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SUMMARY: The toxic effects of thioacetamide (TAA) and carbon tetrachloride on the human body are well recognized. In this study, we examined whether TAA intoxication can induce kidney leukocyte infiltration (measured as leukocyte common antigen CD45) associated with the augmentation of the reactive oxygen species (ROS)/tumor necrosis factor-alpha (TNF-α) axis, as well as biomarkers of kidney injury with and without metformin treatment. Rats were either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being sacrificed after 10 weeks (experimental group) or were pre-treated with metformin (200 mg/kg) daily for two weeks prior to TAA injections and continued receiving both agents until the end of the experiment, at week 10 (protective group). Using basic histology staining, immunohistochemistry methods, and blood chemistry analysis, we observed profound kidney tissue injury such as glomerular and tubular damage in the experimental group, which were substantially ameliorated by metformin. Metformin also significantly (p0.05) increase in kidney expression of CD45 positive immunostaining cells. In conclusion, we found that TAA induces kidney injury in association with the augmentation of ROS/TNF-α axis, independent of leukocyte infiltration, which is protected by metformin.
Son bien conocidosos los efectos tóxicos de la tioacetamida (TAA) y el tetracloruro de carbono en el cuerpo humano. En este estudio, examinamos si la intoxicación por TAA puede inducir la infiltración de leucocitos renales (medida como antígeno leucocitario común CD45) asociada con el aumento de las especies reactivas de oxígeno (ROS)/factor de necrosis tumoral-alfa (TNF-α), así como biomarcadores de daño renal con y sin tratamiento con metformina. A las ratas se les inyectó TAA (200 mg/kg; dos veces por semana durante 8 semanas) antes de sacrificarlas a las 10 semanas (grupo experimental) o se les pretrató con metformina (200 mg/kg) diariamente durante dos semanas antes de las inyecciones de TAA y continuaron recibiendo ambos agentes hasta el final del experimento, en la semana 10 (grupo protector). Usando tinción histológica básica, métodos de inmunohistoquímica y análisis químico de la sangre, observamos una lesión profunda del tejido renal, como daño glomerular y tubular en el grupo experimental, que mejoraron sustancialmente con la metformina. La metformina también inhibió significativamente (p0,05) en la expresión renal de células de inmunotinción positivas para CD45. En conclusión, encontramos que el TAA induce la lesión renal en asociación con el aumento del eje ROS/TNF-α, independientemente de la infiltración de leucocitos, que está protegida por metformina.
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Animals , Male , Rats , Thioacetamide/toxicity , Acute Kidney Injury/drug therapy , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Immunohistochemistry , Biomarkers , Tumor Necrosis Factor-alpha , Reactive Oxygen Species , Leukocyte Common Antigens , Acute Kidney Injury/chemically induced , InflammationABSTRACT
Background & objectives: Studies have shown that insulin resistance and hyperinsulinaemia play a major role in the pathogenesis of polycystic ovary syndrome (PCOS). Therefore, the use of insulin sensitizing drugs in the treatment of PCOS has attracted the attention of medicine and researchers. The aim of this study was to investigate the effects of sitaformin (sitagliptin/metformin) and metformin on the quality of oocyte and embryo in classic PCOS patients undergoing intracytoplasmic sperm injection (ICSI). Methods: Sixty patients of PCOS (25-35 yr) were randomly allocated into three groups (n=20, each group): a metformin-treated group (administered metformin 500 mg twice daily), a sitaformin-treated group (administered sitaformin 50/500 mg twice daily) and a placebo group. Participants in all the groups received the drug two months prior to the start of the ovulation cycle and treatment continued until the day of the oocyte aspiration. Results: Serum insulin and total testosterone levels decreaseed significantly after treatment in both the treatment groups as compared to the placebo (P<0.05). A significant decrease in the number of immature oocytes [MI + germinal vesicle (GV) stage] was observed in metformin and sitaformin groups as compared to the placebo. In addition, sitaformin group when compared to the metformin group showed a significant decrease in the number of immature oocytes (P<0.05). The number of mature and normal MII oocytes increased significantly in both the treatment groups compared to the placebo group (P<0.05). The number of mature and normal oocytes increased in sitaformin group in comparison to the metformin group, but the difference was not significant. There was a significant increase in the number of grade I embryos, fertilization and cleavage rates in the sitaformin group compared to the other groups (P<0.05). Interpretation & conclusions: This is the first study to compare the impact of sitaformin with metformin on oocyte and embryo quality in women with PCOS undergoing a gonadotropin-releasing hormone (GnRH) antagonist cycle. In conclusion, sitaformin can be more effective in decreasing immature oocytes and increasing the quality of embryos than the use of metformin.
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Studies have demonstrated high prevalence of mortality in coronavirus disease (COVID-19) patients with type 2 diabetes mellitus; however, the effects of antidiabetic pharmacotherapy on COVID-19 complications need further exploration. The aim of the study was to explore the association of metformin use and mortality in COVID-19 patients. A literature search was conducted using the databases Medline (via PubMed) and Cochrane Central Register of Controlled Trials until February 09, 2021. Nine studies were included in the meta-analysis, including 12,684 COVID-19 patients. The meta-analysis suggested 37% lower risk of mortality in patients receiving metformin (risk ratio: 0.63; 95% confidence interval: 0.50–0.78; p?<?0.001). However, no significant difference in hospitalization days between the two groups (p?=?0.197) was observed. The analysis revealed significantly lower risk of having obesity (p?<?0.001), hypertension (p?<?0.001), heart failure (p?<?0.001), and cerebrovascular disease (p?=?0.015) in the group receiving metformin. The analysis also demonstrated significantly lower risk of using anticoagulants (p?=?0.015), diuretics (p?<?0.001), and antiplatelets (p?=?0.010) in patients receiving metformin. Our findings suggest that metformin use decreases mortality in COVID-19 patients. However, randomized studies demonstrating the consequences of metformin use are needed to understand the magnitude of the beneficial effects of metformin
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Objective:To explore the roles and mechanisms of metformin in the improvement of cognitive dysfunction induced by chronic cerebral hypoperfusion in rats.Methods:Total 82 SD male rats (SPF grade) aged 3-4 months were randomly divided into four groups: sham operation control group (Con group, n=15), sham operation with metformin treatment group (Met group, n=20), 2-vessel occlusion group (2VO group, n=22), and 2-vessel occlusion with metformin administration group (2VO+ Met group, n=25). The chronic cerebral hypoperfusion model was established by bilateral common carotid artery ligation, and the carotid arteries of rats in Con group and Met group were only separated without ligation.After 2VO operation, rats in 2VO+ Met group and Met group were given metformin solution in drinking water at a dose of 100 mg/kg per day for 4 weeks.After 4-week continuous intervention with metformin, Morris water maze was performed to test the spatial cognitive function of the rats, in vivo electrophysiological technology was used to detect the long-term potential of the rats, and enzyme-linked immunosorbent assay(ELISA) was used to detect the concentrations of inflammatory factor tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6) in the hippocampus.The density of dendritic spines of hippocampal neurons was observed by Golgi staining, and the synaptic structure of hippocampal neurons, especially the vesicle density, was observed by transmission electron microscopy.SPSS 16.0 software was used for statistical analysis.Repetitive measurement ANOVA was used for the escape latency data of 7 days repeated learning training in water maze.One-way ANOVA was used for the comparison of other data among multiple groups, and Dunnett's t test was used for further pairwise comparison. Results:Morris water maze results showed that during 7 days of learning training, the time and group interaction for escape latency was not significant in the 4 groups of rats ( F=0.93, P>0.05), but the time main effect ( F=25.90, P<0.05) and group main effect ( F=13.20, P<0.05) were significant.Morris water maze test showed that from the 3rd to 7th day, the escape latencies in 2VO group were significantly longer than those in Con group and 2VO+ Met group(all P<0.05). The short-term memory of rats was detected after 1 day of rest.The results showed that the escape latency in 2VO group was significantly longer than that in Con group and 2VO + Met group( P<0.01). The retention time and crossing times in the platform area of 2VO rats were less than those in Con group and 2VO + Met group ( P<0.01). Electrophysiological results showed that the relative field excitatory postsynaptic potential slope of 2VO group (1.29±0.09) was significantly lower than that in Con group (2.07±0.09) and 2VO + Met group (1.69±0.08)( P<0.01). ELISA results showed that TNF-α level in hippocampal tissue of 2VO group was significantly higher than that in Con group and 2VO+ Met group; IL-1β and IL-6 levels in hippocampal tissue of 2VO group were significantly higher than those in Con group and 2VO + Met group.Density of dendritic spines in hippocampal neurons of 2VO group was significantly lower than that in Con group and 2VO+ Met group.The density and proportion of immature dendritic spines in hippocampal neurons of 2VO group were significantly higher than those in Con group and 2VO + Met group.Synaptic vesicle density of neurons in CA1 area of hippocampus in 2VO group ((230.29±19.44) vescicles/μm 2) was significantly lower than that in the Con group ((414.52±13.17) vescicles/μm 2) and 2VO+ Met group ((313.19±12.42) vescicles/μm 2). Conclusion:Metformin can reduce neuroinflammation of hippocampus with chronic cerebral hypoperfusion and improve synaptic plasticity and cognitive dysfunction.It may have potential application value in the treatment of vascular cognitive dysfunction.
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Objective:To investigate the clinical effect of dapagliflozin combined with metformin on type 2 diabetes mellitus (T2DM).Methods:A total of 100 patients with T2DM who received treatment in The Second People's Hospital of Hefei from June 2019 to May 2021 were included in this study. They were randomly divided into a control group ( n = 50) and an experimental group ( n = 50). The control group was treated with metformin, and the experimental group was treated with dagglitazin combined with metformin. All patients were treated for 3 months. Blood glucose index, blood lipid level, and the incidence of adverse reactions were compared between the two groups. Results:After treatment, fasting blood glucose, 2-hour post-prandial blood glucose, and glycosylated hemoglobin in the experimental group were (5.56 ± 0.37) mmol/L, (8.32 ± 0.23) mmol/L, and (6.17 ± 0.26)% respectively, which were significantly lower than (6.96 ± 0.48) mmol/L, (9.58 ± 0.39) mmol/L, and (7.27 ± 0.26)% respectively in the control group ( t = 3.59, 6.92, 5.03, all P < 0.05). The total cholesterol and triglyceride in the experimental group were (3.58 ± 0.53) mmol/L and (1.25±0.26) mmol/L, respectively, which were significantly lower than (4.94 ± 0.58) mmol/L and (1.93 ± 0.18) mmol/L in the control group ( t = 3.16, 4.25, both P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Conclusion:Dapagliflozin combined with metformin can effectively control blood glucose and blood lipid in T2DM patients without increasing adverse reactions.
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Objective:To investigate the clinical efficacy of liraglutide combined with metformin in the treatment of type 2 diabetes mellitus in overweight or obese patients.Methods:The clinical data of 120 overweight or obese patients with type 2 diabetes mellitus admitted to Bayannur Hospital from January 2020 to June 2021 was retrospectively analyzed. They were divided into study and control groups ( n = 60/group) according to different treatments. The study group was treated with liraglutide combined with metformin, and the control group was treated with metformin alone. All patients were treated for 12 weeks. Clinical efficacy was compared between the two groups. Results:After treatment, body mass, body mass index, fasting blood glucose, 2-hour postprandial blood glucose, glycated hemoglobin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, visceral fat area, and insulin resistance index in the study group were (71.51 ± 10.12) kg, (25.98 ± 2.63) kg/m 2, (6.09 ± 0.99) mmol/L, (9.08 ± 2.39) mmol/L, (6.75 ± 1.13)%, (4.43 ± 0.88) mmol/L, (1.76 ± 0.68) mmol/L, (2.29 ± 0.90) mmol/L, (108.21 ± 26.46) cm 2 and (3.57 ± 1.45), respectively, which were significantly lower than (75.57 ± 7.11) kg, (27.91 ± 2.46) kg/m 2, (7.02 ± 0.95) mmol/L, (11.26 ± 2.86) mmol/L, (7.28 ± 1.04)%, (5.24 ± 1.11) mmol/L, (2.19 ± 0.70) mmol/L, (2.86 ± 0.97) mmol/L, (118.32 ± 28.63) cm 2, and (4.28 ± 2.07) respectively in the control group ( t = 2.54, 4.15, 5.23, 4.53, 2.66, 4.45, 3.43, 3.39, 2.01, 2.19, all P < 0.05). High-density lipoprotein cholesterol in the study group was significantly higher than that in the control group [(1.55 ± 0.28) mmol/L vs. (1.20 ± 0.32) mmol/L, t = -6.38, P < 0.05]. The grade of nonalcoholic fatty liver disease in the study group was significantly superior to that in the control group ( Z =-2.16, P < 0.05). Conclusion:Liraglutide combined with metformin can effectively improve blood glucose and lipid levels, and reduce insulin resistance, body weight, visceral adipose tissue and liver hepatocellular fatty deposits in overweight or obese patients with type 2 diabetes mellitus.
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The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed inde-pendently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endo-thelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.
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Age-related eye diseases are a series of ophthalmic diseases caused by degenerative disease of ocular tissues, and age-related macular degeneration(ARMD), age-related cataract(ARC), diabetic retinopathy(DR)and glaucoma are the four most common age-related eye diseases. With the increasing aging of the global social population, the incidence of these eye diseases is also increasing year by year. Metformin is currently one of the most commonly used hypoglycemic agents in clinical practice. It has become the drug of choice for treating type 2 diabetes after more than 60 years of clinical practice. In recent years, metformin has shown great potential in the prevention and treatment of tumors, systemic diseases and age-related diseases, and the mechanisms of action involved in anti-oxidative stress, anti-inflammation, and induction of autophagy are also closely related to the pathological changes of age-related eye diseases. The paper aims to review the current research status and potential application value of metformin in age-related eye diseases.
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Objective:To explore the effects of metformin on levels of peripheral blood regulatory T cells (Treg)/Th17 cells and related cytokines in patients with type 2 diabetes mellitus (T2DM) and influenza A.Methods:A total of 108 patients with T2DM and influenza A treated in Zhejiang Veteran Hospital were prospectively enrolled between April 2021 to April 2022. According to different medication methods, they were divided into observation group (54 cases, oseltamivir + metformin) and control group (54 cases, oseltamivir + gliclazide). The average usage time and dosage of oseltamivir, concentration of blood lactate and blood gas level, counts of Th17 and Treg cells, and levels of related cytokines in the two groups were compared before and after treatment.Results:The average usage time and dosage of oseltamivir, and concentration of blood lactate were higher in observation group than control group: (8.94 ± 0.88) d vs. (7.23 ± 0.79) d, (1.32 ± 0.15) g vs. (1.08 ± 0.11) g, (1.83 ± 0.43) mmol/L vs. (1.61 ± 0.32) mmol/L, P<0.05. The differences in pH, partial pressure of arterial oxygen (PaO 2) and partial pressure of arterial carbon dioxide (PaCO 2) between the two groups had no statistically significant before and after treatment ( P>0.05). After treatment, the differences in count of Treg cells, interleukin-10 (IL-10), interleukin-4 (IL-4), CD 3+, CD 4+ and CD 4+/CD 8+ between the observation group and the control group were statistically significant: (35.48 ± 5.64)% vs. (42.53 ± 6.17)%, (30.49 ± 4.72) ng/L vs. (35.64 ± 5.08) ng/L, (32.15 ± 3.06) ng/L vs. (35.33 ± 3.12) ng/L, (61.39 ± 3.28) % vs. (66.27 ± 3.05)%, (34.12 ± 1.93)% vs. (36.59 ± 2.61)%, 1.26 ± 0.34 vs. 1.52 ± 0.41, P<0.05. After treatment, the count of Th17 cells, Th17/Treg, interleukin-17 (IL-17) and γ-interferon (IFN-γ) in the observation group were higher than those in the control group:(8.69 ± 1.42)% vs. (7.94 ± 2.03)%, 0.24 ± 0.06 vs. 0.19 ± 0.05, (17.67 ± 3.11) ng/L vs. (12.18 ± 3.42) ng/L, (287.48 ± 45.12) ng/L vs. (254.27 ± 41.09) ng/L, P<0.05. During treatment, the difference in incidences of adverse reactions between the two groups had no statistically significant ( P>0.05). Conclusions:Oseltamivir combined with metformin can recover the balance of Th17/Treg cells in patients with T2DM and influenza A to a certain extent. Clinically, level of blood lactate should be monitored.
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Objective:To investigate the effect of liraglutide combined with metformin on overweight and obese patients with type 2 diabetes mellitus (T2DM) after short-term intensive insulin pump therapy.Methods:A total of 80 overweight and obese patients with T2DM admitted to Ningguo People′s Hospital from November 2018 to December 2020 were selected as the research subjects. After 1 week of intensive insulin pump therapy, they were divided into two groups according to the random number table method. The observation group received liraglutide combined with metformin therapy, the control group received metformin combined with sitagliptin therapy, both for 16 weeks. The blood glucose, blood lipids, body weight and other indicators were compared between the two groups after treatment. The occurrence of adverse drug reactions in the two groups was compared.Results:The levels of fasting plasma glucose (FPG), 2 h postprandial blood glucose (2hPG), and glycosylated hemoglobin (HbA 1c) in the observation group after treatment were lower than those in the control group :(5.14 ± 0.54) mmol/L vs. (5.92 ± 0.71) mmol/L, (5.91 ± 0.83) mmol/L vs. (6.84 ± 0.92) mmol/L, (5.33 ± 0.57)% vs. (6.30 ± 0.82)%, there were statistical differnces ( P<0.05). The triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels had no significant differences ( P>0.05). After treatment, the islet beta cell function index (HOMA-β) and insulin sensitivity index (ISI) in the observation group were higher than those in the control group: 26.84 ± 3.32 vs. 22.15 ± 3.11, -3.84 ± 0.17 vs. -4.09 ± 0.20, and the insulin resistance index (HOMA-IR) was lower than that in the control group: 2.01 ± 0.17 vs. 2.64 ± 0.21, the differences were statistically significant ( P<0.05). After treatment, the waist circumference (WC), body mass index (BMI) and hip-to-waist ratio in the observation group were lower than those in the control group: (95.10 ± 4.08) cm vs. (97.14 ± 4.48) cm, (24.33 ± 1.62) kg/m 2 vs. (26.15 ± 1.40) kg/m 2, 0.89 ± 0.11 vs. 1.11 ± 0.20, the differences were statistically significant ( P<0.05). There was no significant difference in the incidence of adverse drug reactions between the two groups during treatment ( P>0.05). Conclusions:Liraglutide combined with metformin has better clinical effect on overweight and obese T2DM patients after short-term intensive insulin pump therapy, and can better improve their pancreatic islet function.
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Objective:To evaluate the effect of Tongbu Qijing Acupuncture combined with metformin hydrochloride tablet on polycystic ovary syndrome (PCOS) combined with insulin resistance (IR) of kidney-deficiency phlegm dampness type.Methods:Randomized controlled trial. 84 patients with PCOS and IR in the hospital were enrolled as the observation objects between November 2019 and November 2021. According to random number table method, they were divided into observation group (Tongbu Qijing Acupuncture combined with metformin hydrochloride tablets) and control group (oral metformin hydrochloride tablets), 42 in each group. All were treated for 3 courses of treatment (1 month/course). TCM syndromes were scored before and after treatment. The height, weight, waist circumference and hip circumference of patients were measured to calculate body mass index (BMI) and waist-hip ratio (WHR). The levels of serum TG, TC, LDL-C and HDL-C were detected by biochemical analyzer, fasting blood glucose (FPG) was detected by glucose oxidase method, fasting insulin (FINS) was detected by electrochemiluminescence method, and insulin resistance index (HOMA-IR) was calculated. The recovery rates of menstruation and ovulation were observed and compared after treatment, and the clinical curative effect was evaluated.Results:There were significant differences in total response rate between observation group and control group [95.24% (40/42) vs. 80.95% (34/42); χ2=4.09, P=0.043]. After treatment, scores of TCM syndromes, BMI and WHR in observation group were significantly lower than those in the control group ( t=20.36, 23.77, 3.44, P<0.01). After treatment, serum FPG [(4.86±0.51) nmol/L vs. (5.41±0.55) nmol/L, t=4.75], FINS [(8.31±0.85) mU/L vs. (10.11±1.02) mU/L, t=8.79] levels and HOMA-IR [(1.88±0.19) vs. (2.44±0.25), t=11.97] in observation group were significantly lower than those in the control group ( P<0.01). After treatment, levels of serum TG, TC and LDL-C in observation group were significantly lower than those in the control group ( t=16.54, 4.81, 5.35, P<0.01), while HDL-C was significantly higher than that of the control group ( t=6.78, P<0.01). After treatment, there were significant differences in recovery rates of menstruation and ovulation between observation group and control group [57.14% (24/42), 47.62% (20/42) vs. 80.95% (34/42), 69.05% (29/42); χ2=5.57, 3.97, P<0.05]. Conclusion:Tongbu Qijing Acupuncture combined with metformin hydrochloride tablet can effectively improve syndromes and signs, regulate glucose-lipid metabolism, reduce IR and promote the recovery of menstruation and ovulation in patients with PCOS and IR.
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OBJECTIVE@#To explore the association between the use of metformin and the risk of ischemic stroke in patients with type 2 diabetes.@*METHODS@#A prospective cohort study was designed from the Fangshan family cohort in Beijing. According to metformin use at baseline, 2 625 patients with type 2 diabetes in Fangshan, Beijing were divided into metformin group or non-metformin group and the incidence of ischemic stroke between the different groups during follow-up was estimated and compared by Cox proportional hazard regression model. The participants with metformin were first compared with all the parti-cipants who did not use metformin, and then were further compared with those who did not use hypoglycemic agents and those who used other hypoglycemic agents.@*RESULTS@#The patients with type 2 diabetes were with an average age of (59.5±8.7) years, and 41.9% of them were male. The median follow-up time was 4.5 years. A total of 84 patients developed ischemic stroke during follow-up, with a crude incidence of 6.4 (95%CI: 5.0-7.7) per 1 000 person-years. Among all the participants, 1 149 (43.8%) took metformin, 1 476 (56.2%) were metformin non-users, including 593 (22.6%) used other hypoglycemic agents, and 883 (33.6%) did not use any hypoglycemic agents. Compared with metformin non-users, the Hazard ratio (HR) for ischemic stroke in metformin users was 0.58 (95%CI: 0.36-0.93; P = 0.024). Compared with other hypoglycemic agents, HR was 0.48 (95%CI: 0.28-0.84; P < 0.01); Compared with the group without hypoglycemic agents, HR was 0.65 (95%CI: 0.37-1.13; P=0.13). The association between metformin and ischemic stroke was statistically significant in the patients ≥ 60 years old compared with all the metformin non-users and those who used other hypoglycemic agents (HR: 0.48, 95%CI: 0.25-0.92; P < 0.05). Metformin use was associated with a lower incidence of ischemic stroke in the patients with good glycemic control (0.32, 95%CI: 0.13-0.77; P < 0.05). In the patients with poor glycemic control, and the association was not statistically significant (HR: 0.97, 95%CI: 0.53-1.79; P>0.05). There was an interaction between glycemic control and metformin use on incidence of ischemic stroke (Pinteraction < 0.05). The results of the sensitivity analysis were consistent with the results in the main analysis.@*CONCLUSION@#Among patients with type 2 diabetic in rural areas of northern China, metformin use was associated with lower incidence of ischemic stroke, especially in patients older than 60 years. There was an interaction between glycemic control and metformin use in the incidence of ischemic stroke.
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Humans , Male , Middle Aged , Aged , Female , Metformin/adverse effects , Diabetes Mellitus, Type 2/drug therapy , Cohort Studies , Ischemic Stroke/complications , Prospective Studies , Hypoglycemic Agents/adverse effects , Stroke/prevention & control , Retrospective StudiesABSTRACT
OBJECTIVE@#To observe the hypoglycemic effect of electroacupuncture (EA) at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus (T2DM) as well as its effect on expression of adenosine monophosphate activated protein kinase (AMPK) in liver and pancreas.@*METHODS@#Thirty-six male SD rats were randomly divided into a blank group (6 rats) and a model establishing group (30 rats). The rats in the model establishing group were fed with high-fat diet and treated with intraperitoneal injection of low-dose streptozotocin (STZ) to establish T2DM model. The rats with successful model establishment were randomly divided into a model group, a control group, a metformin group, an EA group and a combination group, 6 rats in each group. The rats in the EA group were treated with EA at "Tianshu" (ST 25), dense-disperse wave, 2 Hz/15 Hz in frequency and 2 mA in current intensity, 20 min each time. The rats in the metformin group were treated with intragastric administration of metformin (190 mg/kg) dissolved in 0.9% sodium chloride solution (2 mL/kg). The rats in the combination group were treated with EA at "Tianshu" (ST 25) and intragastric administration of metformin. The rats in the control group were treated with intragastric administration of 0.9% sodium chloride solution with the same dose. All the treatments were given once a day for 5 weeks. After the intervention, the body mass and random blood glucose were detected; the serum insulin level was detected by ELISA; the expression of AMPK and phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) in liver and pancreas was detected by Western blot method; the expression of protein gene product 9.5 (PGP9.5) was detected by immunofluorescence.@*RESULTS@#①Compared with the blank group, the body mass in the model group was decreased (P<0.05); compared with the model group, the body mass in the EA group and the combination group was decreased (P<0.05); the body mass in the EA group and the combination group was lower than the metformin group (P<0.05). Compared with the blank group, the random blood glucose in the model group was increased (P<0.01); compared with the model group, the random blood glucose in the metformin group, the EA group and the combination group was decreased (P<0.01). The random blood glucose in the combination group was lower than the metformin group and the EA group (P<0.05). ②Compared with the blank group, the insulin level in the model group was decreased (P<0.05); compared with the model group, the insulin level in the metformin group, the EA group and the combination group was all increased (P<0.05). The insulin level in the combination group was higher than the metformin group and the EA group (P<0.05). ③Compared with the blank group, the protein expression of AMPK and p-AMPK in liver tissue was decreased (P<0.05), and the protein expression of AMPK and p-AMPK in pancreatic tissue was increased (P<0.05) in the model group. Compared with the model group, the protein expression of AMPK and p-AMPK in liver tissue in the metformin group, the EA group and the combination group was increased (P<0.05, P<0.01); the protein expression of AMPK in pancreatic tissue in the metformin group was increased (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was decreased (P<0.05); the protein expression of p-AMPK in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05). The protein expression of AMPK and p-AMPK in liver tissue in the combination group was higher than that in the metformin group and the EA group (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was less than that in the metformin group (P<0.05), and the expression of p-AMPK protein in pancreatic tissue in the combination group was less than that in the metformin group and the EA group (P<0.05). ④Compared with the blank group, the expression of PGP9.5 in pancreatic tissue in the model group was increased (P<0.01); compared with the model group, the expression of PGP9.5 in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05, P<0.01). The expression of PGP9.5 in pancreatic tissue in the EA group was lower than the metformin group and the combination group (P<0.05).@*CONCLUSION@#Electroacupuncture at "Tianshu" (ST 25) could promote the effect of metformin on activating AMPK in liver tissue of T2DM rats, improve the negative effect of metformin on AMPK in pancreatic tissue, and enhance the hypoglycemic effect of metformin. The mechanism may be related to the inhibition of pancreatic intrinsic nervous system.
Subject(s)
Animals , Male , Rats , Acupuncture Points , AMP-Activated Protein Kinases/genetics , Blood Glucose , Diabetes Mellitus, Type 2/drug therapy , Electroacupuncture , Hypoglycemic Agents , Insulins , Metformin , Rats, Sprague-DawleyABSTRACT
Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications occurring in both type 1 and type 2 diabetes mellitus patients, which often results in patients suffering from severe hyperalgesia and allodynia. Up to now, the clinical therapeutic effect of DPN is still unsatisfactory. Metformin is an anti-diabetic drug that has been safely and widely used for the treatment of type 2 diabetes for decades. Studies have shown that metformin can improve pain caused by DPN, but its effects on the nerve conduction velocity and morphology of the sciatic nerve of DPN, and the mechanism for improving DPN are not clear. Therefore, the STZ-induced model of type 1 DPN in SD rats was used to study the effects of metformin on DPN, and to preliminarily explore its mechanism in this study. All animal experiments were carried out with approval of the Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica (Chinese Academy of Medical Sciences and Peking Union Medical College). After the model was established successfully, STZ diabetic rats were randomly divided into a model group and a metformin treatment group, and 10 normal SD rats were selected as the normal control group, and the rats were intragastrically administered for 12 weeks. The results showed that metformin significantly reduced blood glucose, glycosylated hemoglobin, food consumption and water consumption in STZ rats. Metformin markedly increased the motor nerve conduction velocity and mechanical stabbing pain threshold, prolonged the hot plate latency threshold, and improved the pathological morphological abnormalities of the sciatic nerve in STZ rats. In addition, metformin increased the content of glutathione (GSH), enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and reduced the content of malondialdehyde (MDA) in serum and sciatic nerve of STZ diabetic rats, as well as regulating the expression of genes related to oxidative stress in the sciatic nerve. Metformin obviously reduced the levels of pro-inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 in the serum in STZ rats, and inhibited the gene expression of these inflammatory factors in the sciatic nerve. In summary, metformin significantly increased nerve conduction velocity, improved sciatic nerve morphological abnormalities and pain in DPN rats, which may be related to its effect in improving oxidative stress and reducing inflammation.
ABSTRACT
@#To evaluate bioequivalence and safety of two kinds of metformin hydrochloride sustained-release tablets (test preparation vs reference preparation) under the condition of fed and single administration.A single center, randomized, open, single-dose, two-period, two-sequence, and double-crossover design was used.32 healthy subjects took 0.5 g of test preparation or reference preparation under fed and single-dose administration.4 mL of venous blood was collected from before administration (0 h) to 1, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 12, 15, 24, 36 and 48 h after administration.The concentration of metformin in plasma samples was detected, and then the pharmacokinetic parameters were calculated by WinNonlin 7.0 software.When the 90% confidence intervals of cmax, AUC0-t and AUC0-∞ geometric mean ratio of test preparation and reference preparation were within 80.00%-125.00% equivalent intervals respectively, the bioequivalence of the two preparations was proved.One subject fell off due to adverse events.The main pharmacokinetic parameters of test preparation and reference preparation as follows: cmax were (0.68 ± 0.14) and (0.65 ± 0.11) mg/L, AUC0-t were (7.33 ± 1.65) and (7.00 ± 1.89) h·mg/L, AUC0-∞ were (7.39 ± 1.67) and (7.06 ± 1.91) h·mg/L, respectively.The 90% confidence intervals of the geometric mean ratio of the two main pharmacokinetic parameters were 101.45%-109.14%, 100.08%-112.32% and 100.24%-112.28%, respectively, which fell within the bioequivalence interval of 80.00%-125.00%.There were no serious adverse events and unexpected adverse events during the trial.The results show that test preparation and reference preparation are bioequivalent under fed and single-dose administration, safe and well tolerated in healthy subjects.
ABSTRACT
Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.
Subject(s)
Humans , Metformin/pharmacokinetics , Diabetes Mellitus, Type 2/metabolism , Hypoglycemic Agents/pharmacology , AMP-Activated Protein Kinases/metabolism , AgingABSTRACT
Increased intestinal barrier permeability, leaky gut, has been reported in patients with autism. However, its contribution to the development of autism has not been determined. We selected dextran sulfate sodium (DSS) to disrupt and metformin to repair the intestinal barrier in BTBR T+tf/J autistic mice to test this hypothesis. DSS treatment resulted in a decreased affinity for social proximity; however, autistic behaviors in mice were improved after the administration of metformin. We found an increased affinity for social proximity/social memory and decreased repetitive and anxiety-related behaviors. The concentration of lipopolysaccharides in blood decreased after the administration of metformin. The expression levels of the key molecules in the toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-nuclear factor kappa B (NF-κB) pathway and their downstream inflammatory cytokines in the cerebral cortex were both repressed. Thus, "leaky gut" could be a trigger for the development of autism via activation of the lipopolysaccharide-mediated TLR4-MyD88-NF-κB pathway.
Subject(s)
Mice , Animals , NF-kappa B , Myeloid Differentiation Factor 88/metabolism , Lipopolysaccharides/pharmacology , Toll-Like Receptor 4/metabolism , Autistic Disorder/metabolism , Signal Transduction/physiologyABSTRACT
OBJECTIVES@#Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM).@*METHODS@#A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups.@*RESULTS@#The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population.@*CONCLUSIONS@#Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.
Subject(s)
Humans , Diabetes Mellitus, Type 2/drug therapy , Metformin/therapeutic use , Acidosis, Lactic , Tandem Mass Spectrometry , Hypoxia , GlucoseABSTRACT
Introdução: Diabetes Mellitus é doença metabólica, caracterizada pela deficiência absoluta ou relativa de insulina, que acomete cerca de 382 milhões de pessoas em todo mundo, tendo uma das complicações mais comuns a polineuropatia. A Metformina, medicamento amplamente utilizado como tratamento do Diabetes, foi descrita como responsável, em algumas literaturas, por causar ou agravar deficiência de vitamina B12, que está similarmente relacionada ao desenvolvimento de polineuropatia.Métodos: Nesse sentido, foi conduzido um estudo no município de Soledade RS, com objetivo de verificar se essa relação é condizente com a realidade da localidade. Foram escolhidos 58 pacientes, dos quais 30 responderam questionários adaptados baseados na literatura e na Classificação de Neuropatia de Michigan (MNSS-Brasil), então colhidos 5 ml de sangue venoso da fossa antecubital, preparado soro do qual uma alíquota foi separada para determinação bioquímica da vitamina B12.Resultados: Analisando os resultados, a maioria dos pacientes analisados apresentou sintomas de polineuropatia, e 10% deste, deficiência vitamínica.Conclusão: nenhuma variável explicou a correlação do uso crônico da Metformina, dose e gênero com a deficiência da vitamina B12, o que indica que não há evidências fortes o suficiente que sustentem esse fato, de acordo com as particularidades da localidade analisada.
Introduction: Diabetes Mellitus is a metabolic disease, characterized by absolute or relative insulin deficiency, which affects about 382 million people, with polyneuropathy being one of the most common complications. Metformin, a drug widely used as a treatment for diabetes, has been described as responsible, in some literature, for causing or aggravating vitamin B12 deficiency, which is similarly related to the development of polyneuropathy.Methods: In this sense, a study was conducted in Soledade RS, in order to verify whether this relationship is consistent with the reality of the locality. Fifty-eight patients were selected, of which 30 answered adapted questionnaires based on the literature and on the Michigan Neuropathy Classification (MNSS-Brazil), then 5 ml of venous blood was collected from the antecubital fossa, serum prepared from which an aliquot was separated for biochemical determination of the vitamin B12.Results: Analyzing the results, most of these patients presented symptoms of polyneuropathy and, 10% of them, vitamin deficiency.Conclusion: no variable explained the correlation of chronic use of Metformin, dose and gender with vitamin B12 deficiency, which indicates that there is not enough evidence to support this fact, according to the particularities of the analyzed locality.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Vitamin B 12 Deficiency/diagnosis , Diabetes Mellitus/drug therapy , Diabetic Neuropathies/complications , Metformin/adverse effects , Vitamin B 12/therapeutic use , Surveys and Questionnaires/statistics & numerical dataABSTRACT
Abstract Telomerase enzyme is necessary for the elongation of telomeres while telomerase being critical for aging and cancer. Metformin, ibuprofen, and acetylsalicylic acid used in this research are drugs that millions of people already use and that many are likely to use in future. In this study, the effects of these drugs on telomerase activity of Mus musculus swiss albino mice in liver tissue were investigated and the telomerase activity was measured with a PCR-ELISA based kit. In the study a possible connection between telomerase enzyme activity and activities of antioxidant enzymes was also investigated by determining the activity of superoxide dismutase (SOD) and catalase enzymes. The data obtained show that metformin slightly decreased telomerase enzyme activity in low dose application; however, this change was not statistically significant. In ibuprofen application, there was a significant inhibitory effect when high doses were used; whereas, there was a slight inhibitory effect at low doses. In acetylsalicylic acid application, a slight activator effect was detected; it was not statistically significant, though. Metformin was observed to increase catalase and SOD activities in general while low and high doses of acetyl salicylic acid showed different effects. In addition, ibuprofen caused a statistically significant increase in liver SOD values. It is important to note that this study demonstrated a significant inhibitory effect of ibuprofen on telomerase enzyme activity in animal models..