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Objective To investigate the combined effect and mechanism of metformin (Met) and 2-deoxy-D-glucose (2DG) on cell proliferation and apoptosis in liver cancer cells HepG2 and Hep3B.Methods Wst-1 reagent was used to determine the anti-proliferation effects after treatments with Met and 2DG alone or combined in HepG2 and Hep3B cells.Microscopy was used to observe cell morphological changes after treatments with Met and 2DG alone or combined in HepG2 and Hep3B cells.Cell apoptosis was observed by flow cytometry after treatment of different kinds of drugs.Western blotting was used to analyze the protein expressions of Caspase-3,PARP,Mcl-1 of HepG2.Results The survival rate of HepG2 cells in the combination group was (22.48 ± 0.51)％,and compared with the control group (100.00 ± 5.05)％,Met group (80.68 ±5.10)％ and 2DG group (72.56 ±4.34)％,the differences were statistically significant (P ＜ 0.001;P ＜ 0.001;P =0.001).The survival rate of Hep3B cells in the combination group was (29.16 ± 1.34) ％,and compared with the control group (100.00 ± 1.23) ％,Met group (59.58 ± 1.92) ％ and 2DG group (33.87 ± 1.95) ％,the differences were statistically significant (P ＜ 0.001;P ＜ 0.001;P =0.001).Microscopy observation showed that combined treatment of Met and 2DG caused less viable adherent cells of HepG2,but more floating dead cells.While the combination group also caused a decrease in the density of Hep3B cells,but did not significantly increase the shedding of cells.The apoptosis of HepG2 cells in the combination group was (39.63 ± 0.21) ％,and compared with the control group (7.12 ± 0.14) ％,Met group (12.56 ± 0.35) ％ and 2DG group (15.16 ± 1.93) ％,the differences were statistically significant (P ＜0.001;P ＜ 0.001;P =0.001).The apoptosis of Hep3B cells in the combination group was (12.58 ± 1.03) ％,and compared with the control group (2.82 ± 0.51) ％ and Met group (8.98 ± 0.86) ％,the differences were statistically significant (P ＜ 0.001;P =0.007),but compared with the 2DG group (12.40 ± 1.78) ％,the difference was not statistically significant (P =1.000).Furthermore,Western blotting demonstrated that the combined treatment induced evident Caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavages,and decreased expression of Mcl-1.Conclusion The combination of Met and 2DG can effectively inhibit cell proliferation of HepG2 and Hep3B,and induce apoptosis of HepG2 cells.The mechanism may be involved with Caspase-3 activation,cutting PARP substrate and decreasing Mcl-1 protein.
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Objective To discuss the clinical effect and safety on rosiglitazone applied to patients with early type 2 diabetic nephropathy.Methods Ninety-six patients with early type 2 diabetic nephropathy were divided into the control group(n=48) and the research group (n =48).The patients of the control group were given mefformin treatment, while of research group were given rosiglitazone, both the courses were three months.The urinary albumin excretion rate (UAER), 24 h urine trace albumin (UAE), serum creatinine clearance (SCr) , fasting plasma glucose (FPG), postprandial blood glucose (2 hPG), glycosylated hemoglobin (HbA 1 c), triglycerides (TG), cholesterol (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) before and after treatment and clinical effect between the two groups were compared.Results The HbA1c, FPG, 2 hPG, UAER, UAE, TC, TG of after treatment of all patients decreased obviously,while the HDL-C level increased remarkably, and compared with control group the differences were significant (HbA1 c: (7.32±0.84)％ vs (7.56±0.98)％, FPG: (8.02± 1.42) mmol/L vs (8.16± 1.54) mmol/L, 2 hPG: (11.54±2.11) mmol/L vs (12.02±1.97) mmol/L,UAER: (67.34±6.45) mg/24 h vs (52.56±5.35) mg/24 h,UAE: (108.64±22.64) mg/d vs (68.84± 11.43) mg/d, TC : (5.44± 0.72) mmol/L vs (4.76± 0.51) mmol/L, TG: (2.04± 0.53) mmol/L) vs (1.73±0.46) mmol/L);t =-4.172,-3.973,-4.026,-4.263,-6.634,-5.737,-5.635, -4.735,-4.633;P＜O.05).While there were no statistical significance about SCr before and after treatment(P ＞0.05).The total clinical effect of the research group was obviously higher than that of the control group (87.5％ (42/48) vs 66.7％ (32/48), x2 =5.363,P =0.035).There were not obvious adverse reaction occurred during treatment for all patients.Conclusion Rosiglitazone can effectively reduce the blood glucose in patients with early type 2 diabetic nephropathy and reduce urinary protein excretion, the effect is more obvious than that of metformin.
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ObjectiveTo evaluate the effects on serum homocysteine(Hcy) level,vascular function and carotid intima-media thickness(IMT) in metformin-treated diabetic patients with or without supplementation with folate and Vitamin B12.MethodsA total of 100 newly diagnosed diabetic type 2patients were divided into two groups by random digits table with 50 cases each,90 patients completed study.Forty-seven participants (control group) received a 6-month course of metformin treatment,43 patients (treatment group) received mefformin,folate and Vitamin B12 treatment.The levels of serum Hcy,endothelin-1 (ET-1),carotid IMT,large or small arterial elasticity index (C1,C2),flow-mediated dilatation (FMD) of the brachial artery were evaluated before and after treatment.ResultsThe level of serum Hcy in control group significantly increased compared with before treatment[ (13.4 ± 2.7)μ mol/L vs.(11.1 ± 1.9)μ mol/L],hut the level of serum Hcy in treatment group significantly decreased compared with before treatment [ (9.2 ± 1.8 ) μ mol/L vs. ( 11.3 ± 2.0) μ mol/L ],there was significant difference(P ＜ 0.05 ).A beneficial effect was observed in the serum ET-1,FMD,carotid IMT and C2 in treatment group[ (20.0 ± 6.2)ng/L,( 15.8 ± 7.6)％,(0.8 ± 0.2) mm,(4.1 ± 2.1 ) ml/mm Hg ( 1 mm Hg =0.133 kPa) × 100 vs. (31.3 ±10.1 ) ng/L,(9.7 ± 4.5)％,( 1.1 ± 0.4) mm,(2.3 ± 1.0) ml/mm Hg × 100 ] (P ＜ 0.05).The levels of ET-1,FMD,carotid IMT and C2 after treatment in control group [ (24.8 ± 6.8) ng/L,( 12.9 ± 6.3 )％,(0.9 ± 0.3)mm,(3.0 ± 1.4) ml/mm Hg × 100] had significant difference compared with before treatment [ (30.6 ± 8.7)ng/L,(9.8 ± 4.6)％,( 1.0 ± 0.3) mm,(2.2 ± 0.9) ml/mm Hg × 100](P＜ 0.05).However,the results were improved significantly in treatment group than those in control group (P ＜0.05).In treatment group,significant correlation were detected between changes of Hcy and ET- 1 (r =0.43,P ＜ 0.05 ),carotid IMT(r =0.56,P ＜ 0.05),FMD (r =-0.54,P ＜ 0.05 ),C2 (r =-0.37,P ＜ 0.05 ).ConclusionsAdministration of folate and Vitamin B12 can reduce the levels of serum Hcy and ET-1 in metformin-treated type 2 diabetic patients,which exert beneficial effect on carotid IMT,FMD and C2.
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Objective To investigate the effects of mefformin on the differentiation of osteoclastas well as relative mechanism.Methods Raw264.7 cells from the murine macrophage cell line was used.Receptor activator of NF-κB ligand (RANKL) was used to stimulate osteoclast differentiation from Raw264.7 cells.Osteoclast differentiation was assessed by tartrate-resistant acid phosphatase (TRAP) and actin fluorescence staining and counting the TRAP-positive cells after exposure to different concentrations of mefformin (0 μmol/L,400 μmol/L,800 μmol/L and 1000 μmol/L) or rapamicin (100 nmol/L) in the presence of 50 ng/ml RANKL for 5 days.Bone-resorbing activity was evaluated by BD BioCoatTM OsteologicTM Bone Cell Culture System.The expression of osteoclast-specific genes like TRAP,capthesin K,calcitonin receptor (CTR) and matrix metalloproteinase (MMP-9) was evaluated by RT-PCR.The expression of tumor necrosis factor-α(TNF-ct) S6K1Thr389,S6 Ser235/236,4E-BP1Thr37/46 and c-Fos protein was evaluated by ELISA kit and Western blot analysis,respectively.Results Mefformin dose-dependently inhibited RANKL-stimulated osteoclasts differentiation in Raw264.7 cell culture,as manifested by decrease of TRAP-positive multinucleated cells and pit erosion area,down-regulation of TRAP,cathepsin K,CTR and MMP-9 mRNA and reduction of TNF-α and c-Fos protein expression.Further study revealed that RANKL activated mTOR complex 1(mTORC1) signaling,while mefformin impaired RANKL-stimulated mTORC1 signaling.Rapamycin,an mTORCl-specific inhibitor and immunosuppressive macrolides could also prevent RANKL-induced osteoclast differentiation and bone resorption in vitro.Conclusion Mefformin inhibits osteoclastogenesis in vitro,which may due to reduction of TNF-α and c-Fos protein expression,and mTORC1 signaling is involved in this process.
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ObjectiveTo investigate the therapeutic effect of mefformin on type 2 diabetes mellitus (T2DM) complicated with non-alcoholic fatty liver disease (NAFLD).MethodsThe model rats of T2DM complicated with NAFLD were established by feeding high-glucose and high-fat diet, and injection of low dose streptozotocin.The model rats were randomly divided into 2 groups, model group (n = 16) and metformin group (n = 16).Twenty normal rats were set for normal control group.Intragastric administration lasted for 12 weeks.At the end of 16th week (after treated 8 weeks) and 20th week (after treated 12weeks), the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase(AST), fasting blood glucose (FBG),fasting insulin (FINs), triglyceride (TG), total cholesterol (TC) and free fatty acid (FFA) in each group were determined and the level of insulin sensitivity index (ISI) was determined.Meanwhile, pathological changes of liver, the expression of uncoupling protein-2 (UCP-2) mRNA and UCP-2 protein of liver tissues in each group were detected.ResultsThe levels of serum ALT, AST, FBG,FINs, serum TG , TC and FFA were significantly higher and ISI was significantly lower and the expression of UCP-2 protein significantly increased in model group, compared with control group (all P ＜ 0.01).The expression of UCP-2 mRNA at 16th and 20th week in model group were significantly higher than that in control group [(1.789 +0.301) vs (0.245 ±0.087), t =11.02, P ＜0.01 and (1.989 +0.207) vs (0.262+ 0.058), t = 17.93, P ＜ 0.01, respectively].Fatty degeneration of liver tissues was significantly exacerbated in model group.After treatment for 8 weeks and 12 weeks with mefformin, the levels of serum ALT,AST, FBG, serum TG, TC and FFA significantly decreased, ISI significantly increased, fatty degeneration of liver tissues was significantly improved, and the expression of UCP-2 protein significantly decreased,compared with model rats (P ＜ 0.01 or P ＜ 0.05).The expression of UCP-2 mRNA at 16th and 20th week in metformin group were significantly lower than that in model group [(0.665 + 0.088) vs (1.789 ±0.301), t = 7.81, P ＜ 0.01 and (0.610 ± 0.1 02) vs (1.989 ± 0.207), t = 9.98, P ＜ 0.01, respectivelv].ConclusionsMetformin has therapeutic effect on T2DM complicated with NAFLD.
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Objective To compare the clinical effects and safety of treating newly diagnosed type 2 diabetes patients by combining Glargine insulin with Metformin or/and Acarbose. Methods 84 patients with newly diagnosed type 2 diabetes ,who have a history of weight loss, body mass index( BMI )23 ～ 28kg/m2 and poorly controlled blood glucose in Metformin at least a month ,were randomly divided into three groups. Glargine insulin plus Mefformin were used in group A. Glargine insulin plus Acarbose(without mefformin)were used in group B, Glargine insulin, Acarbos and metformin were used in Group C. All three groups were given a 12-week follow-up. Results FBG,2hBG and HbA1c levels were lower in the patients after treatment( P ＜0. 05 ). HbA1c of patients was partly up to the standard in group A and group B,but HbA1c of patients was all up to the standard in group C. The effects in group C were better than those in group A and group B. It had the shortest time to achieve the target and the smallest dose of insulin in group C. BMI in group A and B did not change but decreased in group C(P＞0.05).The incidence of low blood sugar in all three groups was low and no significant difference observed among three groups (P＞0.05). And in all three groups no severe hypoglycemia occurred. Conclusion The method of combining Glargine insulin with Mefformin or/and Acarbose could effectively control blood sugar had little impact on body weight of the newly diagnosed type 2 diabetes patients, and moreover, the incidence of low blood sugar in the newly diagnosed type 2 diabetes patients was lower. It would be the ideal method to treat newly diagnosed type 2 diabetes patients considering the general safety and effectiveness and convenience.
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Objective To observe the effect of insulin glargine plus mefformin on inflammatory factors(IF) in the treatment of patients with newly diagnosed type 2 diabetes(T2DM).Methods 110 patients with newly diagnosed T2DM were given insulin glargine(beginning dose:10 U/d) and mefformin(0.5 g,tid) for 12 weeks;while 100 cases selected for the same period from the normal healthy population were taken as control group.Baseline fasting blood glucose(FPG),2 h postprandial blood glucose(2 hPG),glycosylated hemoglobin (HbA_1c),C-reactive protein(CRP),TNF-α and IL-6 were observed.Results Before treatment,FPG,2 hPG,HbA_1c and IF in T2DM group were obviously higher than those in control group(P＜0.05),but there was no difference in other clinical data (P＞0.05).After 12 weeks treatment,in T2DM group there was a significant improvement in blood glucose targets [FPG from (14.8±3.9) mmol/L to (6.6±2.1) mmoL/L;2 hPG from (17.6±3.3) mmol/L to (8.3±1.2)mmol/L;HbA1c from (9.6±2.7)% to (6.5±0.8)%,t=7.40,8.37,3.98,P＜0.05],and the level of IF also decreased significantly [CRP from (8.8±2.5) mg/L to (5.5±1.4) mg/L;TNFα from (2.9±0.6) ng/L to (1.6±0.2) ng/L;IL-6 from(170.3±22.2) pg/L to (105.9±14.6) pg/L,t=4.61,3.52,5.68,P＜0.05].Conclusions Insulin glargine and mefformin combined therapy can improve glucose metabolism in patients with newly diagnosed T2DM,and decrease the levels of IF.
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Objective To evaluate the efleet of continuous subcutaneous insulin infusion (CSII)combined with mefformin hydroehloride( Met H)on type 2 diabetic patients. Methods 240 patients with type 2 diabetes melli-tus (T2DM) were divided into 3 groups randomly: CSII combined with Met H ( A group: n=80) ; simple CSII ( B group:n=80) ; multiple deliver insulin (MDI) ( C group: n=80). The levels of blood glucose, HbA1 e, therapeutic time, a-mount of insulin, Fins ,C-P, HOMA-IR and IAI were compared among them before and after 10d of treatment. Results GroupA, B eornpared with group C, the levels of HbA1 e significantly deeroased in other two groups [ ( 8.0±3.2)%vs. (6.9±1.4)% and(7.0±1.2)% ] (aU P<0.05),so did the therapeutic time[(6.0±1.9)d vs. (3.0±1.4) and(3.5±1.5) d] and insulin dose[ (55.0±17.0) U/d vs. (38.0±15.0) U/d and(45.0±16) U/d] (all P<0.05). The insulin dose was much less in group A than in group B. Versus group B and C,the HOMA-IR of group A (0.8±0.3 vs. 1.5±0.4 and 1.6±0.4)decreased(P<0.05) ,and IAI(-2.0±4.3 vs. -3.6±4. 2 and -4.1±4.3) increased (all P<0.05), without the function impairments of heart, liver or kidney. Conclusion CSII in combi-nation with mefformin hydreehloride can significantly enhance the treatment effect of the patients with type 2 diabetes mellitns; reduce blood glucose and HbA1 e, improve insulin resistenee,lessen insulin need.
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Objective To evaluate the safety of mefformin in the treatment of elderly type 2 diabetes mellitus(T2DM). Methods Two hundred and forty-three cases of elderly T2DM hospitalized from Jan.1996 to Dec. 2006 were reviewed; the changes of fasting blood glucose(FBG), postprandial blood glucose (PBG), glycosylated hemoglobin (HbA1c), liver and renal function and blood lactic acid were evaluate before and after treatment. Results The mean time of treatment with mefformin was (6.6±3.9) years (3 months-21 years)in these 243 cases. The levels of FBG, PBG and HbAlc significantly reduced after treatment with mefformin only in 43 cases (17.7%), mefformin combined with other oral hypoglycemic drugs in 124 cases (51.0%) and mefformin combined with insulin in 76 cases (31.3%). There was only 18.1% of the cases with normal range ( > 80 ml/min) of creatinine clearance rate (Ccr), and 25.8% of the cases with Ccr≤50 ml/min. The liver and renal function as well as the blood lactic acid had no significant change after treatment no matter in total cases or in different groups separated by Ccr.Conclusions Mefformin is safety in the treatment of elderly T2DM patients. Ageing is not the contraindication of mefformin. To the patients with high risk, we should monitoring the level of blood lactic acid.
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Objective To compare the efficacy of weight loss,metformin and rosiglitazone in women with polycystic ovary syndrome(PCOS).Methods A randomized controlled trial(RCT)was carried out in Peking Union Medical College Hospital(PUMCH),one hundred and six women with PCOS were assigned to three intervention groups:weight loss,weight loss and metformin,weight loss and rosiglitazone group.Patients were treated with weight loss(diet and exercise),weight loss and mefformin (500 mg three times daily),weight loss and rosiglitazone(4 mg once daily)for three months.Sixty patients completed treatments.Basal body temperature(BBT),total testosterone as well as fasting serum insulin levels and lipid were measured and compared in all patients before and after weight loss.Results No significant differences were found in the baseline characteristics among three groups.In weight loss group 51%(22/43)patients completed treatment,and 23%(5/22)patients resumed ovulation.In weight loss and mefformin group 58%(21/36)patients completed treatment,and 43%(9/21)patients resumed ovulation.In weight loss and rosiglitazone group 63%(17/27)patients completed treatment,and 59% (10/17)patients resumed ovulation.Ovulation rate was significantly higher in weight loss and rosiglitazone group than in weight loss group.There was no significant difference among three groups in body mass index (BMI),waist circumference,waist-hip ratio(WHR),sex hormone,serum fasting insulin and lipid level after treatment.Conclusion Weight loss,metformin and rosiglitazone all can improve ovulation each.