Metformin as target metabolic drug in oncology
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It is well known that metformin is widely used for the treatment of type II diabetes mellitus. However, in numerous epidemiological studies it was shown that patients taking metformin were less likely to have cancer of different localization and had better survival prognosis. Many researchers consider metformin to be a targeted metabolic drug that has many goals: it acts on mitochondria, affects intracellular signaling, blocks channels, inhibits the formation of endothelial and platelet growth factors, reduces the level of vitamins involved in the synthesis of nucleotides and amino acids, etc. It has also been established that metformin belongs to the group of “metabostemness” drugs, that is, it acts on cancer stem cells, blocking their division. We conducted a survey study that highlights the most important mechanisms and fields of application of metformin. The study of the use of this drug in oncology will make it possible to understand the pathogenetic targets of metabolic therapy and the prevention of cancer.목적: 급성 호흡곤란 증후군은 높은 사망률을 보이지만, 저환기요법 외에는 입증된 치료법이 부족한 실정이고, 염증 반응 억제를 통한 치료법은 실패한 상황이다. 경구용 혈당강하제인 metformin이 항염 작용이 있다고 보고되었으나 급성 호흡곤란 증후군의 예후에 미치는 영향은 알려져 있지 않아 이를 알아보고자 하였다. 방법: 2005년 1월 1일부터 2015년 4월 30일까지 서울대학교병원 내과계중환자실에 입실한 급성 호흡곤란 증후군 환자 중 당뇨가 동반된 환자들을 후향적으로 분석하였다. 입원 전 3개월 내 metformin 처방된 경우 metformin 사용군으로 정의되었다. Propensity score matching 후 30일 사망률을 분석하였다. 성적: 당뇨가 동반된 급성 호흡곤란 증후군 환자 128명들 중 metformin 사용군은 33명이었다. Propensity score matching 후 30일 사망률은 metformin 사용군에서 낮았으나 통계적 유의성은 없었다 (42.4 vs. 56.4%, P=0.265). Ventilator free days 와 ICU free days 도양군간 차이는 없었다. 다변량 회귀분석에서 metformin 사용 여부는 30일 사망률을 감소시키는 경향을 보였으나, 역시 통계적인 유의성은 없었다 (s-coefficient -0.19, 95% CI -1.76-1.39, P=0.816). 결론: 중환자실 입실 이전 사용된 metformin 은 급성 호흡곤란 증후군 환자의 사망률을 감소시키는 경향을 보였으나 통계적으로 유의하지는 않았다.
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Metformin was rediscover during the hunt for an antimalarial drug. The French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. Aim: Over View of Metformin. The commonly used medication metformin has definite advantages in terms of issues related to diabetes and glucose metabolism.
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Metformin is an oral hypoglycemic agent that is commonly used in the treatment of type 2 diabetes mellitus. While metformin-associated metabolic acidosis is a widely recognized side effect of this drug, metformin-induced hepatotoxicity has been rarely reported in the literature. We present herein the case of a 52-year-old male in whom metformin-associated lactic acidosis and metformin-induced hepatotoxicity developed.
Lactic acidosis
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As a safe and effective antidiabetic drug , metformin has been considered to be the first line drug for the therapy of diabetes. With further research on metformin, it turns out that metformin can not only lower blood glucose but also display certain benefits for patients with polycystic ovary syndrome and nonalcoholic fatty liver disease, which is independent of the hypoglycemic effect of metformin. Furthermore, metformin can block cancer cells growth by activation of AMP-activated protein kinase and inhibition of mammalian target of rapamycin signaling pathway. In recent years, the effects of metformin on anti-atherosclerosis, endothelial function protection and other cardiovascular benefits have also become a research hotspot.
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To evaluate evidence from the medical literature that metformin is effective in preventing type 2 diabetes.Primary literature was accessed via a MEDLINE search (1966-December 2003) using the terms metformin, type 2 diabetes, and prevention.Two studies evaluated metformin's potential to prevent type 2 diabetes, finding that metformin maintained or reduced fasting blood glucose in non-diabetics. Recently, a large study by the Diabetes Prevention Program showed that metformin may reduce the incidence of diabetes. Researchers compared lifestyle changes, metformin therapy, and placebo groups. They found that both lifestyle changes (58%) and metformin therapy (31%) significantly reduced the occurrence of type 2 diabetes versus placebo.These studies provide evidence that metformin may reduce the occurrence of type 2 diabetes. Because long-term efficacy has not been determined, further studies are needed.
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Pharmacokinetic-Pharmacodynamic Modeling of Metformin for the Treatment of Type II Diabetes Mellitus
Metformin is an antihyperglycemic agent commonly used for the treatment of Type II diabetes mellitus. However, its effects on patients are derived usually from clinical experiments. In this study, a dynamic model of Type II diabetes mellitus with the treatment of metformin is proposed. The Type II diabetic model is a modification of an existing compartmental diabetic model. The dynamic simulation of the metformin effect for a Type II diabetic patient is based on the pharmacokinetic and pharmacodynamic relationship with a human body. The corresponding model parameters are estimated by optimization using clinical data from published reports. Then, the effect of metformin in both intravenous and oral administration on a Type II diabetes mellitus model are compared. The combination treatment of insulin infusion plus oral metformin is shown to be superior than the monotherapy with oral metformin only. These results are consistent with the clinical understanding of the use of metformin. For further work, the model can be analyzed for evaluating the treatment of diabetes mellitus with different pharmacological agents.
Pharmacodynamics
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Metformin is the most widely prescribed drug to treat patients with type II diabetes, for whom retrospective studies suggest that metformin may have anticancer properties. However, in experiments performed with isolated cells, authors have reported both pro- and anti-apoptotic effects of metformin. The exact molecular mechanism of action of metformin remains partly unknown despite its use for over 60 years and more than 17,000 articles in PubMed. Among the various widely recognized or recently proposed targets, it has been reported consistently that metformin is capable of inhibiting mitochondrial respiratory chain Complex I. Since most of the effects of metformin have been replicated by other inhibitors of Complex I, it has been suggested that the mechanism of action of metformin involved the inhibition of Complex I. However, compared to conventional Complex I inhibitors, the metformin-induced inhibition of Complex I has unique characteristics. Among these, the most original one is that the concentrations of metformin required to inhibit Complex I are lower in intact cells than in isolated mitochondria. Experiments with isolated cells, mitochondria or Complex I were generally performed using millimolar concentrations of metformin, while plasma levels remain in the micromolar range in both human and animal studies, highlighting that metformin concentration is an important issue. In order to explain the effects in animals based on observations in cells and mitochondria, some authors proposed a direct effect of the drug on Complex I involving an accumulation of metformin inside the mitochondria while others proposed an indirect effect (the drug no longer having to diffuse into the mitochondria). This brief review attempts to: gather arguments for and against each hypothesis concerning the mechanism by which metformin inhibits Complex I and to highlight remaining questions about the toxicity mechanism of metformin for certain cancer cells.
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Mitochondrial respiratory chain
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Studies on the additional properties of metformin continue despite the long period of its use as an antihyperglycemic drug. Metformin is a member of the biguanide class of drugs and is successfully used for many years in type 2 diabetes mellitus patients with normal weight, overweight, and obesity both in monotherapy and in combination with other sugar-lowering drugs. It can be used as a drug for the management of T2DM due to its high sugar-lowering activity, low risk of hypoglycemia when used as monotherapy, neutral effect on weight with its further moderate reduction, good safety profile, and availability for most patients. A decreased peripheral insulin resistance under the influence of metformin leads to increased utilization of glucose in the liver, muscles and adipose tissue, which results in an antihyperglycemic effect and, as a consequence of this, improvement of the disease management, preventing or slowing down the development of late complications of type 2 diabetes mellitus. Metformin has a proven track record as a drug with many positive effects, which was confirmed in numerous studies in patients with various complications of diabetes mellitus and concomitant pathologies. The article presents data on the use of metformin in patients with type 2 diabetes mellitus for the purpose of preventing sarcopenic obesity and managing its symptoms. Metformin presents some features of interest in preventing the development and treatment of non-alcoholic fatty liver disease and polycystic ovary syndrome.
Biguanide
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Metformin 广泛地为类型 2 糖尿病(T2D ) 的处理被用作首要的反糖尿病的药。作为首先指向肝的药， metformin 压制肝的葡萄糖生产(HGP ) ，用作 metformin 由改进 T2D 的多糖症的主要机制。生物化学地， metformin 压制 gluconeogenesis 并且刺激 glycolysis。Metformin 也禁止 glycogenolysis，它是极其贡献提高的 HGP 的一条小径。当在多糖症上产生有益的效果时， metformin 也改进胰岛素抵抗并且与 T2D 在病人改正 dyslipidemia。metformin 的这些有益的效果含有为在管理非酒精的脂肪肝的 metformin 的一个角色疾病。是从人和动物研究由结果支持了， metformin 改进肝的脂肪变性并且压制肝发炎。机械学地，肝的方面上的 metformin 的有益的效果通过腺苷被调停激活 monophosphate 的蛋白质 kinase (AMPK ) 依赖者和 AMPK 独立的小径。另外， metformin 通常是安全的并且可以也与另外的长期的肝疾病有益于病人。
Gluconeogenesis
Biguanide
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목적: Metformin은 암 발생 위험 및 사망률을 낮추는 효과가 있다. 당뇨를 동반한 4기 대장암 환자에서 metformin의 효과는 알려져 있지 않으며, 이번 연구는 당뇨를 동반한 4기 대장암 환자에서 항암약물요법 반응 및 생존율에 대한 metformin의 효과를 후향적으로 알아보고자 하였다. 대상 및 방법: 당뇨를 동반한 4기 대장암으로 진단된 106명의 환자 중 완화항암약물치료를 받은 81명의 환자와 근치적 수술을 시행한 25명의 환자를 대상으로 후향적 연구를 하였다. 각 군에서 metformin 사용여부에 따라 대상 환자의 임상적 특징 및 종양반응, 생존율 등을 조사하여 비교하였다. 결과: 완화항암약물요법을 시행한 환자군에서 metformin 복용군과 비복용군으로 나누어 단변량 및 다변량 분석을 시행한 결과, 항암약물요법 후 첫 번째 반응평가, 표적 병변의 크기 변화율, 무진행 생존율, 전체 생존율은 차이가 없었다. 근치적수술 환자군에서 무병 생존율은 metformin 복용군이 비복용군에 비하여 높았고(p=0.012), 다변량 분석에서도 암 재발률이 유의하게 적었다(HR, 0.024; 95% CI 0.001-0.435; p=0.010). 그러나 전체 생존율에서는 차이가 없었다. 결론: 당뇨를 동반한 4기 대장직장암 환자에서 근치적 수술 후 metformin을 복용하는 것은 암 재발률을 감소시키는 효과를 나타냈다.
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