Metformin enhances certain insulin actions in cultured rat hepatoma cells

Summary The effect of the oral antidiabetic agent metformin on insulin regulation of glycogen metabolism, tyrosine-aminotransferase activity, and [1-¹⁴C]aminoisobutyric acid uptake was studied in H4IIE cultured rat hepatoma cells. Metformin enhanced both basal (from 0.213±0.016 to 0.262±0.024 nmol/mg protein,p<0.01) and insulin stimulated [³H] glucose incorporation into glycogen in a time-dependent and dose-dependent manner. A small effect of metformin was seen at 1 μmol/l, and its greatest effects were obtained at 10 μmol/l. At the same concentrations, metformin did not influence basal tyrosine-aminotransferase activity but it potentiated insulin stimulated tyrosine-aminotransferase activity (+ 29.2±1.4%,p<0.01) and prevented the loss of tyrosine-aminotransferase responsiveness to insulin in H4IIE cells desensitised by a previous exposure to insulin. In contrast, metformin had no effect on basal or insulin-stimulated [1-¹⁴C]aminoisobutyric acid uptake. Over the concentrations of metformin that enhanced insulin action in H4IIE cells, the drug had no significant effect on insulin binding to its receptor. These studies suggest, therefore, that metformin may influence cellular metabolism by potentiating certain insulin actions through mechanisms that may be beyond insulin receptor binding.     

Effect of plasma metformin concentrations on serum lipid levels in type II diabetic patients

Summary In this study we evaluated the relationships between plasma metformin levels, measured by reversed-phase high-performance liquid chromatography, and serum lipid levels in 20 metformintreated, type II diabetic patients. Mean fasting plasma metformin concentration was 490 ± 188 ng/ml. No correlation was found between daily dose of drug and lipid parameters. A significant correlation emerged between circulating metformin concentration and serum triglycerides (r=−0.574, p<0.01), HDL-cholesterol (r=0.583, p<0.01) and HDL₂-cholesterol (r=0.670, p<0.05). Multiple linear regression analysis showed that the correlation between plasma metformin concentration and serum triglycerides still remained significant after correction for other clinical and metabolic parameters. Total cholesterol and HDL₃-cholesterol were not correlated with metformin concentrations. These results demonstrate the clinical usefulness of measuring plasma metforminc concentrations and indicate that some effects of metformin on lipid metabolism depend on the drug plasma levels.     

达格列净联合利拉鲁肽治疗2型糖尿病的临床研究

目的 探究达格列净联合利拉鲁肽治疗2型糖尿病患者的临床效果。方法 收集2017年1月—2019年4月在郑州人民医院治疗的2型糖尿病患者126例,随机分为对照组（63例）和治疗组（63例）。对照组口服盐酸二甲双胍片,0.5 g/次,3次/d,同时于睡前皮下注射利拉鲁肽注射液0.6 mg,1周后根据患者肠道反应增加至1.2 mg,1次/d。治疗组早餐前口服达格列净片,10 mg/次,1次/d;利拉鲁肽注射液的用法同对照组。两组患者治疗时间均为3个月。观察两组患者临床疗效,同时比较治疗前后两组患者糖化血红蛋白（HbA1c）、空腹血糖（FPG）、餐后2 h血糖（2 h PG）、体质量指数（BMI）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、对纤溶酶原激活物抑制物-1（PAI-1）和胱抑素C（CysC）水平。结果 治疗后,对照组和治疗组临床有效率分别为79.37%和93.65%,两组比较差异有统计学意义（P<0.05）。治疗后,两组患者HbA1c、FPG、2 h PG、BMI、IL-6、TNF-α、PAI-1、CysC均显著降低（P<0.05）,且治疗组上述指标比对照组更低（P<0.05）。结论 达格列净联合利拉鲁肽治疗2型糖尿病患者效果显著,且不增加不良反应,降低发生糖尿病血管并发症的风险。     

联合沙格列汀与二甲双胍治疗2型糖尿病的临床疗效分析

目的探讨二甲双胍联合沙格列汀治疗2型糖尿病效果。方法96例糖尿病患者随机分为二甲双胍组、联合用药组各48例,二甲双胍组给二甲双胍,0.5 g,tid,po;联合用药组另加沙格列汀片,5mg,qd,po。结果治疗6个月以后,联合用药组空腹血糖(FBG)(6.01±0.97)mol/L、餐后2 h血糖(2hPBG)(8.53±1.22)mol/L、糖化血红蛋白HbAlc(6.94±0.88)%、体重指数(BMI)(24.47±1.09)kg/m^2低于二甲双胍组的(7.42±1.04)mol/L、(9.28±1.34)mol/L、(7.14±0.97)%、(25.82±1.22)kg/m^2(P<0.05);总有效率95.83%高于二甲双胍组83.33%(P<0.05)。结论联合沙格列汀与二甲双胍治疗2型糖尿病,显著降低FBG、2hPBG、HbAlc、BMI,提高治疗总有效率。     

格列美脲联合二甲双胍对老年糖尿病的治疗作用研究

目的探讨格列美脲联合二甲双胍对老年糖尿病的治疗作用。方法100例老年糖尿病患者,随机分为二甲双胍组与格列美脲联合二甲双胍组,各50例。二甲双胍组患者采取二甲双胍治疗,格列美脲联合二甲双胍组采取格列美脲联合二甲双胍治疗。比较两组疗效;空腹、餐后血糖达标时间和糖化血红蛋白降低至<6%时间;治疗前后患者血糖、血脂;不良反应发生率。结果格列美脲联合二甲双胍组总有效率为100.00%,高于二甲双胍组的82.00%,差异有统计学意义(P<0.05)。治疗后,格列美脲联合二甲双胍组患者的餐后2 h血糖、空腹血糖、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)均低于二甲双胍组,差异有统计学意义(P<0.05)。格列美脲联合二甲双胍组空腹、餐后血糖达标时间和糖化血红蛋白降低至<6%时间均短于二甲双胍组,差异有统计学意义(P<0.05)。格列美脲联合二甲双胍组用药期间出现腹泻症状1例(2.00%);二甲双胍组用药期间出现腹泻症状1例(2.00%),两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论格列美脲联合二甲双胍治疗老年糖尿病效果确切,可有效改善血糖和血脂,且无明显不良反应,安全性高。     

二甲双胍与美沙拉嗪在小鼠结肠炎中的疗效比较

目的 探讨二甲双胍与美沙拉嗪在治疗小鼠结肠炎中的疗效差异性。方法 选取6 ~ 8周龄的C57BL/6雄性小鼠32只,随机分为Control组、硫酸葡聚糖（DSS）组、DSS+美沙拉嗪组、DSS+二甲双胍组,每组8只。Control组小鼠自由饮用高压灭菌双蒸水,并每日予0.2 ml 磷酸盐缓冲液（PBS）灌胃。采用3%DSS诱导C57BL/6雄性小鼠结肠炎模型。DSS组小鼠自由饮用3%DSS溶液,每日予0.2 ml PBS灌胃,DSS+美沙拉嗪组、DSS+二甲双胍组自由饮用3%DSS溶液,予100 mg/（kg·d） 的美沙拉嗪或100 mg/（kg·d） 二甲双胍灌胃。评估各组小鼠体质量变化、结肠长度、疾病活动指数、组织病理学改变及肠道炎症因子表达情况。结果 与DSS组相比,DSS+二甲双胍与DSS+美沙拉嗪组均可降低小鼠结肠炎所致的体质量丢失、疾病活动度评分、组织病理学评分及肠道炎症因子表达水平（P均< 0.05）,但DSS+二甲双胍组与DSS+美沙拉嗪组上述指标比较差异均无统计学意义（P均> 0.05）。结论 二甲双胍可以减轻DSS诱导的小鼠结肠炎,其疗效不亚于美沙拉嗪。     

Specific interpretation of hair concentrations in 2 fatal metformin intoxication cases

Hair analysis is very useful for toxicological investigations since, by providing a wider detection window, it gives the possibility to perform a retrospective study on the historical consumption of a substance. Unfortunately, there are no data available for hair concentrations in metformin-related deaths. In this study, the authors present 2 cases of fatal metformin intoxication in which, for the first time, hair analysis was performed using a specific GC–MS/MS method. Metformin was tested positive in femoral blood (112.3 mg/L and 64.7 mg/L respectively) and cardiac blood (226.9 and 203.2 mg/L) of the two subjects. For case 1, other samples were also tested positive, including vitreous humor (31.1 mg/L) and gastric contents (773.5 mg/L). In case 2, metformin was measured at 844.9 mg/L in urine. Metformin hair concentrations were 28.3–44.8 and 22.5 ng/mg for both cases, respectively. The concentrations found in the 2 fatal cases are clearly higher than those obtained in a previous study with subjects under treatment (0.3–3.8 ng/mg) or those found in 3 post-mortem cases where metformin death was excluded (0.6–1.4 ng/mg). Excessive sweating during the agonal phase due to fatal hypoglycemia could explain these elevated concentrations as sweat can have contaminated the hair.     

Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity

Current evidence strongly suggests that aberrant activation of the nuclear factor kappa B (NF-kB) signaling cascade is connected to carcinogenesis. The matrix metalloproteinases (MMP) which are also the key agents for tumor metastasis may be potent candidates for tumor diagnosis in clinics. In this in vitro study, we hypothesized that metformin with an effective dose can inhibit tumor cell proliferation and metastasis by modulating the expressions of MMP-2 and -9 and interfering with NF-kB signaling in primary breast cancer cells (PBCCs). 300 000 cells per ml were obtained from biopsies of breast tumors from five human donors. The cell viability and proliferation were tested. Immunocytochemistry was performed for MMP-2, MMP-9, and NF-kB, and enzyme-linked immunosorbent assay for NF-kB activity, quantitative real-time PCR for RELA/p65, IkBα, MMP-2, and MMP-9. Three different doses of metformin (5, 10, and 25 mM) (Met) reduced the viability and proliferation of PBCCs in a dose-dependent manner, maximum inhibition was observed at 25 mM Met. The expression of RELA/p65 was not affected by 25 mM Met. Nuclear immunoreactivity and activity of NF-kB reduced while cytoplasmic NF-kB (p65) elevated by 25 mM Met compared to non-treatment (P < 0.05). The expression and immunoreactivity of MMP-9 but not MMP-2 were decreased by 25 mM Met treatment, compared with the non-treatment (P < 0.05). Metformin may have an essential antitumor role in the invasion and metastasis pathways of PBCCs by downregulating the MMP-9 expression blocking both the activity and nuclear translocation of NF-kB.     

补肾调冲方在多囊卵巢综合征中的辅助治疗作用及机制研究

目的 探讨补肾调冲方治疗多囊卵巢综合征（PCOS）的临床疗效对氧化应激的影响。方法 选取我院2016年1月-2018年12月符合PCOS诊断标准的病例100例,以随机数表法随机分为观察组和对照组,每组50例。对照组采取达英-35+来曲唑组进行治疗,观察组在对照组治疗方案的基础上同时给于补肾调冲方治疗,总疗程为6个月经周期,记录两组患者临床资料,检测治疗前后患者脂肪细胞因子、性激素、氧化应激等指标。结果 治疗后,观察组内脂素（visfatin,VF）、瘦素（leptin,LEP）、体质量指数（body mass index,BMI）、腰臀比（waist-to-hip ratio, WHR）,睾酮（testosterone,T）、促黄体生成激素（luteotropic hormone,LH）、卵泡刺激素（follicle-stimulating,FSH）、LH/FSH,丙二醛（malondialdehyde ,MDA）水平以及流产率显著低于对照组;脂联素（adiponectin,APN）水平,雌二醇（estradiol,E2）水平,超氧化物歧化酶（superoxide dismutase,SOD）、谷胱甘肽过氧化物酶（Glutathione peroxidase,GSH）水平,排卵率及妊娠率水平显著高于对照组（P<0.05）,差异有统计学意义。结论 补肾调冲方对PCOS有较好的治疗作用,可减轻患者体质量,有效调节性激素水平,其机制可能与其改善氧化应激状态,缓解胰岛素抵抗有关。     

灵芝多糖联合二甲双胍对2型糖尿病模型大鼠氧化应激的影响

目的研究灵芝多糖联合二甲双胍对2型糖尿病大鼠氧化应激的影响。方法 采用斯泼累格·多雷（SD）大鼠高脂饮食4周后,腹腔注射小剂量链脲佐菌素30 mg.kg-1造模。成模后将大鼠随机分为模型对照组、灵芝多糖组（给予灵芝多糖600 mg.kg-1）、二甲双胍组（给予二甲双胍600 mg.kg-1）及联合用药组（给予灵芝多糖300 mg.kg-1＋二甲双胍300 mg.kg-1）,另设正常对照组。给药治疗12周末测量大鼠空腹血糖;测定血清超氧化物歧化酶（SOD）、丙二醛（MDA）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GSH-Px）、总胆固醇（TC）、三酰甘油（TG）水平。结果用药组空腹血糖水平均低于模型对照组（P<0.01）,其中联合用药组血糖显著低于单独用药组（P<0.01）。与模型对照组比较,用药组血清TC、TG水平明显下降（P<0.05或P<0.01）,与单独用药组比较,联合用药组血清TC、TG水平明显降低（P<0.05或P<0.01）;与模型对照组比较,用药组血清SOD水平明显升高（P<0.01）;与单独用药组比较,联合用药组血清SOD水平明显升高（P<0.05）。与模型对照组比较,用药组血清MDA水平明显降低（P<0.01）,联合用药组血清MDA较单独用药组明显降低（P<0.05）。与模型对照组比较,用药组血清CAT、GSH-Px水平明显升高（P<0.05或P<0.01）,联合用药组血清CAT、GSH-Px水平较单独用药组明显升高（P<0.05）。结论 灵芝多糖、二甲双胍联合用药能够有效对抗2型糖尿病大鼠体内氧化应激作用,效果优于单独用药,其机制可能与增强体内SOD、CAT、GSH-Px水平及调节血脂障碍有关。