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Metformin is a medication that is widely used for lowering blood sugar in patients with type 2 diabetes. Metformin was shown to have significant antidepressant effects; however, it is not clear whether metformin treatment improves outcomes in patients with type 2 diabetes who have concomitant depressive symptoms. A total of 475 patients with type 2 diabetes mellitus with depressive symptoms were included in this study and divided into metformin and nonmetformin groups according to whether they were taking metformin. The DASS-21 was used to assess patients' depression and anxiety scores before and after a 24-week intervention. In addition, general information about whether the patients had developed complications from diabetes and whether they had been diagnosed with other diseases was assessed. (1) After 24 weeks, anxiety and depression scores were significantly lower in the metformin group than in the nonmetformin group. (2) The prevalence of depressive symptoms was significantly greater in female type 2 diabetic patients than in male patients (OR = 2.039, 95 % CI = 1.160–3.568). (3) People with type 2 diabetes who develop complications from diabetes (OR = 1.794, 95 % CI = 1.015–3.171) and those diagnosed with other conditions are more likely to experience depressive symptoms. Metformin has an ameliorative effect on type 2 diabetes. However, women, those with diabetes complications, and those with type 2 diabetes who are also diagnosed with other conditions are more likely to experience depressive symptoms. • Metformin Intervention Improves Depressive Symptoms in Patients with Type 2 Diabetes Mellitus After 24 Weeks of Intervention. • Metformin improves anxiety in patients with T2D. • There is a significant gender difference in the distribution of depressive symptoms in patients with type 2 diabetes, with women with type 2 diabetes more likely to experience depressive symptoms. • Complications of diabetes and other diseases are also risk factors for depressive symptoms. [ABSTRACT FROM AUTHOR]

Patients with diabetes face a 2‐4‐fold greater cardiovascular risk compared to those without diabetes. Both metformin and acetylsalicylic acid (aspirin) treatment have demonstrated a significant reduction in this risk. This single‐center, open‐label, sequence randomized, 2 × 2 crossover, single‐dose clinical trial evaluated the pharmacokinetics profile and comparative bioavailability of a novel oral fixed‐dose combination (FDC) of metformin/acetylsalicylic acid (500/100 mg tablet) versus the reference mono‐drugs administered concomitantly, metformin 500 mg tablet and acetylsalicylic acid 100 mg tablet, in 22 healthy Mexican adult volunteers under fasting conditions. Blood samples were collected predose and at specified intervals across a 24‐hour period following administration and were analyzed for metformin and salicylic acid using high‐performance liquid chromatography coupled with tandem mass spectrometry. Test products were considered to have comparative bioavailability if confidence intervals of natural log‐transformed (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration‐time curve form 0 up to last sampling time (AUC0‐t), and (area under the plasma drug concentration‐time cruve from 0 up to infinity (AUC0∞) data were within the range of 80%‐125%. The results obtained from the present clinical study demonstrate the comparative bioavailability of the FDC when compared with the coadministration of reference mono‐drugs. There were no adverse events or adverse reactions reported throughout the study. [ABSTRACT FROM AUTHOR]

Background: Metformin is a safe and effective medication for type 2 diabetes (T2D) that has been proposed to decrease the risk of aging related disorders including Alzheimer's disease (AD) and Alzheimer's disease related disorders(ADRD). Objective: This review seeks to summarize findings from studies examining the association of metformin with AD/ADRD related outcomes. Methods: This is a narrative review of human studies, including observational studies and clinical trials, examining the association of metformin with cognitive and brain outcomes. We used PubMed as the main database for our literature search with a focus on English language human studies including observational studies and clinical trials. We prioritized studies published from 2013 until February 15, 2024. Results: Observational human studies are conflicting, but those with better study designs suggest that metformin use in persons with T2D is associated with a lower risk of dementia. However, these observational studies are limited by the use of administrative data to ascertain metformin use and/or cognitive outcomes. There are few clinical trials in persons without T2D that have small sample sizes and short durations but suggest that metformin could prevent AD/ADRD. There are ongoing studies including large clinical trials with long duration that are testing the effect of metformin on AD/ADRD outcomes in persons without T2D at risk for dementia. Conclusions: Clinical trial results are needed to establish the effect of metformin on the risk of AD and ADRD. [ABSTRACT FROM AUTHOR]

Aims: Metformin has been attributed to cardiovascular protection even in the absence of diabetes. Recent observations suggest that metformin influences the gut microbiome. We aimed to investigate the influence of metformin on the gut microbiota and hypertensive target organ damage in hypertensive rats. Methods: Male double transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR), a model of angiotensin II‐dependent hypertension, were treated with metformin (300 mg/kg/day) or vehicle from 4 to 7 weeks of age. We assessed gut microbiome composition and function using shotgun metagenomic sequencing and measured blood pressure via radiotelemetry. Cardiac and renal organ damage and inflammation were evaluated by echocardiography, histology, and flow cytometry. Results: Metformin treatment increased the production of short‐chain fatty acids (SCFA) acetate and propionate in feces without altering microbial composition and diversity. It significantly reduced systolic and diastolic blood pressure and improved cardiac function, as measured by end‐diastolic volume, E/A, and stroke volume despite increased cardiac hypertrophy. Metformin reduced cardiac inflammation by lowering macrophage infiltration and shifting macrophage subpopulations towards a less inflammatory phenotype. The observed improvements in blood pressure, cardiac function, and inflammation correlated with fecal SCFA levels in dTGR. In vitro, acetate and propionate altered M1‐like gene expression in macrophages, reinforcing anti‐inflammatory effects. Metformin did not affect hypertensive renal damage or microvascular structure. Conclusion: Metformin modulated the gut microbiome, increased SCFA production, and ameliorated blood pressure and cardiac remodeling in dTGR. Our findings confirm the protective effects of metformin in the absence of diabetes, highlighting SCFA as a potential mediators. [ABSTRACT FROM AUTHOR]

Summary: Objective: To summarize the literature on pharmacotherapy for managing paediatric obesity. Methods: A systematic review and meta‐analysis were conducted of randomized controlled trials (RCTs) with <18‐year‐olds of pharmacotherapeutic agents published up to November 2022. Estimates of effect for outcomes were presented relative to minimal important differences and GRADE certainty of evidence. We examined data on patient/proxy‐reported outcome measures (PROMs), cardiometabolic risk factors, anthropometry and adverse events (AEs). Results: Overall, 35 RCTs were included. Trials examined metformin (n = 26), glucagon‐like peptide‐1 receptor agonists (GLP1RAs) (n = 7) and a lipase inhibitor (orlistat; n = 2). Intervention duration varied (3−24 months). Metformin had little to no benefit on PROMs (e.g., health‐related quality of life [HRQoL]; 6 RCTs), moderate reductions in triglycerides, a moderate decline in insulin resistance, a small to moderate decline in BMI z‐score (BMIz) and a moderate increase in mild to moderate gastrointestinal AEs. Response to GLP1RAs was heterogeneous and results of subgroup analysis demonstrated variability of impact. Liraglutide (2 RCTs) resulted in a small reduction in HOMA‐IR and BMIz, but little to no benefit on other outcomes. Exenatide (4 RCTs) had a moderate reduction on blood pressure and a small decrease in BMIz with little to no benefit on other outcomes. Semaglutide (1 RCT) had a small benefit on HRQoL, a small reduction on SBP, a moderate reduction on total cholesterol and LDL‐cholesterol, a large reduction on triglyceride, and a very large decline in BMIz accompanied by a small increase in mild to moderate gastrointestinal AEs. Orlistat had a moderate reduction in DBP and little to no benefit in other outcomes measured, but had a very large increased risk of mild to moderate gastrointestinal AEs. Serious AEs were rare and for interventions with sufficent AE reporting, were considered not likely attributable to the interventions. Conclusion: Few studies examined the impact of pharmacotherapy on PROMs. There is evidence that metformin and GLP1RAs lead to important improvements in cardiometabolic and anthropometric outcomes while accompanied by mild to moderate AEs. Long‐term effectiveness and safety of GLP1RAs remain to be evaluated. [ABSTRACT FROM AUTHOR]

The harmful effects of PM2.5 on human health, including an increased risk of chronic kidney disease (CKD), have raised a lot of attention, but the underlying mechanisms are unclear. We used the Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) to simulate the inhalation of PM2.5 in the real environment and established an animal model by exposing C57BL/6 mice to filtered air (FA) and Particulate Matter (PM2.5) for 8 weeks. PM2.5 impaired the renal function of the mice, and the renal tubules underwent destructive changes. Analysis of NHANES data showed a correlation between reduced kidney function and higher blood levels of PM2.5 components, polychlorinated biphenyls (PCBs) and dioxins, which are Aryl hydrocarbon Receptor (AhR) ligands. PM2.5 exposure induced higher levels of AhR and CYP1A1 and oxidative stress as evidenced by the higher levels of ROS, MDA, and GSSG in kidneys of mice. PM2.5 exposure led to AhR overexpression and nuclear translocation in proximal renal tubular epithelial cells. Inhibition of AhR reduced CYP1A1 expression and PM2.5-increased levels of ROS, MDA and GSSG. Our study suggested metformin can mitigate PM2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway. These findings illuminated the role of AhR/CYP1A1 pathway in PM2.5-induced kidney injury and the protective effect of metformin on PM2.5-induced cellular damage, offering new insights for air pollution-related renal diseases. [ABSTRACT FROM AUTHOR]

Introduction: We aim to evaluate the efficacy and safety of pioglitazone/metformin fixed-dose combination (FDC) versus uptitrated metformin in patients with type 2 diabetes mellitus (T2DM) without adequate glycemic control. Methods: A total of 304 patients were recruited from 15 hospitals in China and randomly assigned (1:1) to the test group (pioglitazone/metformin FDC, 15/500 mg) or the control group (uptitrated metformin, 2000–2500 mg/day). The primary endpoint was the proportion of patients with glycated hemoglobin A1c (HbA1c) ≤ 6.5% and ≤ 7.0% at week 16. The secondary outcomes included the change from baseline in glucose, serum lipids, and liver function. Full analysis set (FAS) and per-protocol set (PPS) were used for analyses. Results: In the test group, 103 (69.59%) patients reached HbA1c ≤ 7.0% (FAS, P = 0.009), with 68 (45.95%) patients achieved HbA1c ≤ 6.5 (FAS, P = 0.043). More reduction in HbA1c, homeostatic model assessment for insulin resistance, and diastolic pressure was found. Bodyweight, body mass index, and high-density lipoprotein cholesterol increased markedly. The changes of triglycerides, alanine transaminase, aspartate aminotransferase, and high-sensitivity C-reactive protein decreased noticeably. There were no significant differences in rates of adverse events between the two groups. Conclusions: Pioglitazone/metformin FDC was superior to uptitrated metformin among patients with T2DM without adequate glycemic control. Trial Registration Number: This trial is registered with the Chinese Clinical Trial Registry (ChiCTR1900028606). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: We evaluated the efficacy and safety of cofrogliptin, a novel dipeptidyl peptidase‐4 inhibitor taken once every 2 weeks (Q2W), compared with linagliptin (taken daily) in patients with type 2 diabetes inadequately controlled on metformin in China. Materials and Methods: In this phase 3 randomized, double‐blind, active‐controlled, multicentre study, patients were randomly assigned 1:1:1 to receive cofrogliptin 10 mg Q2W, cofrogliptin 25 mg Q2W, or linagliptin 5 mg daily, all as an add‐on treatment to metformin, for 24 weeks. Eligible patients could enter an open‐label extension period and receive cofrogliptin 25 mg Q2W for an additional 28 weeks. The primary endpoint was change in glycated haemoglobin from baseline to 24 weeks, with a non‐inferiority margin of 0.4% for cofrogliptin versus linagliptin treatment. Results: Overall, 465 patients entered the 24‐week treatment period (median age: 57.0 years). The least‐squares mean (standard error) change in glycated haemoglobin from baseline to week 24 was −0.96 (0.063), −0.99 (0.064) and −1.07 (0.065) for the cofrogliptin 10 mg, cofrogliptin 25 mg and linagliptin 5 mg groups, respectively. The between‐group difference met the predefined margin for non‐inferiority of cofrogliptin (10 and 25 mg) versus linagliptin treatment. The incidence of common adverse events (≥5% patients) during the 24‐week treatment period was similar between treatment groups. There were no serious hypoglycaemic events. Conclusion: In Chinese patients with type 2 diabetes inadequately controlled on metformin, the glucose‐lowering effect of cofrogliptin (Q2W) was non‐inferior to linagliptin (daily), with a similar safety profile maintained over 52 weeks of treatment. [ABSTRACT FROM AUTHOR]

Aim: To analyse patterns of glucose‐lowering therapies among people with type 2 diabetes (T2D) in Denmark from 2016 to 2023. Materials and Methods: We examined time trends in the clinical profiles of people with T2D who initiated different glucose‐lowering therapy classes for the first time. We furthermore investigated individual‐level treatment trajectories following first‐ever glucose‐lowering therapy in people with or without cardiorenal disease. The study utilized data from the nationwide Danish health registries and included all individuals who filled a first‐ever prescription for metformin, dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) or insulin, excluding those without HbA1c‐confirmed T2D or probable type 1 diabetes. Results: We included 260 393 individuals initiating a new glucose‐lowering therapy class from 2016 to 2023, during which there were 6‐ and 3‐fold increases in initiators of GLP‐1RAs and SGLT‐2is, respectively. The median HbA1c level at treatment initiation with GLP‐1RAs or SGLT‐2is decreased, from 67‐68 mmol/mol in 2016‐2017 to 57‐58 mmol/mol in 2022‐2023. Among individuals who initiated metformin as first‐line therapy, the proportion who started additional glucose‐lowering therapy within 2 years increased from 25% in 2016 to 40% in 2021. Among the 38% of individuals who had established cardiorenal disease when they initiated first‐ever glucose‐lowering therapy in 2020, 22% used SGLT‐2is and 18% GLP‐1RAs after 2.5 years, compared with 17% and 21% among initiators without cardiorenal disease, respectively. Conclusions: Our study documents a trend towards earlier T2D treatment intensification and an increase in the use of GLP‐1RAs and SGLT‐2is in Denmark. However, optimal T2D treatment is still not received by most individuals with early T2D and established cardiorenal disease. [ABSTRACT FROM AUTHOR]

Aim: To highlight oversimplified quality‐adjusted life year (QALY) calculations and incremental cost‐effectiveness ratios (ICERs) regarding lifestyle metformin and placebo as flaws in the trial‐based (Diabetes Prevention Program) cost‐effectiveness analysis. Materials and Methods: We revised the QALY calculations to conform to convention and calculated appropriate ICERs using both original and revised QALYs results. We used several additional health economics tools to present results, showing the consistency of each method and the added value of each. We presented net monetary benefits, assessed decision uncertainty and calculated net losses. We also used graphics, making correct interpretation clearer and allowing illustration and calculation of technical and economic inefficiencies of treatments that were not cost‐effective. Results: ICERs with either QALY calculation indicated that metformin was technically and economically inefficient and not cost‐effective. There was virtually no decision uncertainty. All methods employed pointed to an identical conclusion. Conclusions: In contrast to original claims, although lifestyle was cost‐effective in diabetes prevention, metformin was not, and acting otherwise imposes significant monetary and health costs. Various available tools of economic evaluation would probably have prevented the original misinterpretation by the authors had they been used. The varied tools implemented here illustrate with a common example their consistency and value to the field, showing how to depict the results in various ways. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of dapagliflozin versus placebo as an add‐on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination. Patients and Methods: In this multicentre, randomized, double‐blind, placebo‐controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable‐dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level. Results: In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was −0.70% (−7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2‐h postprandial plasma glucose, fasting insulin, uric acid and gamma‐glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups. Conclusion: Dapagliflozin add‐on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients. [ABSTRACT FROM AUTHOR]

Objective: Abdominal Aortic Aneurysms (AAA) growth remains a process not fully understood. The objective of this study was to analyze risk factors associated with changes in AAA diameter in a Mexican cohort. Methods: An observational study in which we analyzed the entirely of patients in which an AAA was reported in a Computed Tomography (CT) study from 2014 to 2021 who had a follow-up CT. We divided them by groups depending on the diagnosis of type 2 diabetic mellitus and pharmacological history (diabetic vs non-diabetic, metformin vs non-metformin intake and statin vs non-statin intake). We compared pre and post follow-up AAA diameters using paired t-tests. A multivariate analysis was performed in order to identify independent variables associated with an increased growth rate. Statistical analysis was performed on Stata 17. Results: During the studied period 72 (39.77%) patients had a follow-up CT. Mean age was 75 years (±9.05) and 52 (72.22%) were men. When comparing infra-renal largest diameter through time based on metformin intake, a significant difference was found only in the metformin non-intake group (42.05 ± 12.54 vs45.34 ± 12.06 [ P = 0.02]), in contrast the metformin intake group measures were non-significantly different (36.13 ± 7.04 vs 37.00 ± 4.51; P = 0.57) through follow-up. In the multivariate analysis AAA largest diameter at diagnosis correlated with significantly increased growth rate (coeff = 0.06, P < 0.05). Conclusions: AAA diameters appear to change through time in a non-linear pattern influenced by different epidemiological and clinical factors. Metformin intake appears to promote a stability in AAA diameter growth in our studied population. [ABSTRACT FROM AUTHOR]

In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin's influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging. [Display omitted] • Metformin prevents brain atrophy, elevating cognitive function in aged male primates • Metformin slows the pace of aging across diverse male primate tissues • Metformin counterparts neuronal aging, delivering geroprotection via Nrf2 in male primates Prolonged metformin treatment diminishes the multidimensional biological age and alleviates neuronal aging through the Nrf2 pathway in male primates. [ABSTRACT FROM AUTHOR]

Background: Knee osteoarthritis (KOA) is a common musculoskeletal disorder. Therapeutic ultrasound (US) is a safe and effective treatment for KOA. It relieves knee pain and enhances function. Metformin (MF) regulates chondrocytes, hence providing chondroprotection. Furthermore, it efficiently reduces knee articular cartilage degeneration and retards the progression of osteoarthritis. However, the localized administration of MF by phonophoresis for KOA has yet to be studied. Purpose: To assess the possible effects of metformin phonophoresis (MFPH) plus exercise therapy (EX) compared to MFPH alone or the US on knee pain, function, and range of motion (ROM) in chronic KOA patients. Methods: Seventy-eight patients with unilateral mild to moderate chronic KOA were included. Patients were randomly assigned to three groups: group A (MFPH + EX), group B (MFPH alone), and group C (US). The US group used an acoustic-neutral gel, while the MFPH group used a gel containing 1.2% MF. The exercises included hamstring stretches, calf stretches, and knee strengthening exercises. Treatment in the three groups continued for four weeks (three sessions per week). The Visual Analog Scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the goniometer were used to assess knee pain, function disability, and ROM, respectively. All measures were recorded before, 2 weeks, and 4 weeks after the intervention in all groups. Multivariate Analysis of Variance (MNOVA) was performed to compare the effects within and between groups for knee ROM and function disability. The Kruskal-Wallis test and the Friedman test analyzed the pain intensity. Results: When the baseline patient characteristics were compared, there were no significant differences in means of age, gender, body mass index (BMI), or lower limb dominance across the three groups (p > 0.05). After 4 weeks of intervention, clinical outcomes significantly improved in all three groups (p < 0.05). However, patients in the MFPH + EX group improved significantly in all outcomes compared to the MFPH and US groups (p < 0.05). Conclusion: Post-treatment results showed a statistically and clinically significant improvement in pain intensity, knee ROM, and function in the MFPH group; however, combining MFPH with exercises is more beneficial in reducing KOA symptoms. Trial registration: Clinical Trial Registry at (pactr.samrc.ac.za) database. NO: PACTR202311507335269. Date: November 9, 2023 (retrospectively registered). [ABSTRACT FROM AUTHOR]

The neurotoxicant trimethyltin (TMT) triggers cognitive impairment and hippocampal neurodegeneration. TMT is a useful research tool for the study of Alzheimer's disease (AD) pathogenesis and treatment. Although the antidiabetic agent metformin has shown promising neuroprotective effects, however, its precise modes of action in neurodegenerative disorders need to be further elucidated. In this study, we investigated whether metformin can mitigate TMT cognition impairment and hippocampal neurodegeneration. To induce an AD-like phenotype, TMT was injected i.p. (8 mg/kg) and metformin was administered daily p.o. for 3 weeks at 200 mg/kg. Our results showed that metformin administration to the TMT group mitigated learning and memory impairment in Barnes maze, novel object recognition (NOR) task, and Y maze, attenuated hippocampal oxidative, inflammatory, and cell death/pyroptotic factors, and also reversed neurodegeneration-related proteins such as presenilin 1 and p-Tau. Hippocampal level of AMP-activated protein kinase (AMPK) as a key regulator of energy homeostasis was also improved following metformin treatment. Additionally, metformin reduced hippocampal acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP)-positive reactivity, and prevented the loss of CA1 pyramidal neurons. This study showed that metformin mitigated TMT-induced neurodegeneration and this may pave the way to develop new therapeutics to combat against cognitive deficits under neurotoxic conditions. [ABSTRACT FROM AUTHOR]

AbstractContext:Objectives:Materials and Methods:Results:Conclusion:Insulin resistance and a disturbed lipid profile are common associations with type 2 diabetes mellitus (T2DM) and different skin diseases, particularly psoriasis (PsO).We investigated potential therapeutic mechanisms of metformin in a murine animal model of psoriasiform lesions in T2DM.Forty-two rats were randomly divided into control, PsO, and type II DM (T2DM) groups. After confirmation of DM, the type II diabetic rats were allocated into T2DM+ PsO, T2DM+ PsO+ systemic metformin (S. met), T2DM+ PsO+ topical metformin (T. met)), and T2DM+ PsO + combined metformin (C. met). PsO was induced by topical imiquimod.Systemic administration of the cornerstone antidiabetic drug, metformin, was able to improve insulin resistance and lipid profile. At molecular levels, both topical and systemic metformin significantly increased AMP-activated protein kinase (AMPK), and lowered keratinocyte growth factor (KGF) / “Signal transducer and activator of transcription” (STAT)3 protein levels, and the IL-17RA and IL-17RC gene expression.Although its glucose-controlling effect was not optimum, T.met gel served anti-psoriatic and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Background: Cancer and diabetes mellitus are quite common diseases found together worldwide. A considerable amount of evidence is available for the rapid development and presentation of various types of cancer in the type 2 diabetes mellitus (DM2) population as compared with the population without diabetes. The objective of the study is to formulate and evaluate 5-fluorouracil (5-FU) and metformin (MET) nanoparticles (NPs) and to establish the characteristic features of the biodegradable NPs. 5-FU and MET NPs with chitosan as a biodegradable polymer were formulated by the ionotropic cross-linking method. 0.25 gm of MET and 0.25 gm of 5-FU were dissolved in 100 ml of distilled water, and stock solution was prepared. 5 ml of stock solution was slowly mixed into the chitosan solution to obtain the mixture of drugs and chitosan. The tripolyphosphate reserve liquid was dripped slowly into the chitosan solution with constant stirring until the opaline appearance was noticed in the mixture, then filtered, and dried. The NPs were evaluated for their physical properties and drug release kinetics. Cell proliferation assay was done using human colorectal carcinoma cell line (HCT 116). Results: The formulation composed of 1.5 w/v of chitosan, 0.25 w/v of MET, and 5-FU had an average particle diameter of 198.7 nm. The polydispersity index was 0.757. Thermal and infrared spectroscopy results indicated the drugs and polymers selected for the formulation were unique without any identifiable interaction. The NPs were spherical in appearance, with numerous pours on the surface, which was evident when microscopically examined. Uniformity in drug release was observed, and the formulation demonstrated excellent release kinetics. HTC 116 cell line confirmed that the maximum percentage of cell death and minimum viability of cells were observed while using the combination of MET and 5-FU-NPs as compared to the pure MET or 5-FU alone. Conclusion: MET and 5-FU-loaded chitosan NPs were found to have excellent physiochemical properties, particle size, and drug release from the polymer in a controlled manner. Half-maximal inhibitory concentration value (IC50) of MET and 5-FU-NPs was found to be significantly less as compared to MET and 5-FU alone or the combination. [ABSTRACT FROM AUTHOR]

Abstract\nKEY POLICY HIGHLIGHTSMetformin is known for its antioxidant properties and ability to ameliorate metabolic dysfunction-associated fatty liver disease (MAFLD) and is the focus of this study. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is linked to MAFLD risk. This study investigated the effects of metformin on ferroptosis in free fatty acid (FFA)-treated Huh7 hepatoma cells and its association with MAFLD risk. Using Western blot, immunofluorescence, and ELISA, this study revealed that FFA treatment led to increased intracellular fat and iron accumulation, heightened Lp-PLA2 expression, reduced levels of the cysteine transporter SLC7A11 and glutathione peroxidase 4 (GPX4), altered glutathione (GSH)/oxidized glutathione (GSSG) ratios, generation of reactive oxygen species (ROS), and initiation of lipid peroxidation, which ultimately resulted in cell ferroptosis. Importantly, metformin reversed FFA-induced iron accumulation, and this effect was attenuated by ferrostatin-1 but enhanced by erastin, RSL3, and si-GPX4. Additionally, metformin activated antioxidant and antiapoptotic mechanisms, which reduced lipid peroxidation and suppressed Lp-PLA2 expression in FFA-treated Huh7 cells. In conclusion, our findings indicate that metformin may protect against MAFLD by inhibiting iron accumulation and Lp-PLA2 expression through the ROS, ferroptosis, and apoptosis signaling pathways. This study highlights potential therapeutic strategies for managing MAFLD-related risks and emphasizes the diverse roles of metformin in maintaining hepatocyte balance.Metformin lowered Lp-PLA2 levels in human Huh7 hepatoma cells.Both fatty acid and iron metabolism improved after metformin treatment.Metformin alleviated oxidative stress, apoptosis, lipid peroxidation and ferroptosis.Metformin lowered Lp-PLA2 levels in human Huh7 hepatoma cells.Both fatty acid and iron metabolism improved after metformin treatment.Metformin alleviated oxidative stress, apoptosis, lipid peroxidation and ferroptosis. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) affects 6–20% of women worldwide, with insulin resistance and hyperinsulinemia occurring in 50-70% of patients. Hyperinsulinemia exacerbates oxidative stress, contributing to PCOS pathogenesis. N-acetylcysteine (NAC) is an antioxidant and insulin sensitizer that shows promise as a therapeutic for PCOS. Our current study aimed to investigate the effects of NAC supplementation on endocrine-metabolic parameters in PCOS mice and its effect on ovulation induction (OI) efficacy in women with PCOS. Methods: Female C57BL/6 mice were orally administered letrozole (LE) to induce PCOS and then randomly divided into groups receiving daily oral administration of 160 mg/kg NAC (PCOS + NAC group), 200 mg/kg metformin (PCOS + Met group), or 0.5% carboxymethyl cellulose (drug solvent) (pure PCOS group) for 12 days. Healthy female mice served as pure controls. Estrous cycles were monitored during the intervention. Metabolic and hormone levels, ovarian phenotypes, antioxidant activity in ovarian tissues, and oxidative stress levels in oocytes were assessed post-intervention. Furthermore, a pragmatic, randomized, controlled clinical study was conducted with 230 PCOS women, randomly assigned to the NAC group (1.8 g/day oral NAC, n = 115) or the control group (n = 115). Patients in both groups underwent ≤ 3 cycles of OI with sequential LE and urinary follicle-stimulating hormone (uFSH). Cycle characteristics and pregnancy outcomes were compared between groups. Results: Similar to metformin, NAC supplementation significantly improved the estrous cycles and ovarian phenotypes of PCOS mice; reduced the LH concentration, LH/FSH ratio, and T level; and increased glucose clearance and insulin sensitivity. Notably, NAC significantly reduced oocyte ROS levels and increased the mitochondrial membrane potential in PCOS mice. Additionally, NAC significantly enhanced enzymatic and nonenzymatic antioxidant activities in PCOS mouse ovaries, whereas metformin had no such effect. In the clinical trial, compared to women in the control group, women receiving NAC had significantly lower average uFSH dosage and duration (p < 0.005) and significantly greater clinical pregnancy rates per OI cycle and cumulative clinical pregnancy rates per patient (p < 0.005). Conclusion: NAC supplementation improved endocrine-metabolic parameters in PCOS mice and significantly enhanced OI efficacy with sequential LE and uFSH in women with PCOS. Therefore, NAC could be a valuable adjuvant in OI for women with PCOS. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sepsis complicated by myocardial injury is characterized by a high mortality. Metformin can prevent sepsis-induced myocardial dysfunction byexerting anti-inflammatory effects, improving oxidative stress, and reducing apoptosis. However, it is unclear whether metformin-induced autophagy plays an important role in the protective effect against sepsis-induced myocardial injury. OBJECTIVE: To explore the effect of metformin pretreatment on myocardial injury in septic mice. METHODS: A total of 40 male Kunming mice were randomly divided into sham operation group, model group, metformin group, and metformin+ 3-methyladenine group, with 10 mice in each group. The latter two groups were intraperitoneally injected with metformin for 14 days at a fixed time every day, and the metformin+3-methyladenine group was intraperitoneally injected with 3-methyladenine 1 hour before modeling. Twenty-four hours after the last injection of metformin, cecal ligation and perforation were used to construct a model of myocardial injury in septic mice. The sham operation group was not ligated and perforated. All mice were sacrificed 24 hours after surgery, and blood and myocardial specimens were collected. The levels of inflammatory factors and myocardial injury markers in serum were detected by ELISA. The mRNA expression of autophagy markers LC3B and p62 in myocardial tissue was detected by RT-qPCR. The protein expression of LC3B, Beclin-1, p62, p-AMPK, and AMPK in myocardial tissue was detected by western blot. The pathological changes in myocardial tissue were detected by hematoxylin-eosin staining. RESULTS AND CONCLUSION: Autophagy was inhibited in septic mice with myocardial injury. Compared with the sham operation group, the levels of serum tumor necrosis factor-α, interleukin-1β, interleukin-6, creatine kinase isoenzyme, and troponin T were increased in the model group (P < 0.05), but there was no significant difference in p62, LC3II/LC3I, and p-AMPK/AMPK between the two groups (P > 0.05). Compared with the model group, the levels of tumor necrosis factor-α, interleukin-6, creatine kinase isoenzyme, troponin T, and p62 were decreased in the metformin group (P < 0.05), while LC3II/LC3I, p-AMPK/ AMPK and Beclin-1 level were increased (P < 0.05). Compared with the metformin group, the levels of tumor necrosis factor-α, interleukin-6, creatine kinase isoenzyme, troponin T, and p62 were increased in the metformin+3-methyladenine group (P < 0.05), while LC3II/LC3I and Beclin-1 level were decreased (P < 0.05). Myocardial hematoxylin-eosin staining indicated that myocardial fibers arranged normally in the sham operation group, but disorderedly in the model group, with interstitial edema and a large number of infiltrated inflammatory cells. A small amount of vacuolar changes were observed in the metformin group. The arrangement of myocardial fibers in the metformin+3-methyladenine group was slightly disordered, with more vacuolar changes. To conclude, metformin pretreatment may reduce myocardial injury in septic mice by activating the AMPK signaling pathway and inducing autophagy. [ABSTRACT FROM AUTHOR]

Aim: Given that metformin is often recommended for the management of type 2 diabetes mellitus, it is clinically significant to consider the potential interactions between metformin and other medications. In this study, we aimed to identify potential drug-drug interactions associated with metformin by retrospectively analyzing the prescriptions of patients taking metformin. Materials and Methods: Metformin-containing prescription data of five independent community pharmacies in Konya province for the year 2023 were analyzed retrospectively. Medscape®, Drugs® and LexiComp® software programs were used to detect potential drug-drug interactions. As a result of power analysis with the G Power program, 400 patients were included in the study with an effect size of 0.25, type 1 error of 0.05 and confidence interval of 0.95. Results: Kendall's W value indicating the agreement between Medscape®, Drugs®and LexiComp® software programs was calculated as 0.061. In terms of potential drug-drug interactions of metformin, the agreement between the software programs was observed to be slight. The highest agreement between the programs was observed between Medscape® and LexiComp® (Kappa coefficient=0.44). Conclusion: Since potential drug-drug interactions are common in prescriptions for patients taking metformin, these interactions should be carefully monitored. Clinicians should use multiple interaction programs to identify potential drug-drug interactions of metformin. [ABSTRACT FROM AUTHOR]

Simple Summary: Benign Prostatic Hyperplasia (BPH) is a prevalent condition among aging men, and recent research suggests it may be influenced by high cholesterol levels, especially oxidized LDL (OxLDL). However, how this happens is still not fully understood. This study aimed to explore how elevated OxLDL levels affect prostate cell growth and the release of small particles called extracellular vesicles (EVs), which cells use to communicate. By studying mice on a high-fat diet and human prostate cells exposed to OxLDL, we found that these conditions led to increased cell growth, potentially worsening BPH. We also discovered that OxLDL stimulated the production of EVs, further promoting cell proliferation. However, the drug metformin, commonly used to treat diabetes, was able to reduce this harmful growth. These findings provide new insights into how OxLDL may drive BPH progression and suggest that metformin could be a promising treatment to delay its development, potentially benefiting many men worldwide. Background: Clinical and experimental evidence has linked Benign Prostatic Hyperplasia (BPH) with dyslipidemic and hypercholesterolemic conditions, though the underlying cellular mechanisms remain unclear. This study investigates the impact of dyslipidemia, specifically oxidized LDL (OxLDL), on prostatic stromal cell proliferation and the release of extracellular vesicles (EVs). Methods: Mice were fed a high-fat diet, and human prostatic stromal cells (HPSCs) were treated with OxLDL. Proliferation assays and EV characterization were performed to assess the role of EVs in BPH progression. Results: Pro-atherogenic conditions significantly increased cell proliferation in both murine prostatic cells and HPSCs. Treatment with metformin effectively inhibited OxLDL-induced proliferation. Additionally, OxLDL stimulated the production and release of pro-proliferative EVs by HPSCs, which further promoted cellular proliferation. Conclusions: The findings suggest that dyslipidemia drives prostatic stromal cell proliferation and EV secretion, contributing to BPH progression. Metformin demonstrates potential as a therapeutic agent to mitigate these effects, offering insight into novel strategies for BPH management. This study highlights the complex interaction between dyslipidemia, cell proliferation, and extracellular communication in the context of BPH pathogenesis. [ABSTRACT FROM AUTHOR]

Background/Objectives: Metformin (Met), an oral drug used to treat type II diabetes, is known to control blood glucose levels. Metformin carbon quantum dots (MetCQDs) were prepared to enhance the bioavailability and effectiveness of metformin. Several studies have shown that carbon quantum dots (CQDs) have attractive properties like small particle size, high penetrability, low cytotoxicity, and ease of synthesis. CQDs are made from a carbon source, namely, citric acid, and a heteroatom, such as nitrogen. The active molecule can be a carbon source or a heteroatom, as reported here. Methods: This study aims to produce MetCQDs from an active molecule. MetCQDs were successfully produced by microwave-based production methods and characterized. The effect of the MetCQDs was tested in Wistar albino rats following a Streptozocin-induced diabetic model. Results: The results show that the products have a particle size of 9.02 ± 0.04 nm, a zeta potential of −10.4 ± 0.214 mV, and a quantum yield of 15.1 ± 0.045%. Stability studies and spectrophotometric analyses were carried out and the effectiveness of MetCQDs evaluated in diabetic rats. The results show a significant reduction in blood sugar levels (34.1–51.1%) compared to the group receiving only metformin (37.1–55.3%) over a period of 30 to 360 min. Histopathological examinations of the liver tissue indicate improvement in the liver health indicators of the group treated with MetCQDs. Conclusions: Based on these results, the products have potential therapeutic advantages in diabetes management through their increased efficacy and may have reduced side effects compared to the control group. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a complex metabolic disorder characterized by persistent hyperglycemia, resulting from either insufficient insulin production, insulin resistance, or a combination of both. The accumulation of free radicals significantly contributes to the advancement of diabetes and its associated complications. Aim: This study aims to evaluate the effectiveness of a combination of metformin and vitamin C in patients diagnosed with type 2 DM. Materials and Methods: The study involved 120 patients diagnosed with type 2 DM, who underwent a thorough medical history review, clinical examination, and biochemical assessments, including HbA1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), total antioxidant capacity (TAC), and superoxide dismutase 2 (SOD2). Participants were subsequently divided into two groups, with 60 individuals in each. Group A received metformin at a dosage of 500 mg twice daily. In comparison, Group B was administered metformin at 1000 mg along with 1000 mg of vitamin C daily, divided into two doses, for three months. FPG and PPG were measured weekly over the three months, and HbA1c, TAC, and SOD2 levels were assessed at the end of the study. Data analysis was performed using SPSS software version 26.0. Results: After three months of treatment, both groups exhibited a significant decrease in FPG, PPG, and HbA1c levels (p<0.05). However, TAC and SOD2 levels showed a substantial increase in Group B (p<0.05). Conclusion: Both treatment groups experienced a notable reduction in blood glucose levels; however, patients receiving vitamin C in combination with metformin demonstrated a significant increase in TAC and SOD2 levels, indicating a reduction in oxidative stress. Therefore, the addition of vitamin C to antidiabetic therapy may help mitigate oxidative stress-related complications associated with diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aims: The safety of continuing metformin during a hospital admission has not been robustly demonstrated. We evaluated the association of continuing metformin in hospital with the risk for a hospital‐acquired complication (HAC). Methods: This is a retrospective observational study of patients admitted to a medical or surgical ward. We considered those with diabetes who continued metformin (DM/MET group), those who discontinued metformin upon admission (DM/MET‐STOP), and those with diabetes not on metformin just prior to and during admission (DM/NoMET). We prepared propensity score‐matched (PSM) control groups from admitted patients without diabetes. The likelihood of a HAC was determined using a Kaplan–Meier survival analysis. A Cox proportional hazards model was employed to calculate the hazard ratio, adjusted for covariates. Results: Of the 4446 (14%) patients with diabetes, 3331 (10%) were prescribed metformin on admission, and it was continued in 2557 patients. HAC occurred in 5.5% of DM/MET group and 6.4% of the PSM control group. Continuation of metformin was associated with a lower likelihood of HAC, adjusted hazard ratio 0.85 (95% CI 0.69, 1.04), p = 0.117 compared to a PSM‐matched control group without diabetes. The DM/NoMET and DM/MET‐STOP groups had an increased risk for HAC, adjusted HR 1.77 (1.44, 2.18), p < 0.001 and 2.57 (2.10, 3.13), p < 0.001, as compared to their respective PSM control groups. Conclusion: An individualized assessment to continue metformin during hospital admission was associated with a reduced likelihood of HAC, with the caveat that there was limited matching to non‐diabetes controls. This finding warrants further exploration. [ABSTRACT FROM AUTHOR]

The article examines the ongoing challenges in diabetes management despite advancements in treatment and monitoring technology. Topics include the urgent need for effective decision-making tools for healthcare providers to support diabetes care, the significant role of Blood Glucose Monitoring (BGM) in diabetes management, and the limitations and accessibility issues surrounding Continuous Glucose Monitoring (CGM) that affect its adoption among individuals with diabetes.

This work combines experimental and computational modeling studies for the preparation of a composite of metformin and an organoclay, examining the advantages of a Tunisian clay used for drug delivery applications. The clay mineral studied is a montmorillonite-like smectite (Sm-Na), and the organoclay derivative (HDTMA-Sm) was used as a drug carrier for metformin hydrochloride (MET). In order to assess the MET loading into the clays, these materials were characterized by means of cation exchange capacity assessment, specific surface area measurement, and with the techniques of X-ray diffraction (XRD), differential scanning calorimetry, X-ray fluorescence spectroscopy, and Fourier-transformed infrared spectroscopy. Computational molecular modeling studies showed the surface adsorption process, identifying the clay–drug interactions through hydrogen bonds, and assessing electrostatic interactions for the hybrid MET/Sm-Na and hydrophobic interactions and cation exchange for the hybrid MET/HDTMA-Sm. The results show that the clays (Sm-Na and HDTMA-Sm) are capable of adsorbing MET, reaching a maximum load of 12.42 and 21.97 %, respectively. The adsorption isotherms were fitted by the Freundlich model, indicating heterogeneous adsorption of the studied adsorbate–adsorbent system, and they followed pseudo-second-order kinetics. The calculations of ΔGº indicate the spontaneous and reversible nature of the adsorption. The calculation of ΔH° indicates physical adsorption for the purified clay (Sm-Na) and chemical adsorption for the modified clay (HDTMA-Sm). The release of intercalated MET was studied in media simulating gastric and intestinal fluids, revealing that the purified clay (Sm-Na) and the modified organoclay (HDTMA-Sm) can be used as carriers in controlled drug delivery in future clinical applications. The molecular modeling studies confirmed the experimental phenomena, showing that the main adsorption mechanism is the cation exchange process between proton and MET cations into the interlayer space. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a prevalent disease in the general population and also a well-established risk factor for the development of ischemic stroke. Patients who have been diagnosed with diabetes have a 20% higher risk for developing ischemic stroke in comparison to non-diabetic individuals. The aim of the current systematic review is to provide the latest evidence regarding the association between antidiabetic treatment and the prevention of ischemic stroke. Methods: A comprehensive search in scientific literature databases PUBMED, COCHRANE, and SCOPUS was conducted. The studies that were deemed as eligible for this review were those that examined the clinical benefits of therapeutic strategies in terms of preventing ischemic strokes. Results: A total of 32 studies met the established selection criteria. The included studies showed that pioglitazone treatment significantly reduced the risk for recurrent stroke in patients with DM. Furthermore, in the context of primary prevention, the improvement in glycemic control after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RA) semaglutide and dulaglutide was associated with a reduction in the risk of ischemic stroke in diabetic subjects. Metformin monotherapy may reduce stroke risk, while dipeptidyl peptidase 4 inhibitors, sodium-glucose co-transporter 2 inhibitors, and insulin do not seem to affect the incidence of stroke. Conclusions: The findings of the present systematic review suggest that pioglitazone and GLP-1RA may decrease the risk of stroke. Further studies are needed to provide additional data regarding the preventive effect of novel antidiabetic drugs, such as dual glucose-dependent insulinotropic polypeptide/GLP-1RA agents, on stroke. [ABSTRACT FROM AUTHOR]

Introduction We previously showed that a 3-week oral metformin (MET) treatment enhances the osteogenic potential of bone marrow stromal cells (BMSCs) and improves several bone histomorphometric parameters in Wistar rats with metabolic syndrome (MetS). However, the skeletal effects of extended periods of MET need to be completely elucidated. Hence, in this study, the impact of a prolonged (3-month) MET treatment was investigated on bone architecture, histomorphometric and biomechanics variables, and osteogenic potential of BMSCs in Wistar rats with or without MetS. Materials and Methods Young male Wistar rats (n=36) were randomized into four groups (n=9) that received either 20% fructose (F), MET (MET), F plus MET treatments (FMET), or drinking water alone (Veh). Rats were euthanized, blood was collected, and bones were dissected and processed for peripheral quantitative computed tomography (pQCT) analysis, static and dynamic histomorphometry, and bone biomechanics. In addition, BMSCs were isolated to determine their osteogenic potential. Results MET affected trabecular and cortical bone, altering bone architecture and biomechanics. Furthermore, MET increased the pro-resorptive profile of BMSCs. In addition, fructose-induced MetS practically did not affect the the structural or mechanical variables of the skeleton. Conclusion A 3-month treatment with MET (with or without MetS) affects bone architecture and biomechanical variables in Wistar rats. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Metformin (Met) has been reported to play the key role in the pathogenesis of polycystic ovary syndrome (PCOS). However, the precise mechanisms underlying the actions of Met in PCOS remain incompletely understood. This study aimed to confirm the mechanism of Met interacting with a long non‐coding RNA LINC00548 in PCOS. Methods: Ovarian granulosa cells (OGCs) were incubated 500 nM dihydrotestosterone (DHT) to construct PCOS in vitro model and then were treated 20 μM Met. A series of cell experiments including Cell Counting Kit‐8, Terminal uridine nucleotide end labeling, and flow cytometry were performed to confirm the changes of OGC survival ability. Quantitative real‐time polymerase chain reaction was conducted to determine the levels of LINC00548, whereas Western blotting was applied to determine the levels of androgen receptor (AR) and klotho. Results: Met improved the cell viability and suppressed cell apoptosis in DHT‐treated OGCs. LINC00548 downregulated in DHT‐treated OGCs was upregulated by Met, and its overexpression further enhanced the positive effects of Met on the survival ability of DHT‐treated OGCs. In addition, Met could induce the upregulation of LINC00548 to suppress the activation of AR/klotho pathway in DHT‐treated OGCs. Conclusion: Overall, this study discovers that Met enhances the survival ability of OGCs in PCOS by elevating LINC00548 expression to suppress AR/klotho pathway. [ABSTRACT FROM AUTHOR]

This study investigated the antiobesity effects of black ginger extract (BGE) in high-fat diet (HFD)-induced obese mice. Mice were divided into six groups: normal diet control (NC, AIN-93G normal diet), 60% HFD control (HFD), HFD containing metformin at 250 mg/kg b.w. (Met, positive control), and HFD containing BGE at 5, 10, or 20 mg/kg b.w. for 15 weeks. BGE administration significantly prevented HFD-induced increases in weight gain, organ weight, and adipose tissue mass. Furthermore, it resulted in decreased adipogenesis and lipogenesis-related factors, including phosphorylated mitogen-activated protein kinase, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding proteins, sterol regulatory element-binding protein 1, phosphorylated cAMP response element-binding protein, glucose-6-phosphate dehydrogenase, fatty acid synthase, dephosphorylated ATP-citrate lyase, dephosphorylated acetyl-CoA carboxylase, and lipoprotein lipase, in white adipose tissues. Moreover, BGE administration enhanced lipolysis in white adipose tissue, as evidenced by elevated levels of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and protein kinase A, along with reduced levels of perilipin and phosphodiesterase 3B. BGE induced thermogenesis in brown adipose tissues, as reflected by the increased expression of AMP-activated protein kinase, uncoupling protein 1, and carnitine palmitoyltransferase 1 and decreased levels of fatty acid-binding protein 4. In conclusion, this study provides comprehensive evidence supporting the antiobesity effects of BGE, elucidating the underlying molecular mechanisms involved in preventing weight gain, suppressing adipogenesis, promoting lipolysis, and stimulating thermogenesis. These findings suggest the potential therapeutic utility of BGE in combating obesity and associated metabolic disorders (KHGASP-2023-034). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus is the most common medical condition in pregnancy, disproportionately affecting overweight or obese women and those from non-White populations. The lack of standardised screening and diagnostic consensus contributes to varying prevalence. Conventional risk factor-based screening can leave women undiagnosed, leading to increased risk of harm. If diet and lifestyle modifications fail to achieve glycaemic targets, prompt treatment should be initiated to manage glucose levels. A planned birth is crucial to ensure the best outcomes. Postpartum, women need screening for type 2 diabetes and other cardiometabolic risk factors, enrollment in diabetes prevention programmes, and counselling on the increased risk of future cardiometabolic disease for themselves and their offspring, highlighting the importance of ongoing prevention and management strategies. [ABSTRACT FROM AUTHOR]

Background Hypothesis/Objectives Methods Results Conclusions and Clinical Relevance 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.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.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.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.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. [ABSTRACT FROM AUTHOR]

Retention of drug in the harsh environment of gastrointestinal tract is a major problem faced in oral delivery system as drugs are prone to a pre-mature release in the presence of digestive enzymes in the acidic media. This reduces the bioavailability of the drug and causes other side effects in the stomach. The composite is prepared through an economically viable and green method consisting of polymers such as guar gum, chitosan and poly(vinyl alcohol) for retention of metformin in the gastric media. Montmorillonite clay was incorporated into the composite to improve its mechanical property. Physical properties such as thickness, folding endurance, swelling capacity and transparency of the films were assessed and further characterized using techniques such as Fourier Transform Infrared spectrometry, X-Ray Diffractometry, Differential Scanning Calorimetry and Scanning Electron Microscopy. The prepared films were thin and flexible with an average thickness of 90 μm and exhibited good UV resistance. Metformin containing formulation exhibited ≤ 12% drug release in the simulated gastric fluid (1.2 pH), which satisfied the primary aim of the work. The drug release kinetics evaluated using various mathematical models revealed that Korsemeyer-Peppas was the best fit model and showed R2 ≥ 0.986 revealing diffusion-controlled release pattern. Based on the results, the prepared composites could significantly resist early release of metformin in the stomach and improve its bioavailability in the system. This pH-sensitive composite can be anticipated as potential carrier for drugs experiencing pre-mature release in the gastric media. [ABSTRACT FROM AUTHOR]

In this study, we successfully fabricated and characterized core–shell electrospun nanofibers using a PCL–PEG/PCL–PEG system for the simultaneous sustained delivery of metformin and glibenclamide for the treatment of type II diabetes. The FTIR analysis confirmed the presence of the loaded drugs within the fibers, while XRD results indicated that the fibers were predominantly in the amorphous phase. FESEM micrographs revealed cylindrical fiber morphology with an average diameter ranging from 100 to 380 nm, and TEM imaging confirmed the core–shell structure. The effects of various parameters, including core/shell flow ratio, core PEG molecular weight, and shell electrical conductivity, on fiber properties and drug release kinetics were investigated. Notably, a higher shell/core flow ratio of 8:1 resulted in a 21% decrease in the total releasable drug amount ( A ∞ ) for metformin compared to a 1:1 ratio. Additionally, increasing the core PEG molecular weight from 6 to 35 kDa led to a 16% reduction in A ∞ for glibenclamide. Through mathematical modeling and optimization, the ideal formulation was identified, exhibiting an A ∞ of 4.67 mg/g and 4.19 mg/g for metformin and glibenclamide, respectively. The 60% release time (T60) for this optimized formulation was 83.28 h for metformin and 91.26 h for glibenclamide, demonstrating extended-release behavior. The comprehensive evaluations and mathematical modeling suggest that the presented core–shell drug release system outperforms fibers of the same material produced by conventional electrospinning, suggesting a promising approach for improving medication adherence in type II diabetes management. [ABSTRACT FROM AUTHOR]

Purpose: Metformin (MTF) shows promise in protecting against physical decline in osteoarthritis (OA), but how it works remains unclear. We studied MTF's effects on gut permeability and its link to physical performance in OA patients. Methods: We studied four groups: control (n = 72), OA non-diabetic (n = 58), OA diabetic on MTF (n = 55), and OA diabetic on other anti-diabetics (n = 57). We measured zonulin levels, as intestinal permeability marker, hand-grip strength (HGS), Oxford knee scoring (OKS) to determine OA severity, and short performance physical battery (SPPB) to determine physical functions. Results: Patients suffering from OA showed a reduction in HGS and SPPB scores with raised plasma zonulin than controls, irrespective of disease severity. MTF decreased plasma zonulin levels and improved OKS, gait speed, HGS, and SPPB scores in OA patients. However, OA patients taking other anti-diabetic medications demonstrated higher levels of plasma zonulin, reduced HGS, and SPPB scores. Furthermore, a robust correlation of plasma zonulin and HGS, OKS, gait speed, and SPPB scores in OA patients on MTF was observed. Moreover, we found reduced oxidative stress and inflammation associated with these alterations in OA patients treated with MTF. Conclusion: MTF improves HGS and physical performance by lowering zonulin levels, preserving gut permeability in OA patients. [ABSTRACT FROM AUTHOR]

Introduction: ISIS 449884, a 2′-O-methoxyethyl antisense oligonucleotide that targets the glucagon receptor (GCGR), has demonstrated an ability to reduce hepatic glucose output and lower the blood glucose level. The primary objective of this study was to investigate the safety and efficacy of ISIS 449884 as an add-on to metformin in a population of Chinese patients with type 2 diabetes mellitus (T2DM). Method: This was a multicenter, placebo-controlled (2:1), randomized, double-blind, parallel-enrollment, multiple-dose phase II study in Chinese patients with T2DM. A total of 90 patients who were uncontrolled by stable metformin monotherapy were randomized into three cohorts. Thirty subjects were enrolled in each cohort and received injections of ISIS 449884 (50 mg or 60 mg weekly or 100 mg every other week) or a corresponding volume of placebo (0.25 mL and 0.3 mL weekly or 0.5 mL every other week) subcutaneously in a 2:1 ratio for 16 weeks. Results: The primary efficacy endpoint was analyzed in 88 subjects (ISIS 449884, n = 59; placebo, n = 29). The corrected LS mean change from baseline in glycated hemoglobin (HbA1c) at week 17 in the pooled ISIS 449884 treatment group was − 1.31% (95% CI − 1.66%, − 0.96%), and that in the pooled placebo group was 0.15% (95% CI − 0.37%, 0.66%). The LS mean difference between the two groups was − 1.46% (95% CI − 1.92%, − 1.00%, P < 0.001). Treatment-emergent adverse events (TEAEs) occurred in 53/60 subjects (88.3%) and 25/30 subjects (83.3%) in the pooled ISIS 449884 treatment group and the pooled placebo group, respectively, with similar incidences. Drug-related TEAEs occurred in 41/60 subjects (68.3%) and 9/30 subjects (30.0%), respectively. TEAEs of grade 3 or higher occurred in 5/60 (8.3%) subjects and 2/30 (6.7%) subjects, respectively, and none of them were drug related. Conclusions: The ISIS 449884 injection add-on to metformin significantly reduced HbA1c in patients with T2DM uncontrolled by stable metformin monotherapy and showed an acceptable benefit/risk profile. Clinical Trial Registration: www.chinadrugtrials.org.cn, CTR20191096. [ABSTRACT FROM AUTHOR]

Objectives: The mannose phosphotransferase system (Man-PTS) plays crucial roles in the adaptive metabolic activity of Enterococcus faecalis (E. faecalis) in adverse environments. The aim of this study was to evaluate the role of Man-PTS in the alkaline resistance of E. faecalis against calcium hydroxide (CH) and the effect of metformin (Met) on the alkaline resistance of E. faecalis to CH. Materials and methods: The regulatory role of Man-PTS EII in the alkaline resistance of E. faecalis was firstly investigated using a wild-type highly alkaline-resistant E. faecalis XS 003, standard ATCC 29212 and Man-PTS EIID gene deficient (△mptD) and overexpressing (+mptD) strains of E. faecalis. RNA sequencing of Met-treated E. faecalis was performed to further validate the effect of Met on Man-PTS. The effect of Met on CH resistance of E. faecalis was verified by evaluating the survival, membrane potential and permeability, intracellular pH and ATP, and the expression of Man-PTS EII and membrane transporter-related genes of E. faecalis. The effect of Met on the ability of CH to remove E. faecalis biofilm on the dentin surface was also tested. The in vivo therapeutic effect of Met plus CH (CHM) was further investigated in a rat apical periodontitis model induced by E. faecalis XS 003. Results: Man-PTS EII significantly promoted the survival ability of E. faecalis in CH and enhanced its resistance to CH. The inhibition of Man-PTS EII by Met resulted in reduced alkaline resistance of E. faecalis in the presence of CH, while also enhancing the antimicrobial properties of CH against E. faecalis biofilm on dentin. Additionally, Met plus CH showed the synergistically promoted intra-canal E. faecalis infection control and healing of periapical lesion in rats. Conclusions: Met could significantly reduce the alkaline resistance of E. faecalis against CH through the modulation of Man-PTS EII, and improved the antibacterial effect of CH against E. faecalis infection both in vitro and in vivo. Clinical relevance: Met could significantly enhance the ability of CH to control E. faecalis infection through reducing the alkaline resistance of E. faecalis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

AbstractIn this study, the anti-inflammatory, antioxidative, and protective effects of ghrelin were investigated in a fat-fed streptozotocin (STZ) rat model and compared with metformin, diabetes and the healthy control groups. Histopathological evaluations were performed on H&E-stained pancreas and brain sections. Biochemical parameters were investigated by enzyme-linked immunosorbent assay. Blood glucose levels were significantly decreased with ghrelin or metformin treatments than the diabetes group. STZ administration increased brain, renal and pancreatic IL-1β, TNF-α and MDA while decreasing GPX, CAT, SOD, and NGF levels. Ghrelin increased renal GPX, CAT, NGF pancreatic GPX, SOD, CAT, NGF and brain SOD, NGF while it decreased renal, pancreatic and brain IL-1β, TNF-α and MDA levels. Ghrelin reduced neuronal loss and degeneration in the cerebral cortex and hippocampus and greatly ameliorated diabetes-related damage in pancreas. In conclusion, the data suggested that ghrelin is an effective candidate as a protectant for reducing the adverse effects of diabetes. [ABSTRACT FROM AUTHOR]

Background: The anti-neoplastic activity of metformin is a subject of current debate. Preclinical data have suggested that metformin enhances PD-L1 anti-tumor effects in various cancer entities by decreasing insulin levels and inducing energetic stress. However, its impact on PD-L1 expression remains unclear in a clinical setting. Therefore, we aim to investigate the impact of metformin treatment in type 2 diabetes mellitus (DM) patients on PD-L1 expression in patients with oral squamous cell carcinoma (OSCC). Methods: We performed a retrospective analysis of patients with DM and OSCC treated at our tertiary referral center over a period of 12 years. The tumor proportion score (TPS), immune cell score (IC), and combined positive score (CPS) were used to quantify PD-L1 expression. PD-L1 expression of patients receiving metformin was compared to a control group without metformin prescription. Results: A total of 68 patients diagnosed with OSCC and DM were analyzed, with 24 receiving and 44 not receiving metformin therapy. No statistically significant differences were identified between the metformin and non-metformin groups for any of the scores (TPS: p = 0.818; IC: p = 0.748; CPS: p = 0.387). Conclusions: In contrast to previous studies, we could not find significant differences in PD-L1 expression between patients with and without metformin intake. Further research needs to shed light on the exact mechanism of metformin in different tumor entities. A comprehensive understanding of metformin's role in cancer therapy could provide valuable insights for potential use of metformin as an adjuvant treatment to immune checkpoint therapy. [ABSTRACT FROM AUTHOR]

Our hypothesis is that myoinositol and metformin in pregnant women with high-risk factors for glucose intolerance would reduce insulin resistance and consequently lower the incidence of gestational diabetes mellitus (GDM), a metabolic disorder of pregnancy characterized by maternal hyperglycemia due to deficient response to physiological insulin resistance, which may have a negative impact on perinatal outcome and long-term sequelae. In recent years, this pathology has become increasingly important given the global obesity epidemic and the delay in becoming pregnant, especially in industrialized countries. For this reason, the attempt to prevent, rather than cure, gestational diabetes is particularly important. In addition to lifestyle changes (especially diet and doing more exercise), myoinositol and metformin are the most promising factors at the moment, although not all RCTs published so far agree on their real effectiveness. A review of the articles published so far allows us to assume, albeit with some distinctions, that they can play a positive role. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is the ninth-leading cause of cancer-related deaths worldwide. Diabetic patients have an increased risk and mortality rates for PC. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and metformin (Met) are widely used anti-diabetic medications. Both Met and SGLT2 inhibitors have anticancer properties in PC, but nothing is known concerning their combined effect. So, we investigated the in vitro effect of SGLT2 inhibitors combined with Met. Canagliflozin and dapagliflozin possessed cytotoxic, antiproliferative, and pro-apoptotic properties in the tested PC cell lines. In PANC-1 cells, the antimigratory and pro-apoptotic effects were enhanced when dapagliflozin was combined with Met, and G1 cell cycle arrest was enhanced when dapagliflozin or canagliflozin was combined with Met. In AsPC-1 cells, the cytotoxic effect and the G1 cell cycle arrest were enhanced when canagliflozin and dapagliflozin, respectively, were combined with Met. Only the cytotoxic effects of SGLT2 inhibitors, but not the combination treatments, involved PI3K and JNK-dependent pathways in AsPC-1 cells. In conclusion, combination treatments increased the anticancer effects in a cell type-dependent way in the two investigated cell lines. Additionally, the cytotoxic effect of SGLT2 inhibitors was dependent on the PI3K and JNK pathways in AsPC-1 cells, but Met appears to act via a distinct mechanism. [ABSTRACT FROM AUTHOR]

Background: Metformin plays a major part in the treatment of polycystic ovarian syndrome.Trials are being conducted to compare the effectiveness of combination of metformin with cabergoline in the treatment of hyperprolactinemia and polycystic ovarian syndrome. Objectives: The purpose of this study is to compare the effectiveness of metformin monotherapy and combination therapy with cabergoline versus metformin for the management of polycystic ovarian syndrome with hyperprolactinemia. Methodology: An extensive search up until 31 May 2024 of electronic databases (PubMed, Registry of Controlled Clinical Trials, Web of Sciences, SCOPUS) to find pertinent studies. An analysis was conducted with both observational data and randomized clinical trials. To compute the standard mean difference, weighted mean difference, odds ratio, and 95% confidence interval, RevMan (v5.3) was utilized. Primary outcomes that were assessed included body-mass index, regular menstruation, weight change, prolactin, testosterone, and dehydroepiandrosterone-sulfate levels. Results: Three randomized controlled trials and 1 observational study, taking a total patient population of n = 535, were part of our final analysis. Prolactin (SMD = −3.23 95% CI: (−4.90, −1.55)) and dehydroepiandrosterone-sulfate levels (SMD = −0.27 95% CI: (−0.52, −0.01)) were significantly lower in the metformin and cabergoline combination therapy group; monthly regularity was also significantly higher (OR = 3.07 95% CI: (2.09, 4.51)). Statistically, there was no significant difference in weight, body-mass index, or testosterone levels. Conclusions: In the treatment of polycystic ovarian syndrome, the combination of metformin and cabergoline significantly lowers prolactin levels and encourages regular menstrual cycles. Although metformin has the potential to suppress testosterone levels, more investigation is required to determine how combination therapy affect dehydroepiandrosterone-sulfate and testosterone levels. It's interesting to note that while neither intervention had a substantial impact on weight or body-mass index, metformin and cabergoline combination therapy outperformed metformin monotherapy in terms of supporting regular menstrual cycles. Customized therapy approaches are essential, and large-scale trials involving a variety of groups are required to comprehend the safety and effectiveness of treatments. Plain language summary: Efficacy of metformin compared to metformin and cabergoline combination In this study, 2 therapies for women with high prolactin levels—a hormone associated with PCOS—were examined. Their goal was to determine which combination of metformin and cabergoline produced the best results.Observational data and randomized clinical trials were included while searching through several databases for pertinent studies. Researchers discovered that the combination of metformin and cabergoline was superior to using metformin alone in reducing prolactin and another hormone called DHEAS. The menstrual periods of women receiving the combined therapy were also more regular. However, there wasn't much difference in weight, body mass index (BMI), or testosterone levels between the 2 groups. In summary, it appears that the combination of cabergoline and metformin is a more effective way to treat the symptoms of PCOS, which include irregular periods and elevated prolactin levels. To find out how it impacts other hormones and whether it's long-term safe and effective, further research is still required. [ABSTRACT FROM AUTHOR]

Metformin is the most commonly prescribed medication for treating type 2 diabetes (T2D). It is known that metformin can alter the gut microbiome, which influences the effectiveness of metformin treatment. We posited that if the gut microbiome, a reservoir of the resistome, is altered, then the resistome should change as well. To test this hypothesis, we reanalyzed microbiome data generated by Wu et al. (Nat Med 23(7):850–858, 2017), identifying antibiotic resistance genes (ARGs) and bacterial species. Through read-based analysis, we observed that the abundance of ARGs indeed changed in many samples treated with metformin. Moreover, the altered pattern was sufficiently heterogeneous across individual samples to allow subcategorization. We also found a strong correlation between the abundance of multidrug-resistant ARGs (MDR-ARGs) and the presence of E. coli. The contig-based analysis led to the same conclusion: an increase in MDR-ARGs due to metformin was associated with an increase in E. coli. In relation to this, we were able to confirm that the majority of MDR-ARGs are likely to originate from E. coli. These results suggest that metformin may have the potential side effect of increasing E. coli carrying ARGs, particularly MDR-ARGs, which could be a concern in T2D therapy that relies on metformin. [ABSTRACT FROM AUTHOR]

Background: Recent studies have highlighted type 2 diabetes (T2DM) as a significant risk factor for the development of metabolic dysfunction-associated fatty liver disease (MAFLD). This investigation aimed to assess electroacupuncture's (EA) impact on liver morphology and function in T2DM rats, furnishing experimental substantiation for its potential to stall MAFLD progression in T2DM. Methods: T2DM rats were induced by a high-fat diet and a single intraperitoneal injection of streptozotocin, and then randomly assigned to five groups: the T2DM group, the electroacupuncture group, the metformin group, combination group of electroacupuncture and metformin, combination group of electroacupuncture and Compound C. The control group received a standard diet alongside intraperitoneal citric acid - sodium citrate solution injections. After a 6-week intervention, the effects of each group on fasting blood glucose, lipids, liver function, morphology, lipid droplet infiltration, and fibrosis were evaluated. Techniques including Western blotting, qPCR, immunohistochemistry, and immunofluorescence were employed to gauge the expression of key molecules in AMPK-associated glycolipid metabolism, insulin signaling, autophagy, and fibrosis pathways. Additionally, transmission electron microscopy facilitated the observation of liver autophagy, lipid droplets, and fibrosis. Results: Our studies indicated that hyperglycemia, hyperlipidemia and IR promoted lipid accumulation, pathological and functional damage, and resulting in hepatic steatosis and fibrosis. Meanwhile, EA enhanced the activation of AMPK, which in turn improved glycolipid metabolism and autophagy through promoting the expression of PPARα/CPT1A and AMPK/mTOR pathway, inhibiting the expression of SREBP1c, PGC-1α/PCK2 and TGFβ1/Smad2/3 signaling pathway, ultimately exerting its effect on ameliorating hepatic steatosis and fibrosis in T2DM rats. The above effects of EA were consistent with metformin. The combination of EA and metformin had significant advantages in increasing hepatic AMPK expression, improving liver morphology, lipid droplet infiltration, fibrosis, and reducing serum ALT levels. In addition, the ameliorating effects of EA on the progression of MAFLD in T2DM rats were partly disrupted by Compound C, an inhibitor of AMPK. Conclusions: EA upregulated hepatic AMPK expression, curtailing gluconeogenesis and lipogenesis while boosting fatty acid oxidation and autophagy levels. Consequently, it mitigated blood glucose, lipids, and insulin resistance in T2DM rats, thus impeding liver steatosis and fibrosis progression and retarding MAFLD advancement. [ABSTRACT FROM AUTHOR]

Lifestyle modifications, metformin, and linagliptin reduce the incidence of type 2 diabetes (T2D) in people with prediabetes. The gut microbiota (GM) may enhance such interventions' efficacy. We determined the effect of linagliptin/metformin (LM) vs metformin (M) on GM composition and its relationship to insulin sensitivity (IS) and pancreatic β-cell function (Pβf) in patients with prediabetes. A cross-sectional study was conducted at different times: basal, six, and twelve months in 167 Mexican adults with prediabetes. These treatments increased the abundance of GM SCFA-producing bacteria M (Fusicatenibacter and Blautia) and LM (Roseburia, Bifidobacterium, and [Eubacterium] hallii group). We performed a mediation analysis with structural equation models (SEM). In conclusion, M and LM therapies improve insulin sensitivity and Pβf in prediabetics. GM is partially associated with these improvements since the SEM models suggest a weak association between specific bacterial genera and improvements in IS and Pβf. [ABSTRACT FROM AUTHOR]