Effects of insulin-sensitising agents in mice with hepatic insulin resistance

Aims/hypothesis The metabolic abnormalities of insulin resistance are ameliorated by insulin sensitisers via different mechanisms. Metformin decreases hepatic glucose output, whereas rosiglitazone (RSG) is an agonist for peroxisome proliferator activated receptor (PPAR), highly expressed in fat. To gain insight into the mechanisms of action of these drugs, we compared their actions in two models of insulin resistance: the obese, hyperglycaemic ob/ob mouse and the liver specific insulin receptor knockout (LIRKO) mouse.Methods Control, ob/ob, and LIRKO mice were divided into three groups that received metformin (300 mg/kg body weight/day), RSG (3 mg/kg body weight/day), or placebo for 3 weeks.Results In the presence of the severe hepatic insulin resistance of the LIRKO mouse, neither metformin nor RSG had any significant effect on glucose or insulin tolerance tests. On the other hand, RSG decreased serum concentrations of total cholesterol, LDL, and HDL in LIRKO mice. Adipocyte PPAR gene and protein expression, and adipocyte size were all increased in LIRKO mice treated with RSG, whereas fat-cell size in control animals was decreased by RSG.Conclusion/interpretation TZDs probably improve some lipid parameters of the dysmetabolic syndrome associated with diabetes mellitus even in the presence of absolute hepatic insulin resistance, but both metformin and TZDs require an operating insulin signalling system in the liver for their effects in glucose homeostasis.Abbreviations TZD Thiazolidinedione - RSG rosiglitazone - LIRKO liver specific insulin receptor knockout     

不同厂家盐酸二甲双胍普通片和缓释片体外溶出度分析

目的：建立盐酸二甲双胍片的溶出度试验方法,对6个厂家生产的盐酸二甲双胍普通片和4个厂家生产的缓释片含量和溶出度进行测定。方法：以纯化水1000ml作为溶出介质,采用转篮法测定溶出度,转速均为100r·min-1,温度为（37．0±0．5）C,用紫外分光光度法测定含量,测定波长为233nm,并对溶出参数进行了S-N—K统计学处理。结果：各厂家生产的盐酸二甲双胍片含量均符合药典规定,但各厂家盐酸二甲双胍片的溶出参数（T50、Td、m）差异明显。结论：不同厂家生产的盐酸二甲双胍片的溶出度行为明显不一致,进行溶出度检查有助于控制质量。     

二甲双胍对三阴性乳腺癌细胞作用的实验研究

目的探讨二甲双胍对三阴性乳腺癌的作用及可能机制。方法不同浓度的二甲双胍作用三阴性乳腺癌细胞MDA-MB-231后,采用MTT法检测细胞增殖,流式细胞仪检测细胞凋亡,Western blot技术检测ERK1/2、pERK1/2的表达水平,将肿瘤细胞接种裸鼠后给予二甲双胍治疗,观察肿瘤组织的抑瘤率。结果不同浓度的二甲双胍与乳腺癌MDA-MB-231细胞共培养后,随着二甲双胍浓度的逐渐增加,MDA-MB-231细胞的增殖抑制也逐渐增加。经统计学分析发现,二甲双胍20mM组与对照组比较;二甲双胍30mM组与20mM组、对照组比较;二甲双胍40mM组与30mM组、20mM组、对照组比较;二甲双胍50mM组与40mM组、30mM组、20mM组、对照组比较,差异均有统计学意义(t分别=16.04;4.36、29.24;21.33、23.46、40.61;3.70、31.80、33.16、64.17,P均<0.05)。乳腺癌MDA-MB-231细胞经二甲双胍处理后,细胞凋亡率(27.31%)明显高于对照组(2.36%),两者比较,差异有统计学意义(t=29.93,P<0.05)。经二甲双胍处理的MDA-MB-231细胞,其ERK1/2的磷酸化水平降低。将乳腺癌MDA-MB-231细胞接种于裸鼠,经二甲双胍治疗后,肿瘤组织的抑瘤率明显高于对照组,两者比较,差异有统计学意义(t=37.63,P<0.05)。结论二甲双胍对三阴性乳腺癌细胞有抑制作用,其机制可能是抑制EGFR信号通路的分子活化。     

二甲双胍对多囊卵巢综合征患者内分泌功能的影响

目的探讨二甲双胍对多囊卵巢综合征(PCOS)合并胰岛素抵抗(IR)患者内分泌的影响。方法 P-COS合并IR患者50例于自然月经或撤退性出血第2天开始服用二甲双胍12周,观察治疗前后血清促卵泡生成素(FSH)、黄体生成素(LH)、睾酮、雌二醇、雄烯二酮、性激素结合蛋白(SHBG)浓度、胰岛素(INS)水平以及血糖的变化。结果治疗后患者各时相INS水平显著下降,差异有统计学意义(P<0.01);患者血清LH、LH/FSH比值、睾酮和雄烯二酮水平均显著下降,差异有统计学意义(P<0.01);SHBG水平显著升高,差异也有统计学意义(P<0.01)。结论二甲双胍通过改善IR降低INS水平,改善患者临床症状和内分泌指标,使PCOS患者异常的血激素相得到明显改善。     

二甲双胍对雌激素受体表达不同乳腺癌细胞的作用

目的:探讨二甲双胍对雌激素受体(ER)表达不同的乳腺癌细胞的作用效果差异,并初步研究相关分子机制。方法:药物干预细胞后,采用MTT检测细胞增殖、流式细胞术(FCM)检测细胞周期以及凋亡、RT-PCR检测细胞HIF-1α的mRNA转录水平。结果:药物干预细胞后,各组细胞增殖均受到药物的抑制作用,且随药物浓度以及作用时间的增加而增强(P<0.05)。其中二甲双胍对于MCF-7(ER+)细胞的抑制率在各浓度组均高于MDA-MB-231(ER-)细胞(P<0.05)。FCM检测提示:二甲双胍对MCF-7(ER+)乳腺癌细胞G1期阻滞明显,且呈浓度依赖性增加(P<0.05)。但对于MDA-MB-231(ER-)细胞仅有20 mmol/L和40 mmol/L浓度组与对照组相比差异有显著性(P<0.05);且比同浓度组MCF-7(ER+)细胞G1期的阻滞百分比低(P<0.05)。二甲双胍对于两种乳腺癌细胞的凋亡作用不明显(P>0.05)。RT-PCR检测HIF-1α的mRNA表达水平提示:两种乳腺癌细胞HIF-1α的mRNA表达水平均随药物浓度增加而减少(P<0.05)。结论:二甲双胍对ER阳性乳腺癌细胞的抑制作用优于ER...     

二甲双胍的心脏保护作用

二甲双胍是临床上广泛应用的治疗2型糖尿病的药物。近年来不断有证据表明二甲双胍具有心脏保护作用,可提高心肌供能,促进一氧化氮的合成,改善胰岛素抵抗、抗炎、抗纤维化,抑制心肌细胞凋亡。同时研究显示二甲双胍的药理作用是通过激活腺苷激活的蛋白激酶实现。腺苷激活的蛋白激酶是一种重要的激酶,在调节糖脂代谢方面发挥着重要作用。     

Review: Metformin: Potential benefits and use in chronic kidney disease

Diabetes mellitus is the commonest cause of end‐stage renal failure in both Australia and New Zealand. In addition, the burden of diabetes is prominent in those with chronic kidney disease who have not yet reached the requirement for renal replacement therapy. While diabetes is associated with a higher incidence of mortality and morbidity in all populations studied with kidney disease, little is known about optimal treatment strategies for hyperglycaemia and the effects of glycaemic treatment in this large group of patients. Metformin is recommended as the drug of first choice in patients diagnosed with type 2 diabetes in the USA, Europe and Australia. There are potential survival benefits associated with the use of metformin in additional to recent studies suggesting benefits in respect to cardiovascular outcomes and metabolic parameters. The use of metformin has been limited in patients with renal disease because of the perceived risk of lactic acidosis; however, it is likely that use of this drug would be beneficial in many with chronic kidney disease. Thus the potential benefits and harms of metformin are outlined in this review with suggestions for its clinical use in those with kidney disease.     

Induction of ovulation

This review explores the pathophysiology associated with anovulation which affects 30% of cases of infertility. It provides an overview of the evidence based management of different groups of anovulation including role of adjuvant therapies. Anovulation can be effectively managed with induction of ovulation, the aim of which is to restore normal physiological ovulatory function. Weight optimization is the cornerstone of management in functional hypogonadotropic hypogonadism and polycystic ovarian syndrome (PCOS). The aim is to achieve monofollicular development, minimizing the risk of ovarian hyperstimulation and multiple pregnancies. The holistic approach involves induction of ovulation along with health education regarding lifestyle modifications and need for long term hormone replacement therapy in appropriate cases.     

Pharmacokinetic Interaction Between Rosuvastatin and Metformin in Healthy Korean Male Volunteers: A Randomized,Open-label, 3-period,Crossover, Multiple-dose Study

Purpose

Rosuvastatin is indicated for hypercholesterolemia or dyslipidemia and metformin mainly for type 2 diabetes. These 2 drugs are frequently prescribed in combination due to the high comorbidity of the 2 diseases. However the nature of pharmacokinetic interaction between the 2 drugs has not been previously investigated. The purpose of our study was to investigate the pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers.

Methods

This was a randomized, open-label, 6-sequence, 3-period, crossover, multiple-dose study. Eligible subjects, aged 20 to 50 years and within 20% of the ideal body weight, received 1 of the following 3 treatments for each period once daily for 5 consecutive days with a 10-day washout period between the treatments: monoadministration of rosuvastatin 10 mg tablet, monoadministration of metformin 750 mg tablet, and coadministration of rosuvastatin 10 mg tablet with metformin 750 mg tablet. Blood samples were collected up to 72 hours after the last dose and pharmacokinetic parameters for rosuvastatin and metformin were compared between combination and monotherapy. Adverse events were investigated and evaluated based on subject interviews and physical examinations.

Findings

Among the 36 enrolled subjects, 31 completed the study. The coadministration of rosuvastatin with metformin produced a significant pharmacokinetic interaction in rosuvastatin C_ss,max, with the 90% CI for the geometric mean ratio (coadministration:monoadministration) being 110.27% to 136.39% (P = 0.0029), whereas no significant interaction was observed in rosuvastatin AUC_tau, yielding the 90% CI of 104.41% to 118.95%. When metformin was coadministered with rosuvastatin, no significant pharmacokinetic interaction was observed for C_ss,max and AUC_tau of metformin, yielding the 90% CIs of the geometric mean ratio for coadministration to monoadministration as 87.38% to 102.54% and 86.70% to 99.08%, respectively. Overall, 19 mild and 1 moderate adverse events occurred in 12 subjects, with no significant differences in the incidence among the 3 treatments.

Implications

Although the C_ss,max of rosuvastatin was significantly influenced by coadministration with metformin, the degree of interaction seen was considered clinically insignificant, with no significant interaction observed in the other pharmacokinetic measures between the 2 drugs. These results imply that drug effects of rosuvastatin and metformin will also not be significantly influenced by coadministration of the 2 drugs. All treatments were well tolerated and no serious adverse events occurred. ClinicalTrials.gov identifier: NCT01526317.