ObjectiveTo investigate the effect of Metformin (MET) on the anxiety behavior of mice with Pentylenetetrazol (PTZ)-induced epilepsy and the mechanisms. MethodsSixty male 8-week-old C57BL/6 mice were randomly divided into normal control group (Normal), Temporal lobe epilepsy (TLE) model control group (TLE-con), TLE + MET treatment group (TLE-MET), and normal mice + MET intervention group (MET-con) (n=15/group). In the TLE-con group and the TLE-MET group, mice were injected intraperitoneally with PTZ every other day to establish the TLE model, while mice in the Normal group and the MET group were given the same dose of normal saline. During PTZ administration, mice in the TLE-MET treatment group and the MET-con group were intraperitoneally injected with MET at 200 mg/(kg·d) every other day, for 14 times in a total of 28 days. The mice in the Normal group and the TLE-con group were intraperitoneally injected with the same amount of normal saline. Open field test (OFT) and elevated cross maze (EPM) were used to evaluate the anxiety behavior of mice in each group, and the Western blotting analysis was performed to detect expression of Toll like receptor 4 (TLR4), Nuclear factor-kappa B (NF-κB) p65 in brain tissues. ResultsCompared with the Normal group, the TLE-con group showed decreased times in the open arm in the EPM test (P<0.01) and in the center of open field in the OFT test (P<0.01), while MET intervention could increase the times of epileptic mice in the central area and the open arm (P<0.05). Compared with the Normal group, the expression of TLR4 and NF-κB in the cerebral cortex in the TLE-con group was increased significantly (P<0.05), while MET intervention could partially decrease the expression of TLR4 and NF-κB in the cerebral cortex of epileptic mice (P<0.05). ConclusionMET may improve the anxiety behavior of epileptic mice by reducing the inflammatory TLR4–NF-κB pathway.
Objective To observe the synergistic effect of metformin and anti-vascular endothelial growth factor (VEGF) in the treatment of diabetic retinopathy. Methods This study was composed of clinical data review and in vitro cell experiment. Ten patients (12 eyes) with diabetic macular edema treated with anti-VEGF drugs were included in the study. Patients were randomly divided into the VEGF group (anti-VEGF drug therapy) and the combined treatment group (anti-VEGF drug combined with metformin). The changes of visual acuity and central retinal thickness (CRT) were compared between the two groups. As far as the in vitro experiment was concerned, vascular endothelial cells were divided into the control group (normal cells), the VEGF group (50 ng/ml VEGF), the anti-VEGF group (50 ng/ml VEGF+2.5 μg/ml of conbercept), and the combined group (50 ng/ml VEGF +2.5 μg/ml of conbercept +2.0 mmol/L of metformin). And then MTT cell viability assay, scratch assay and real-time quantitative polymerase chain reaction assay were performed to analyze the cell viability, cell migration and mRNA level of VEGFR2, protein kinase C (PKC)-α and PKC-β successively. ResultsReview of clinical trial shows that the CRT recovery rates in the combined treatment group were much higher than that in the VEGF group at 3 month after the operation, while the difference was statistically significant (t=−2.462, P＜0.05). In vitro cell experiment results showed that VEGF induction upregulated the viability and mobility of vascular endothelial cells obviously compared with control group, at the same time, the use of anti VEGF drugs can effectively reverse the trend, in contrast, combination of metformin and anti-VEGF showed a more superior effect to some extent (P＜0.05). In the VEGF group, the mRNA expression of VEGFR2, PKC-αand PKC-β were significantly increased compared with the control group (P＜0.01); while the mRNA expression of VEGFR2, PKC-αand PKC-β in the combination group decreased significantly compared with the VEGF group and the control group (P＜0.05). However, in the anti-VEGF group, the mRNA expression of VEGFR2, PKC-αand PKC-β were decreased, but has failed to reach the level of statistical learn the difference. ConclusionsThe combination of metformin and anti-VEGF drugs can reduce the CRT of diabetic retinopathy patients and inhibit the proliferation and migration of retinal vascular endothelial cells which induced by VEGF. The synergistic mechanism may be related to the inhibitory effect of metformin on the expression of VEGFR and PKC.
Objective To formulate an evidence-based treatment plan for a patient with gestational diabetes mellitus. Methods Based on the clinical questions raised from a real-life patient of gestational diabetes mellitus, we searched ACP Journal Club (1991 to Dec. 2006), The Cochrane Library (Issue 4, 2006), MEDLINE (1966 to Dec. 2006) and Chinese Biological Medical Database (1980 to Dec. 2006) for systematic reviews, randomized controlled trials, cohort and case-control studies. We used the following keywords: gestational diabetes, metformin, and pregnancy complication. The quality of the included studies was assessed.Results One meta-analysis (from MEDLINE) and two randomized controlled trials (from the Cochrane Central Register of Controlled Trials) were included. These studies concluded that there was no clear evidence on the benefits of metformin for gestational diabetes. Based on the current evidence, integrated with clinical expertise and the patient’s values, metformin was not used for this patient. Instead, intensive dietary control, blood glucose control, and appropriate exercise were administered. After this individual treatment, the patient gave birth to a healthy baby in 39+4 Weeks. Conclusion The appropriate management for gestational diabetes mellitus has been formulated with the approach of evidence-based medicine. Large-scale, methodologically-sound trials are required.
Objective To assess the effects and safety of sitagliptin combined with metformin in treating type 2 diabetes mellitus. Methods The Cochrane Library, PubMed, EMbase, CNKI, WanFang Data, VIP and CBM were searched to collect the randomized controlled trials (RCTs) on sitagliptin combined with metformin in treating Type 2 diabetes mellitus (T2DM) from inception to November, 2012. References of included studies were also retrieved. Two reviewers independently screened studies according to exclusion and inclusion criteria, extracted data, and assessed the methodological quality. Then, meta-analysis was performed using RevMan 5.1 software. Results 7 RCTs involving 2 917 patients were included. The results of meta-analysis showed that, compared with metformin alone, sitagliptin combined with metformin effectively improved HbA1c levels (WMD= –0.62%, 95%CI –0.76 to –0.47, Plt;0.000 1) and fasting plasma glucose levels (WMD= –0.7 mmol/L, 95%CI –1.03 to –0.37, Plt;0.000 01), and increased insulin sensitivity and β-cell function. But there was no significant difference between the two groups in the incidences of gastrointestinal reactions and hypoglycemia. Conclusion Compared with using metformin alone, sitagliptin combined with metformin can improve glycemic control, enhance insulin sensitivity and better β-cell function more effectively and both have a similar effect on weight lose, but there is no significant difference he incidences of gastrointestinal reactions and hypoglycemia. The above conclusion should be verified by more large-scale high-quality studies in future due to the limitations of the methodological quality and sample size of the included studies.
Objective To evaluate the efficacy and safety of rosiglitazone versus metformin in treating polycystic ovary syndrome (PCOS). Methods Randomized controlled trials (RCTs) about rosiglitazone versus metformin in treating PCOS were retrieved on computer in MEDLINE, The Cochrane Library, EMbase, EBSCO, CBM, CNKI, Chinese Medical Association Journal Database and VIP from the date of their establishment to December 2010. The trials were screened according to the inclusion and exclusion criteria by two reviewers independently, the data were extracted, the methodological quality was assessed, and finally meta-analysis was conducted with Stata 11.0 software. Results A total of six RCTs involving 286 PCOS patients were included. The results of meta-analyses showed that there was no significant difference between rosiglitazone and metformin in improving PCOS patients’ insulin sensitivity (SMD= –0.14, 95%CI –0.46 to 0.19, P=0.412) and lowering androgen levels (SMD=0.05, 95%CI –0.26 to 0.36, P=0.747). However, the effect of rosiglitazone was inferior to metformin in lowing patients’ weight with a significant difference (SMD=0.34, 95%CI 0.11 to 0.58, P=0.004). The rosiglitazone showed a lower incidence rate of adverse reaction compared with metformin. Conclusion Compared with metformin, the rosiglitazone is eqully effective in improving PCOS patients’ insulin sensitivity and lowering androgen levels, and has a lower incidence rate of adverse reaction although it is inferior to metformin in lowing patients’ weight. So rosiglitazone is more applicable for the patients who are of underweight or cannot tolerate the gastrointestinal side effects induced by metformin. There is no enough evidence for this conclusion due to the small sample size and limited number of RCTs. More high-quality, large-sample and multicentered RCTs are required to guide clinical treatment and benefit patients.
Objective To explore the role of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) in estrogen-induced proliferation of endometrial cancer, and explore whether metformin inhibits the proliferation of endometrial cancer cells through ERα and ERβ. Methods Stable transfected Ishikawa cells were constructed by lentivirus. The effects of down-regulated ERα and ERβ on estrogen-induced Ishikawa cell proliferation were detected by methyl thiazolyl tetrazolium assay. The effects of down-regulated ERα and ERβ on estrogen-induced Ishikawa cell cycle were detected by flow cytometry. In addition, quantitative real-time polymerase chain reaction and Western blotting assays were used to detect changes in the expression of cyclinD1 and P21 involved in cell cycle regulation. The effects of down-regulated ERα and ERβ on estrogen-induced Ishikawa cell proliferation were observed by adding metformin to estrogen treatment. Results Down-regulation of ERα inhibited the proliferation and cell cycle of Ishikawa cells (P<0.05). Down-regulation of ERα also inhibited the expression of cyclinD1 and promoted the expression of P21 (P<0.05). Down-regulation of ERα counteracted the effect of estrogen-induced cell proliferation, cell cycle, and the expression changes of cyclinD1 and P21 (P<0.05). Down-regulation of ERβ promoted the proliferation and cell cycle of Ishikawa cells (P<0.05). Down-regulation of ERβ also promoted the expression of cyclinD1 and inhibited the expression of P21 (P<0.05). Down-regulation of ERβ enhanced the effect of estrogen-induced cell proliferation, cell cycle, and the expression changes of cyclinD1 and P21 (P<0.05). Metformin inhibited the proliferation of estrogen-induced Ishikawa cells (P<0.05), while in the down-regulated ERα Ishikawa cells or down-regulated ERβ Ishikawa cells, the inhibition of metformin on Ishikawa cells disappeared (P<0.05). Conclusions ERα may promote estrogen-induced proliferation of endometrial cancer cells, while ERβ may inhibit estrogen-induced proliferation of endometrial cancer cells. In addition, ERα and ERβ may also mediate the inhibitory effect of metformin on endometrial cancer cells.
ObjectiveTo observe the effect of metformin on the polarization state and photoreceptor cell activity of microglia (BV2 cells) in a high glucose environment. MethodsAn experimental study. BV2 cells were divided into a control group, a high glucose group, and a metformin+high glucose group. The cells in the high glucose group were cultured with 75 mmol/L glucose in the medium; the cells in the metformin+high glucose group were pretreated with 2 mmol/L metformin for 12 h and then placed in 75 mmo/L glucose concentration medium. The relative expression of M1 marker inducible nitric oxide synthase (iNOS), CD86 and M2 markers arginase 1 (Arg-1), and CD206 protein were detected by Western blot. Interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-4 were detected by enzyme-linked immunosorbent assay (ELISA). BV2 cells were co-cultured with mouse retinal photoreceptor cells (661W cells) for 24 h. The proliferation rate of 661W cells in each group was measured by methyl thiazolyl tetrazolium (MTT) colorimetric assay; the apoptosis rate of 661W cells in each group was measured by flow cytometry and terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL). An independent sample t-test was used for comparison between groups. ResultsWestern blot assay showed that the relative expression of iNOS and CD86 protein was increased and the relative expression of Arg-1 and CD206 protein was decreased in BV2 cells in the high glucose group compared with the control group, and the differences were all statistically significant (t=－16.783, －11.605, 4.325, 4.649; P＜0.05); compared with the high glucose group, the relative expression of iNOS and CD86 protein was decreased and the relative expression of Arg-1 and CD206 protein was increased in BV2 cells in the metformin + high glucose group compared with the high glucose group, and the differences were all statistically significant (t=7.231, 5.560, －8.035, －8.824; P＜0.01). ELISA results showed that compared with the control group, the BV2 cells in the high glucose group had increased IL-6, TNF-α content and IL-4 content was decreased in BV2 cells in the high glucose group compared with the control group, and the differences were all statistically significant (t=－64.312, －127.147, 71.547; P＜0.001); compared with the high glucose group, IL-6 and TNF-α content was significantly decreased and IL-4 content was significantly increased in BV2 cells in the metformin+high glucose group, and the differences were all statistically significant (t=44.426, 83.232, －143.115; P＜0.001). After co-culture of BV2 cells with 661W cells for 24 h, the results of MTT colorimetric assay showed that compared with the control group, the activity of 661W cells in the high glucose group was significantly reduced, and the difference was statistically significant (t=7.456, P＜0.01); compared with the high glucose group, the activity of 661W cells in the metformin+high glucose group was increased (t=－3.076, P＜0.05). TUNEL method and flow cytometry showed that the apoptosis rate of 661W cells in the high glucose group was significantly higher compared with the control group, and the differences were both statistically significant (t=－22.248, －22.628; P＜0.001); compared with the high glucose group, the apoptosis rate of 661W cells in the metformin+high glucose group was significantly decreased, and the difference was statistically significant (t=11.767, 6.906; P＜0.001, 0.01). ConclusionIn the high glucose environment, metformin inhibited the inflammatory response and attenuated the apoptosis of photoreceptor cells by regulating the polarization of microglia toward the M2 type.
ObjectiveTo explore the relationship between metformin use and the risk and prognosis of esophageal cancer in patients with diabetes.MethodsThe PubMed, Web of Science, EMbase, VIP, WanFang and CNKI databases were searched by computer to identify relevant studies from inception to August 21, 2021. Newcastle-Ottawa scale (NOS) was used to evaluate research quality. The STATA 12.0 software was used to conduct the statistical analysis.ResultsA total of 14 studies involving 5 605 218 participants were included finally. NOS of all researches were≥6 points. The pooled results indicated that metformin use could decrease the risk of esophageal cancer in diabetics (OR=0.84, 95%CI 0.71-1.00, P=0.045), and could also prolong the overall survival of diabetics with esophageal cancer (HR=0.89, 95%CI 0.80-0.99, P=0.025).ConclusionMetformin use can not only decrease the risk of esophageal cancer in patients with diabetes, but also improve the prognosis of diabetics with esophageal cancer significantly. However, more prospective high-quality studies are still needed to verify the conclusion.
Objective To evaluate the efficacy and safety of metformin for metabolic syndrome. Methods We searched The Cochrane Library, MEDLINE, EMBASE, China Biological Medicine Database, VIP, and CMAC up to the year of 2007. Handsearches and additional searches were also conducted. Randomized controlled trials of metformin for metabolic syndrome were included. Two reviewers independently extracted data from eligible studies and evaluated the quality of included studies. Meta-analysis was performed for the results of homogeneous studies by The Cochrane Collaboration’s software RevMan 4.2.9. Results Six trials involving a total of 2442 patients with metabolic syndrome were included. Meta-analysis was not performed due to the apparent heterogeneity. Metformin, compared with placebo, exhibited more favorable effects in reducing the proportion of patients with metabolic syndrome (RR 1.27, 95% CI 1.01 to 1.60), the proportion of patients with low HDL-c (RR 1.61, 95%CI 1.16 to 2.23), wide waist circumference (RR 1.64, 95%CI 1.06 to 2.55), and high FPG (RR 1.55, 95%CI 1.17 to 2.05). Metformin was also more effective in improving FPG and insulin sensitivity. The addition of metformin to atenolol plus nitrendipine was superior to atenolol plus nitrendipine alone in reducing the proportion of patients with high TG (RR 5.57, 95%CI 1.56 to 19.84), abdominal obesity (RR 14.47, 95%CI 3.34 to 62.61), and IGT (RR 16.51, 95%CI 6.06 to 45.0). Compared with low-fat diet therapy, metformin was superior in improving FPG, 2-hour postload plasma glucose, and insulin sensitivity. No differences were observed between metformin and acarbose in the reduction of TG and FPG, but metformin was less effective than acarbose in improving 2-hour postload plasma glucose. No adverse drug reactions were reported. Conclusion Metformin has beneficial effects in reducing the incidence of high FPG, IGT, and abdominal obesity. It also proved beneficial in reducing the prevalence of metabolic syndrome and increasing insulin sensitivity. The therapeutic effects of metformin on blood pressure, obesity, and lipid profile are uncertain. There is insufficient evidence to recommend the use of metformin in the treatment of metabolic syndrome due to low methodological quality, small sample size, and limited number of trials. More high quality, large-scale randomized controlled trials are required.
ObjectiveTo observe the effect of metformin on airway remodeling in asthma and its possible mechanism.MethodsTwenty-eight B/N rats were randomly divided into control group, asthma group, metformin intervention group and rapamycin intervention group. After that, the asthma model was established and intervened with metformin and rapamycin. The airway resistance and airway reactivity were measured 48 hours after the last challenge, and then the lung tissue samples were collected. Histopathological examination was used to observe airway inflammatory cell infiltration, goblet cell proliferation, airway wall fibrosis and remodeling, as well as airway smooth muscle proliferation. The expression of AMPK/mTOR pathway related proteins was detected by Western blot.ResultsCompared with the asthma group, metformin and rapamycin significantly reduced the airway responsiveness induced by high concentration of acetylcholine (P<0.05), reduced the infiltration of inflammatory cells in lung tissue and the changes of airway wall structure (P<0.05), reduced goblet cell proliferation in airway epithelium, collagen fiber deposition in lung tissue and bronchial smooth muscle hyperplasia (P<0.05). Further studies showed that the effects of metformin and rapamycin were related to AMPK/mTOR pathway. Compared with the asthma group, metformin and rapamycin could significantly reduce the expression of p-mTOR, p-p70s6k1 and SKP2, while p21 protein expression was significantly increased (P<0.05). In addition, metformin and rapamycin had similar effects (P>0.05).ConclusionMetformin can alleviate airway hyperresponsiveness and airway remodeling by activating AMPK and then inhibiting mTOR pathway, which may be a potential drug for treating asthma and preventing airway remodeling.