Genotoxicity evaluation of metformin and glimepiride by micronucleus assay in exfoliated urothelial cells of type 2 diabetes mellitus patients

Micronucleus (MN) assay was performed on the exfoliated urothelial cells to detect the genotoxic effects of the anti-hyperglycemic drugs, metformin and glimepiride in T2DM patients and to use it as a biomarker for DNA damage by assessing the frequency of micronuclei in the exfoliated urothelial cells. A total of 201 subjects (147 T2DM patients & 54 Normal cases) were selected from diverse age groups (25–75 years) and the mean MN frequency was examined per 1000 cells in all the subjects. Relative to the control group (5.02 ± 1.01), an increased MN frequency was observed in females (26.15 ± 2.15) when compared to males (23.08 ± 2.09) in T2DM patients. Further analysis showed that there was a profound increase in the number of MN in the patients using metformin alone (23.02 ± 4.44), or combination of metformin & glimepiride (24.98 ± 2.87) than to the subjects using glimepiride alone (17.52 ± 3.28). It has been proven by this simple, reliable and non-invasive method that metformin has a potential role in causing genotoxicity and that the MN observed in exfoliated urothelial cells could be used as a reliable biomarker in monitoring the genotoxic risk of the anti-hyperglycemic drugs.     

糖耐量异常患者凝血功能变化及二甲双胍的干预效应

目的 探讨糖耐量异常患者凝血功能变化及二甲双胍的干预效应.方法 将100例糖耐量异常患者按照随机数字表法分为试验1组和试验2组,每组50例,另选择健康志愿者50例作为对照组.试验2组给予二甲双胍治疗,试验1组给予安慰剂治疗.治疗前后各组行口服葡萄糖耐量试验(OGTT),检测糖负荷后2h血糖(2 h PBG),并检测糖化血红蛋白以及凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、凝血酶时间(TT)、纤维蛋白原(Fib).结果 治疗前试验1组和试验2组2 h PBG、糖化血红蛋白、Fib均明显高于对照组,Am、PT明显低于对照组,差异有统计学意义(P＜0.05).治疗后试验2组2 h PBG、糖化血红蛋白、Fib明显低于试验1组[(6.6±2.5) mmol/L比(7.9±3.6)mmol/L、(5.2±1.3)％比(5.8±1.4)％、(3.0±1.0) g/L比(3.6±1.2) g/L],APTT、PT明显高于试验1组[(34.3±6.8)s比(31.6±6.5)s、(12.6±0.7)s比(12.3±0.7)s],差异有统计学意义(P＜0.05),且与对照组比较差异无统计学意义(P＞0.05).三组TT比较差异均无统计学意义(P＞0.05).Pearson直线相关分析结果显示,APTT、PT与2hPBG和糖化血红蛋白呈负相关(P＜0.01),Fib与2h PBG和糖化血红蛋白呈正相关(P＜0.01),TT与2hPBG和糖化血红蛋白无相关性(P＞0.05).结论 糖耐量异常患者已出现凝血功能异常,适当的干预治疗可降低心血管疾病的危险因素.     

二甲双胍治疗2型糖尿病大鼠非酒精性脂肪肝疗效

目的 探讨二甲双胍(metformin,Met)对高脂联合链脲佐菌素(STZ)诱导的SD糖尿病大鼠肝脏沉积代谢的影响.方法 健康雄性7～8周龄SD大鼠随机分为高脂组(HF组,n=20)和普通饲料组(NC组,n=10),喂养8周后,以35 mg/kg的剂量一次性腹腔注射STZ得到2型糖尿病(T2 Diabetes Mellitus,T2DM)模型.成模大鼠再随机分成生理盐水组(DM+ saline组,n=10)和二甲双胍干预组(Met,500 mg/(kg.d),n=10),干预时间8周.干预结束后留全血标本并分离血清,收取肝脏组织并称重;检测全血和肝脏组织中的脂质水平;采用Western blot的方法测定小鼠肝脏组织脂代谢相关蛋白的表达.结果 模型组大鼠血清甘油三酯和胆固醇含量明显升高(P＜0.05);二甲双胍治疗后,血清胆固醇和甘油三酯明显降低(P＜0.05);DM大鼠肝功能和氧化应激得到了改善.肝脏组织学检测显示二甲双胍明显降低了肝脏中的脂质沉积;蛋白表达水平,二甲双胍治疗后改善了小鼠肝脏SREBP1及FAS表达水平.结论 二甲双胍干预可改善高脂饮食联合链脲佐菌素(STZ)诱导的SD大鼠的肝脏脂质沉积.     

Effect of metformin on Schwann cells under hypoxia condition

Metformin, which is the first-line drug for the treatment of diabetes mellitus type 2, has been proved to possess beneficial effects on nerve regeneration in many studies. However, the underlying mechanism is currently unclear. The present study was designed to investigate the potential beneficial effect of metformin on SCs under hypoxia condition, which is a biological process at the injury site. The cell number and cell viability of SCs were examined using fluorescence observation and MTT assay. The migration of SCs was evaluated using a Transwell chamber. The expression and secretion of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF) and neural cell adhesion molecule (N-CAM) in SCs were assayed by RT-PCR and ELISA method. The results showed that metformin could help SCs recover from hypoxia injury and inhibit hypoxia-induced apoptosis. In addition, metformin could partially reverse the detrimental effect of hypoxia on cell number, viability, migration and adhesion. Metformin is also capable of maintaining the biological activities of SCs after hypoxia injury, such as increasing the expression and secretion of BDNF, NGF, GDNF, and N-CAM. Further studies showed that pre-incubation with AMPK (5’-AMP-activated protein kinase) inhibitor Compound C might partially inhibit the effect of metformin mentioned above, indicating the possible involvement of AMPK pathway in the beneficial effects of metformin on peripheral nervous system. In conclusion, metformin is capable of alleviating hypoxia-induced injury to SCs and AMPK pathway might be involved in this process.     

二甲双胍对精神分裂症肥胖患者的体重及糖脂代谢的影响

目的:探讨二甲双胍对精神分裂症肥胖患者的体重及糖脂代谢的影响。方法:将66例精神分裂症肥胖患者随机分成研究组和对照组各33例,研究组给予二甲双胍片0.75g/d,对照组给予安慰剂治疗,疗程6个月。于治疗前及治疗6个月末测定空腹血糖(FBG)、胆固醇(TC)、甘油三脂(TG)、高密度脂蛋白(HDL)及低密度脂蛋白(LDL),测量身高和体重,计算体重指数(BMI)。结果:治疗6个月末两组比较,在BMI、FBG、TC、HDL、LDL 5个指标上差异有统计学意义(t=2.54,6.56,7.03,3.86,3.86;P均0.05),而TG水平差异无统计学意义。结论:二甲双胍能有效改善精神分裂症肥胖患者的体重增加及糖脂代谢紊乱,值得临床应用。     

Incidencia,factores relacionados con la presentación,evolución y mortalidad de la acidosis láctica asociada a metformina en el área sanitaria de un hospital de tercer nivel

Objectives

To determine the incidence of metformin-induced lactic acidosis during the period January 2014 to March 2017 in Aragon Healthcare Area III. To analyse the associated clinical and analytical factors and mortality.

二甲双胍对2型糖尿病伴非酒精性脂肪肝大鼠的治疗作用研究

目的 观察二甲双胍对2型糖尿病(T2DM)伴非酒精性脂肪肝(NAFLD)大鼠肝功能及肝组织病理形态学的影响,并探讨其可能的作用机制. 方法 按随机数字表法将36只Wistar大鼠分成正常组(12只)和造模组(24只),采用小剂量链脲佐菌素腹腔注射加高脂饲料喂养建立T2DM伴NAFLD模型. 将造模成功的大鼠随机分为单纯模型组(14 只)和二甲双胍组(10只),比较各组大鼠血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、甘油三酯(TG)、总胆固醇(CHO)和低密度脂蛋白胆固醇 (LDLC-)水平,肝组织TG、CHO、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、一氧化氮(NO)和一氧化氮合酶(NOS)水平. 结果 与正常对照组比较,单纯模型组血清ALT、AST、TG、CHO、LDL-C水平均显著升高(P<0.05);肝组织TG、CHO、NO、NOS水平显著升高(P<0.05),SOD及CAT水平降低(P<0 0.5 ). 与单纯模型组比较,二甲双胍组血清ALT、AST、TG、CHO、LDL-C 水平均显著降低(P <0.05),肝组织 TG、CHO、NO、NOS 水平显著降低(P<0.05);SOD 及CAT水平升高(P<0.05). 结论 二甲双胍治疗可显著改善T2DM伴NAFLD大鼠的脂肪肝,其机制可能与二甲双胍改善肝脏组织应激有关.     

二甲双胍对2型糖尿病大鼠肠道L细胞及味觉受体的影响

目的观察二甲双胍对于2型糖尿病大鼠肠道L细胞功能及味觉受体相关蛋白的影响。方法将18只健康的8~10周龄雄性Wistar大鼠经高糖高脂饮食4周后予链脲佐菌素(STZ)成模。随机分为三组:模型组+二甲双胍、模型组+普食;对照组。分别于成模干预前和干预第6周时行口服糖耐量实验(OGTT),并测血脂及胰高血糖素样肽-1(GLP-1)表达量。第6周时处死大鼠,并留取肠道组织标本运用real-time RT-PCR法检测胰高血糖素原(PG)基因,Western blot检测葡萄糖转运蛋白-2(GLUT-2)、味觉受体T1R2、T1R3及Gαgust蛋白的表达。结果干预后二甲双胍组和正常组的随机血糖均较干预前明显下降,差异有统计学意义(P0.01),且二甲双胍组下降更明显(P0.05)。干预后二甲双胍组血清总胆固醇(CHOL)较干预前明显改善(P0.05),低密度脂蛋白胆固醇(LDL-C)、甘油三酯(TG)均较干预前也有所下降,但差异无统计学意义(P0.05),且与正常组、对照组干预后相比,二甲双胍组CHOL明显下降(P0.01),LDL-C及TG也有所下降,但差异无统计学意义(P0.05)。干预6周后,二甲双胍组空腹血清GLP-1的表达量较干预前增加,且比正常组和对照组高,差异有统计学意义(P0.05);高糖负荷后,二甲双胍组血清GLP-1表达水平明显增加,且与正常组及对照组相比差异有统计学意义(P0.05)。结论二甲双胍具有良好的降糖降脂的作用;二甲双胍可能具有通过上调肠道L细胞内PG基因的表达,从而促进肠道L细胞GLP-1的产生,同时影响GLUT-2、味觉受体及其下游的信号因子Gαgust表达,进而间接起到降糖的作用。     

Metformin Use Is Associated With Better Survival of Breast Cancer Patients With Diabetes: A Meta‐Analysis

Background.

Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pathologic complete response rate than do diabetic patients not receiving metformin, but findings on salvage treatment have been inconsistent. We performed a meta-analysis to assess the effect of adding metformin to standard therapy on the prognosis of breast cancer patients with diabetes.

Methods.

We searched PubMed, Embase, Web of Science (Thomson Scientific), China Knowledge Resource Integrated Database, VIP journal integration platform, and Chinese BioMedical Literature Database from inception to January 10, 2015, without language restrictions, including references related to metformin, breast cancer, and prognosis. We performed the meta-analysis using a random-effects model, with hazard ratios (HRs) and 95% confidence intervals (95% CIs) as effect measures.

Results.

A total of 11 studies consisting of 5,464 breast cancer patients with diabetes were included, comprising 2,760 patients who had received metformin and 2,704 patients who had not. The meta-analysis showed that metformin was associated with better overall survival times (HR: 0.53; 95% CI: 0.39-0.71) and cancer-specific survival times (HR: 0.89; 95% CI: 0.79-1.00). Subgroup analysis revealed that metformin improved the overall survival by 65% after adjusting for hormone receptor expression (HR: 0.35; 95% CI: 0.15–0.84). Taking metformin after the diagnosis of breast cancer was still associated with prolonged overall survival.

Conclusion.

The use of metformin in standard cancer therapy might improve both overall and cancer-specific survivals of diabetic patients with breast cancer.

Implications for Practice:

Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pathologic complete response rate than diabetic patients not receiving metformin, but findings on salvage treatment have been inconsistent. The meta-analysis showed that metformin was associated with better overall survival times and cancer-specific survival times. Subgroup analysis revealed that metformin improved the overall survival by 65% after adjusting for hormone receptor expression. Taking metformin after the diagnosis of breast cancer was still associated with prolonged overall survival. The findings of this study highlight the potential usage of metformin in diabetic patients with breast cancer.     

Effect of ethylene glycol dimethacrylate on swelling and on metformin hydrochloride release behavior of chemically crosslinked pH–sensitive acrylic acid–polyvinyl alcohol hydrogel

Background

The present work objective was to prepare and to observe the effect of ethylene glycol dimethacrylate on swelling and on drug release behavior of pH-sensitive acrylic acid–polyvinyl alcohol hydrogel.

Methods

In the present work, pH sensitive acrylic acid–polyvinyl alcohol hydrogels have been prepared by free radical polymerization technique in the presence of benzoyl peroxide as an initiator. Different crosslinker contents were used to observe its effect on swelling and on drug release. Dynamic and equilibrium swelling studies of prepared hydrogels were investigated in USP phosphate buffer solutions of pH 1.2, 5.5, 6.5 and 7.5 with constant ionic strengths. Hydrogels were evaluated for polymer volume fraction, solvent interaction parameter, molecular weight between crosslinks, number of links per polymer chain, diffusion coefficient, sol–gel fraction and porosity. To demonstrate the release pattern of the drug, zero-order, first-order, higuchi and korsmeyer-peppas models were applied. Quality and consistency of hydrogels was examined by FTIR and surface morphology of hydrogels was examined by SEM.

Results

Decrease in swelling and in drug release was seen by increasing content of ethylene glycol dimethacrylate. A remarkable high swelling was observed at high pH indicating the potential of this hydrogel for delivery of drugs to intestine. By increasing the concentration of ethylene glycol dimethacrylate, porosity decreased. Order of release was observed first order in all cases and the mechanism was non–fickian diffusion. FTIR confirmed the formation of network. SEM results showed the incorporation of drug.

Conclusion

The prepared hydrogels can be suitably used for targeted drug delivery to the intestine.