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Scientific Reports Oct 2023Type 2 diabetes and thyroid function disorders are two common chronic endocrine disorders with the high prevalence in various populations. Metformin is well established... (Meta-Analysis)
Meta-Analysis
Type 2 diabetes and thyroid function disorders are two common chronic endocrine disorders with the high prevalence in various populations. Metformin is well established as the first-line drug therapy for managing diabetes mellitus. In this meta-analysis, we aimed to determine the effect of metformin on serum TSH and FT4 concentrations in patients with type 2 diabetes. We searched PubMed, Scopus, web of science, Cochrane library, and google scholar to collect information on the effect of metformin on serum TSH and FT4 levels. Demographic and clinical information and serum TSH and FT4 concentrations before and after metformin treatment were extracted. Studies on patients over 18 years of age were included. A total of 11 studies including 1147 patients were selected for the final analysis. In hypothyroid patients, the TSH level decreased significantly after treatment with metformin (Hedges's g:1.55, 95%CI 0.93-2.16, p-value < 0.001); FT4 level increased slightly after taking metformin, but the increase was not significant (Heddges's g: - 0.30, 95%CI - 0.90,0.31, p-value = 0.34). In euthyroid subjects, the slight decrease found in TSH and FT4 concentrations was not statistically significant. Metformin reduces TSH levels in hypothyroid patients; however, it has no effect on TSH levels in euthyroid patients. Metformin does not affect serum FT4 levels in euthyroid and hypothyroid patients.
Topics: Humans; Adolescent; Adult; Metformin; Diabetes Mellitus, Type 2; Thyroxine; Thyrotropin; Thyroid Hormones; Hypothyroidism; Triiodothyronine
PubMed: 37907510
DOI: 10.1038/s41598-023-43266-9 -
Free Radical Biology & Medicine Sep 2023Hyperglycemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Currently, no approved drug is available for...
Metformin suppresses cardiac fibroblast proliferation under high-glucose conditions via regulating the mitochondrial complex I protein Grim-19 involved in the Sirt1/Stat3 signaling pathway.
Hyperglycemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Currently, no approved drug is available for preventing or treating diabetes-induced cardiac fibrosis. Metformin has been reported to improve glycemic control and ameliorate diabetic cardiomyopathy. This study aimed to investigate the effects and mechanism of metformin on diabetes-induced cardiac fibrosis and high glucose-induced proliferation of cardiac fibroblasts (CFs). In this study, db/db mice were treated with metformin [250 mg/kg⋅d, gavage]. CFs were cultured in high-glucose medium to mimic an in vitro diabetes model and then subjected to treatment with or without metformin. Cardiac fibrosis was analyzed using immunohistochemistry, Masson's trichrome staining, and Western blot analysis. Cell Counting Kit-8 (CCK-8) assays and cell colony formation assays were used to examine cell proliferation capacity. Transwell and scratch-wound assays were used to detect the migration ability of CFs. Retinoid-interferon-induced mortality-19 (Grim-19), sirtuin1 (Sirt1), and signal transducer and activator of transcription 3 (Stat3) were detected using Western blot analysis. The genes downstream of the Stat3 pathway were detected using quantitative reverse transcription PCR (qRT‒PCR). Metformin treatment markedly attenuated cardiac fibrosis in db/db mice and the proliferation and migration of CFs under high-glucose conditions. Mechanistically, we found an intersection between metformin and Grim-19 using bioinformatics. Metformin was found to suppress the expression of p-Stat3 and elevate the expression of mitochondrial complex I protein Grim-19 and Sirt1, thus inhibiting the proliferation and migration of CFs under high-glucose conditions. Our data suggested that metformin inhibited the proliferation and migration of CFs by regulating the expression of mitochondrial complex I Grim-19 protein involved in the Sirt1/Stat3 signaling pathway under high-glucose conditions, thus providing new ideas for treating diabetes-induced cardiac fibrosis.
Topics: Mice; Animals; Sirtuin 1; Metformin; Diabetic Cardiomyopathies; STAT3 Transcription Factor; Signal Transduction; Cell Proliferation; Electron Transport Complex I; Glucose; Fibroblasts; Fibrosis
PubMed: 37353174
DOI: 10.1016/j.freeradbiomed.2023.06.013 -
International Journal of Molecular... Aug 2023The tumor microenvironment (TME) plays a pivotal role in the fate of cancer cells, and tumor-infiltrating immune cells have emerged as key players in shaping this... (Review)
Review
The tumor microenvironment (TME) plays a pivotal role in the fate of cancer cells, and tumor-infiltrating immune cells have emerged as key players in shaping this complex milieu. Cancer is one of the leading causes of death in the world. The most common standard treatments for cancer are surgery, radiation therapy, and chemotherapeutic drugs. In the last decade, immunotherapy has had a potential effect on the treatment of cancer patients with poor prognoses. One of the immune therapeutic targeted approaches that shows anticancer efficacy is a type 2 diabetes medication, metformin. Beyond its glycemic control properties, studies have revealed intriguing immunomodulatory properties of metformin. Meanwhile, several studies focus on the impact of metformin on tumor-infiltrating immune cells in various tumor models. In several tumor models, metformin can modulate tumor-infiltrated effector immune cells, CD8, CD4 T cells, and natural killer (NK) cells, as well as suppressor immune cells, T regulatory cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). In this review, we discuss the role of metformin in modulating tumor-infiltrating immune cells in different preclinical models and clinical trials. Both preclinical and clinical studies suggest that metformin holds promise as adjunctive therapy in cancer treatment by modulating the immune response within the tumor microenvironment. Nonetheless, both the tumor type and the combined therapy have an impact on the specific targets of metformin in the TME. Further investigations are warranted to elucidate the precise mechanisms underlying the immunomodulatory effects of metformin and to optimize its clinical application in cancer patients.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Immunotherapy; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes
PubMed: 37686159
DOI: 10.3390/ijms241713353 -
Journal of Clinical Oncology : Official... Dec 2023JCO Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin (... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer.
JCO Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin ( placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; = .13. These included 48 contralateral invasive breast cancers (27 metformin 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; = .40 and 136 new nonbreast primary cancers (75 metformin 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.
Topics: Female; Humans; Breast Neoplasms; Canada; Double-Blind Method; Metformin
PubMed: 37695982
DOI: 10.1200/JCO.23.00296 -
Biomedicine & Pharmacotherapy =... Dec 2023Metformin (Met) is the recommended first-line therapeutic drug for type 2 diabetes mellitus (T2DM) and exerts protective effects on β-cell damage. Ferroptosis, a new...
Metformin (Met) is the recommended first-line therapeutic drug for type 2 diabetes mellitus (T2DM) and exerts protective effects on β-cell damage. Ferroptosis, a new form of cell death, is associated with pancreatic islet injury in patients with T2DM. However, the protective effects of Met treatment against β-cell damage through ferroptosis modulation remain under-reported. This study investigated the in vivo effects of Met treatment on pancreatic β-cell ferroptosis using two different diabetic mouse models, namely, low-dose streptozotocin (STZ) and high-fat diet (HFD)-induced diabetic mice and db/db mice. Met treatment significantly restored insulin release, reduced cell mortality, and decreased the overproduction of lipid-related reactive oxygen species in the islets of both STZ/HFD-induced diabetic mice and db/db mice. Administration of the Ras-selective lethal 3 injection significantly attenuated the antiferroptosis effects of Met. Mechanistically, Met treatment alleviated β-cell ferroptosis in T2DM, which was associated with the regulation of the GPX4/ACSL4 axis in the islets. In conclusion, our findings highlight the significance of ferroptosis in T2DM β-cell damage and provide novel insights into the protective effects of Met against islet β cells.
Topics: Humans; Mice; Animals; Diabetes Mellitus, Type 2; Metformin; Diabetes Mellitus, Experimental; Ferroptosis; Insulin-Secreting Cells; Insulin
PubMed: 37924788
DOI: 10.1016/j.biopha.2023.115835 -
Journal of Developmental and Behavioral... Dec 2023We compared cognitive profile and neuropsychological performance in 9-year-old offspring of mothers who were treated with metformin or insulin for gestational diabetes... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
We compared cognitive profile and neuropsychological performance in 9-year-old offspring of mothers who were treated with metformin or insulin for gestational diabetes mellitus (GDM).
METHODS
A total of 172 children whose mothers were randomly assigned to receive either metformin or insulin for GDM were studied at the age of 9 years. Of these children, 127 were from Turku, Finland (63 metformin and 64 insulin), and 45 from Oulu, Finland (19 metformin and 26 insulin). Clinical and demographic background characteristics were obtained at enrolment, birth, and 9-year follow-up. Cognitive profiles were examined at age 9 years with the Wechsler Intelligence Scale for Children. Neuropsychological functions were examined with 2 subtests of the Developmental Neuropsychological Assessment test battery assessing comprehension of instructions and narrative memory, Trail Making Test assessing attention and with Behavioral Rating Inventory of Executive Functioning, including parent-rated and teacher-rated evaluations. Academic functioning was studied with reading fluency subtest of the Screening test for reading, writing, and calculus for first to sixth grades and information about educational support received at school reported by parents.
RESULTS
The cognitive profiles, including indexes of verbal comprehension, perceptual reasoning, working memory, and processing speed, did not differ significantly between metformin-treated and insulin-treated groups. Significant differences were not found between the treatment groups in assessed neuropsychological functions, reading fluency, or received level of support at school.
CONCLUSION
Cognitive and neuropsychological outcomes were similar in 9-year-old children whose mothers had either metformin or insulin treatment of GDM.
Topics: Child; Humans; Female; Pregnancy; Insulin; Diabetes, Gestational; Mothers; Metformin; Cognition
PubMed: 38019468
DOI: 10.1097/DBP.0000000000001233 -
Journal of Ovarian Research Feb 2024To investigate the effects of metformin (MET) monotherapy and pioglitazone plus MET (PIOMET) therapy on gonadal and metabolic profiles in normal-weight women with... (Randomized Controlled Trial)
Randomized Controlled Trial
Metformin versus metformin plus pioglitazone on gonadal and metabolic profiles in normal-weight women with polycystic ovary syndrome: a single-center, open-labeled prospective randomized controlled trial.
OBJECTIVE
To investigate the effects of metformin (MET) monotherapy and pioglitazone plus MET (PIOMET) therapy on gonadal and metabolic profiles in normal-weight women with polycystic ovary syndrome (PCOS).
METHODS
Sixty normal-weight women with PCOS were recruited between January and September 2022 at the Shengjing Hospital of China Medical University. They were randomly assigned to the MET or PIOMET groups for 12 weeks of MET monotherapy or PIOMET therapy. Anthropometric measurements, menstrual cycle changes, gonadal profiles, and the oral glucose insulin-releasing test (OGIRT) were performed at baseline and after the 12-week treatment.
RESULTS
Thirty-six participants completed the trial. MET and PIOMET therapies improved menstrual cycles after the 4- and 12-week treatments; however, there was no statistical difference between the two groups. PIOMET therapy improved luteinizing hormone (LH), luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio, and free androgen index (FAI) levels after the 4-week treatment, whereas MET monotherapy only improved total testosterone (TT) levels compared to baseline (P < 0.05). Both MET and PIOMET therapies improved TT and anti-Mullerian hormone (AMH) levels after the 12-week treatment (P < 0.05). In addition, only PIOMET therapy significantly improved sex hormone-binding globulin (SHBG), FAI, and androstenedione (AND) levels than the baseline (P < 0.05). PIOMET therapy improved SHBG and AMH levels more effectively than MET monotherapy (P < 0.05). Furthermore, PIOMET treatment was more effective in improving blood glucose levels at 120 and 180 min of OGIRT compared to MET monotherapy (P < 0.05).
CONCLUSIONS
In normal-weight women with PCOS, PIOMET treatment may have more benefits in improving SHBG, AMH, and postprandial glucose levels than MET monotherapy, and did not affect weight. However, the study findings need to be confirmed in PCOS study populations with larger sample sizes.
Topics: Female; Humans; Metformin; Polycystic Ovary Syndrome; Pioglitazone; Prospective Studies; Testosterone; Luteinizing Hormone; Follicle Stimulating Hormone; Anti-Mullerian Hormone; Metabolome; Glucose
PubMed: 38374053
DOI: 10.1186/s13048-024-01367-7 -
Journal of the American Heart... Nov 2023Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2... (Randomized Controlled Trial)
Randomized Controlled Trial
Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.
Topics: Male; Adult; Humans; Female; Diabetes Mellitus, Type 2; Prediabetic State; Calcium; Coronary Vessels; Cross-Sectional Studies; Metformin; Cognitive Dysfunction; Calcinosis; Calcium, Dietary; Coronary Artery Disease; Vascular Calcification; Risk Factors
PubMed: 37929764
DOI: 10.1161/JAHA.123.029671 -
Molecules (Basel, Switzerland) Jul 2023Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized,...
Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, . This molecule showed a better potency than metformin, increasing mRNA levels in human Huh-7 hepatic cells. Based on , structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound showed a higher increase in mRNA levels compared with . Metformin, , and compound increased phosphorylated AMPK, but only increased GDF15 protein levels. Overall, these findings indicate that has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and .
Topics: Humans; Diabetes Mellitus, Type 2; AMP-Activated Protein Kinases; Growth Differentiation Factor 15; Metformin; RNA, Messenger
PubMed: 37513338
DOI: 10.3390/molecules28145468 -
International Journal of Biological... Apr 2024Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have...
Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.
Topics: Mice; Animals; Humans; Metformin; Diabetes Mellitus, Type 2; 3-Hydroxybutyric Acid; Lactic Acid; Glycogen Synthase Kinase 3; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 38503370
DOI: 10.1016/j.ijbiomac.2024.130962