who achieved diabetes remission post-MBS, metformin continuation was not associated with relapse of diabetes. This lack of an association indicates that metformin did not provide an additional benefit for maintaining glycaemic control or weight reduction during an average of 5 years postsurgery.

Synthesis and characterization of some Metal ions complexes with mixed ligand of azo dye and Metformin and evaluation of its effectiveness on the growth of some pathogenic bacteria clinically isolated and study of its Toxicity on normal and cancerous Hepatocytes.

Four metal compounds mixed ligand of azo dye ligand (L) and metformin.(Met) were produced at aquatic ethanol for (1:1:1) (M:L:Met). The prepared compounds were identified by utilizing atomic absorption flame, FT.IR and UV-Vis spectrum manners as well as conductivity mensuration. These compounds was assayed of the gained datum the octahedral geometry was proposed into whole prepared complexes.Also in this research was studied represented examining the antibacterial and antifungal impact of the azo dye ligand (L), metformin.(Met) and (Co,Ni, Cu and Cd complexes) on four types of pathogenic, clinically isolated bacteria that are resistant to antibiotic, like Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumonia, and fungi Candida albicans from human in Iraq. The results of the sensitivity test showed the effectiveness of these compounds at a very low condensation of (10-3) in inhibiting the isolated bacteria. On the other hand, cytotoxic effects of the ligand, Met and mix ligand complexes showed anticancer activity on HepG2 cells in a serial condensation 15.6, 31, 62, 125, 250, 500 µg/ml. As the effectiveness of the compounds increases with increasing their condensation, the most effective toxicant on hepatic cancer cells is Met and cd complex and with a rate of 68.5 and 68.3 % respectively.

One-Pot Synthesis of Sustainable Fluorescent Nanomaterials via Microwave Irradiation as a Probe for the Determination of Metformin in Pure and Pharmaceutical Dosage Forms: Greenness and Whiteness Metrics.

A rapid, green and sensitive technique for the determination of metformin determination was developed based on the direct fluorescence enhancement of carbon dots (CDs) induced by the cited drug. The water-soluble CDs were prepared via a one-pot synthesis from avocado peels using domestic microwave. The prepared CDs exhibited strong fluorescence at 405 nm after excitation at 320 nm with a quantum yield of 51%. The fluorescence of CDs was enhanced linearly by increasing the concentration of metformin within the range 0.5-25 µg/mL with limit of detection 0.087 µg/mL and limit of quantification 0.263 µg/mL. The designed probe was proved to be selective toward metformin in the presence of other drugs such as vildagliptin and alogliptin and also in the presence of excipients in the pharmaceutical dosage form. The suggested and reported methods were compared with the help of the whiteness and greenness tools, specifically the white analytical chemistry and analytical greenness metric tools, for assessing hazardous solvents and reagents used.

Therapeutic Effects of Metformin on Central Nervous System Diseases: A Focus on Protection of Neurovascular Unit.

Metformin is one of the most commonly used oral hypoglycemic drugs in clinical practice, with unique roles in neurodegeneration and vascular lesions. Neurodegeneration and vasculopathy coexist in many diseases and typically affect the neurovascular unit (NVU), a minimal structural and functional unit in the central nervous system. Its components interact with one another and are indispensable for maintaining tissue homeostasis. This review focuses on retinal (diabetic retinopathy, retinitis pigmentosa) and cerebral (ischemic stroke, Alzheimer's disease) diseases to explore the effects of metformin on the NVU. Metformin has a preliminarily confirmed therapeutic effect on the retinal NUV, affecting many of its components, such as photoreceptors (cones and rods), microglia, ganglion, Müller, and vascular endothelial cells. Since it rapidly penetrates the blood-brain barrier (BBB) and accumulates in the brain, metformin also has an extensively studied neuronal protective effect in neuronal diseases. Its mechanism affects various NVU components, including pericytes, astrocytes, microglia, and vascular endothelial cells, mainly serving to protect the BBB. Regulating the inflammatory response in NVU (especially neurons and microglia) may be the main mechanism of metformin in improving central nervous system related diseases. Metformin may be a potential drug for treating diseases associated with NVU deterioration, however, more trials are needed to validate its timing, duration, dose, clinical effects, and side effects.

Metformin's cardioprotective role in isoprenaline-induced myocardial infarction: Unveiling insights into the AMPK, NF-κB, JAK2/STAT3 pathways, and cholinergic regulation.

AIM: Despite advancements in treatment modalities, myocardial infarction (MI) remains a significant global cause of mortality and morbidity. Metformin (MET), a commonly used antidiabetic medication, has demonstrated potential in various cardioprotective mechanisms. This study investigated whether MET could alleviate the histopathological, electrocardiographic, and molecular consequences of MI in rats. MATERIALS AND METHODS: The study hypothesis was tested using an isoprenaline (ISOP)-induced MI model, where male Wistar rats were injected with ISOP (85 mg/kg/day, s.c., for 2 days) and treated with MET at the doses of 500 and 1000 mg/kg/day for 18 days or left untreated. KEY FINDINGS: ISOP-treated rats exhibited several indicators of MI, including significant ST-segment depression and prolonged QT-intervals on ECGs, worsened left ventricular histopathology with increased inflammatory cell infiltration, reduced expression of cardiac CHRM2, a cardioprotective cholinergic receptor, adaptive increases in AMPK and α7nAchR levels, and elevated levels of iNOS, NO, STAT3, JAK2, IL-6, TNF-α, and NF-κB. These effects were attenuated in rats treated with either low or high doses of MET. MET administration restored normal ECG recordings, diminished oxidative stress and inflammatory mediators, and downregulated NF-κB expression. Moreover, MET improved CHRM2 expression and normalized α7nAchR levels. Additionally, MET influenced the expression of key signaling molecules such as Akt, STAT3, and JAK2. SIGNIFICANCE: These findings might suggest that MET exerts cardioprotective effects in ISOP-induced MI in rats by mitigating critical inflammatory signaling pathways and regulating protective cholinergic mechanisms in the heart.

Influence of Metformin Discontinuation on Readmission Rate in Patients With Acute Heart Failure.

Background: The consequences of discontinuing metformin in patients with heart failure have not been determined. Knowing that acute exacerbation of chronic heart failure contributes to substantial increases in major adverse cardiovascular events (MACE), we proposed a retrospective study to examine whether discontinuing metformin in patients hospitalized with heart failure impacts mortality and readmission rates. Methods: We conducted a retrospective analysis of patients admitted with a diagnosis of acute heart failure to hospitals in the HCA Healthcare System from 2020 to 2022. Included patients had a prior diagnosis of diabetes mellitus, acute heart failure, and were taking metformin prior to admission. After applying our exclusion criteria, a total of 7740 patients remained. The primary outcomes were 30-, 60-, and 90-day readmission rates and secondary outcomes were mortality and length of stay. Results: Patients who were discharged without a prescription for metformin (NONDIS-MET) were 4.489 (95% CI 3.673-5.488, p < 0.0001) times more likely to have a MACE outcome in 30 days compared to patients who received a discharge order for metformin (DIS-MET). The findings were similar for 60-day and 90-day readmission rates, with NONDIS-MET patients 3.457 (95% CI 2.893-4.131, p < 0.0001) and 2.992 (95% CI 2.534-3.533 p < 0.0001) times more likely to have a MACE outcome than MET patients, respectively. However, when metformin was continued during the patients' hospital stay (CONT-MET) there was no significant association with MACE outcomes, readmission, or mortality rates. Conclusion: We found that diabetic patients admitted with acute heart failure exacerbations had a higher incidence of major adverse cardiac events and were more likely to be readmitted when they were not prescribed metformin after discharge. Our findings agree with prior work showing the cardioprotective effects of metformin; however, continuing metformin during hospital admission did not affect our patients adverse outcomes.

Cardiometabolic outcomes in offspring of women treated with metformin versus insulin for gestational diabetes: A Systematic Review and meta-analysis.

INTRODUCTION: Gestational diabetes mellitus (GDM) is commonly managed with either metformin or insulin, but their comparative effects on offspring cardiometabolic outcomes are not fully understood. OBJECTIVE: To investigate the impact of metformin and insulin, two distinct pharmacological interventions, on cardiometabolic outcomes in offspring of mothers with GDM. METHODOLOGY: Systematic literature review was performed for articles (randomized control trials) published from 1974 to May 2024 using a predefined search strategy. Studies were screened for title and abstract followed by full text. Quality assessment was done using a separate risk of bias tool in line with the PRISMA-2020 checklist. RESULTS: Among 5463 records, five studies (metformin = 409 children or insulin n = 434 children) were included. Offspring of metformin-treated mothers in the age range of 5-9 years had more fat-free mass (kg) by bioimpedance and abdominal (subcutaneous and visceral) fat volume (cm3) by MRI. Fasting plasma glucose and triglycerides were lower in the metformin-treated group for offspring aged 5-9 years. No significant differences were observed for other cardiometabolic outcomes. Limited data available for offsprings less than 5 years of age precluded meta-analysis for the available outcomes, except for body weight, and difference for this was also not significant. CONCLUSION: In short term no major differences has been seen in most of the cardiometabolic outcomes evaluated in the meta-analysis. Future trials with longer follow up are required and in different ethnicities. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-CRD42023450990.

Metformin and the PI3K/AKT signaling pathway: implications for cancer, cardiovascular, and central nervous system diseases.

Recent findings have brought our understanding of diseases at the molecular level, highlighting upstream intracellular pathways as potential therapeutic targets. The PI3K/AKT pathway, a key regulator of cellular responses to environmental changes, is frequently altered in various diseases, making it a promising target for intervention. Metformin is the most known anti-diabetic agent that is known due to its effects on cancer, inflammatory-related diseases, oxidative stress, and other human diseases. It is clearly understood that metformin modulates the activity of the PI3K/AKT pathway leading to a wide variety of outcomes. This interaction has been well-studied in various diseases. Therefore, this review aims to examine PI3K/AKT-modulating properties of metformin in cancer, cardiovascular, and central nervous system diseases. Our findings indicate that metformin is effective in treating cancer and CNS diseases, and plays a role in both the prevention and treatment of cardiovascular diseases. These insights support the potential of metformin in comprehensive strategies for disease management.

Evaluating remission of type 2 diabetes using a metabolic intervention including fixed-ratio insulin degludec and liraglutide: A randomized controlled trial.

AIM: To evaluate the effect on type 2 diabetes remission of short-term intensive metabolic intervention consisting of frequent dietary, exercise and diabetes management coaching, metformin and fixed-ratio insulin degludec/liraglutide. METHODS: In a multicentre open-label randomized controlled trial, insulin-naïve participants within 5 years of diabetes diagnosis were assigned to a 16-week remission intervention regimen or standard care, and followed for relapse of diabetes and sustained remission for an additional year after stopping glucose-lowering drugs. RESULTS: A total of 159 participants aged 57 ± 10 years, with diabetes duration 2.6 ± 1.5 years, body mass index 33.5 ± 6.5 kg/m2, and glycated haemoglobin (HbA1c) level 53 ± 7 mmol/mol were randomized and analysed (79 intervention, 80 control). At the end of the 16-week intervention period, compared to controls, intervention participants achieved lower HbA1c levels (40 ± 4 vs. 51 ± 7 mmol/mol; p < 0.0001), and lost more weight (3.3 ± 4.4% vs. 1.9 ± 3.0%; p = 0.02). There was a lower hazard of diabetes relapse overall in the intervention group compared to controls (hazard ratio 0.63, 95% confidence interval [CI] 0.45, 0.88; p = 0.007), although this was not sustained over time. Remission rates in the intervention group were not significantly higher than in the control group at 12 weeks (17.7% vs. 12.5%, relative risk [RR] 1.42, 95% CI 0.67, 3.00; p = 0.36) or at 52 weeks (6.3% vs. 3.8%, RR 1.69, 95% CI 0.42, 6.82) following the intervention period. CONCLUSIONS: An intensive remission-induction intervention including fixed-ratio insulin degludec/liraglutide reduced the risk of type 2 diabetes relapse within 1 year without sustained remission.