JBC:研究鉴别出糖尿病药物二甲双胍的新型作用靶点

正近日,一项刊登于国际杂志Journal of Biological Chemistry上的研究报告中,来自日本名古屋大学的研究人员利用线虫作为模式动物进行研究,鉴别出了2型糖尿病药物二甲双胍的新型靶点,研究者发现,在果蝇机体中离子交换蛋白NHX-5和其相关的蛋白质或许是潜在的二甲双胍的靶点,这就表明二甲双胍能够控制细胞内吞作用的周期。2型糖尿病是一种常见的糖尿病类型,患者主要特点表现为胰岛素耐受性及高血糖,很多患者都服用二甲双胍药物来进行治疗,二甲双胍能     

二甲双胍与肝细胞癌

二甲双胍作为一种口服降糖药,已被用于2型糖尿病的一线治疗,有报道指出其可以预防和控制多种癌症的发展。肝细胞癌(肝癌)是原发性肝癌的最常见形式,也是最常见的恶性肿瘤之一。目前,流行病学显示二甲双胍可以降低肝细胞癌的发生风险或改善肝癌患者的预后,实验室研究也证实二甲双胍可抑制肝癌细胞生长。因此文章将探讨二甲双胍抑制肝癌生长的相关机制。     

二甲双胍抗肿瘤作用及其分子机制的研究进展

二甲双胍是全球范围内治疗2型糖尿病最常用的药物之一,具有使用方便、疗效好、价格低廉且毒副作用小等优点。近年来大量的流行病学研究及体内外实验研究发现二甲双胍能够用于多种肿瘤的治疗及预防,然而其分子机制尚不十分明确;主要包括调节体内胰岛素/IGF-1轴、激活AMPK信号通路、调控micro RNAs的表达、活化Caspase分子、阻断AGEs-RAGE系统等,这些机制为将来二甲双胍应用于肿瘤的预防及临床治疗提供了重要的理论依据。本文针对糖尿病治疗药物二甲双胍在抗肿瘤中的作用及其分子机制进行全面综述。     

二甲双胍对T2D患者肠道菌群的影响

2型糖尿病是一种由环境和遗传因素共同导致的以高血糖为主的慢性代谢性疾病,其主要的特点是胰岛素分泌不足和胰岛素抵抗。目前2型糖尿病发病率正在快速上升,给我们的未来带来了严峻的挑战。宿主肠道内正常的肠道菌群参与宿主的营养代谢、生长发育等重要生理功能,而研究表明肠道菌群失调与2型糖尿病密切相关。二甲双胍由于廉价、安全、有效成为了目前应用最广泛的降糖药之一,它不仅可以通过依赖及非依赖AMPK途径降糖,越来越多的研究表明它还可以通过改善T2D患者失调的肠道菌群发挥降糖作用。明确二甲双胍对肠道菌群的影响,有助于全面了解二甲双胍的作用机制。     

二甲双胍对老年2型糖尿病患者肠道菌群及血糖血脂的影响

目的 探讨二甲双胍对老年2型糖尿病患者肠道菌群、血糖血脂及炎性因子水平的影响.方法 选取2018年3月至2019年9月我院收治的120例2型糖尿病患者为研究对象,随机分为观察组和对照组,各60例.两组患者均给予常规胰岛素治疗,观察组在此基础上加用二甲双胍治疗.观察两组患者治疗前后肠道菌群变化,胰岛功能水平[空腹胰岛素(...     

吡格列酮和二甲双胍对初诊2型糖尿病患者肠源性内毒素水平的影响

目的:探究吡格列酮和二甲双胍对初诊2型糖尿病患者肠源性内毒素水平的影响。方法:选取初诊2型糖尿病患者105例,随机分为吡格列酮治疗组(52例)和二甲双胍治疗组(53例),以同期性别、年龄匹配的健康体检者42例作为对照组,治疗12周之后比较两组治疗前后肠源性内毒素及相关生化指标的变化情况。结果:治疗前,两治疗组的肠源性内毒素水平均显著高于对照组(P0.05);吡格列酮治疗后,患者肠源性内毒素和hs-CRP水平均下降较为明显(P0.01);而二甲双胍治疗后,仅hs-CRP水平显著下降,差异具有统计学意义(P0.05),而肠源性内毒素下降不明显(P0.05);但两种药物治疗后,肠源性内毒素水平仍高于对照组(P0.01)。结论:吡格列酮可以降低初诊2型糖尿病患者的肠源性内毒素水平,而二甲双胍对肠源性内毒素的下降作用不明显。     

酪酸梭菌活菌胶囊联合二甲双胍对2型糖尿病的治疗

目的研究酪酸梭菌活菌胶囊联合二甲双胍治疗2型糖尿病的效果,为此类患者的治疗提供参考。方法选择2018年1月至2019年1月在我院确诊为2型糖尿病的患者110例,随机将入选患者分为二甲双胍组(单纯采用二甲双胍治疗)和联合用药组(二甲双胍+酪酸梭菌活菌胶囊治疗),各55例。检测2组患者餐后2 h血糖(2hPG)、空腹血糖(FBG)、空腹胰岛素(FINS)、糖化血红蛋白(HBA1c)、胰岛素抵抗指数(HOMA-IR)、CD3~+细胞、CD4~+细胞、免疫球蛋白A(IgA)、免疫球蛋白M(IgM)、超敏C反应蛋白(hs-CRP)、血管内皮生长因子(VEGF)及白介素-1β(IL-1β)水平。结果联合用药组患者治疗后2hPG、FBG、FINS、HBA1c、HOMA-IR、hs-CRP、VEGF及IL-1β水平均低于二甲双胍组(均P0.05)。联合用药组患者治疗后血液CD3~+细胞、CD4~+细胞、IgA、IgM水平均高于二甲双胍组(均P0.05)。联合用药组患者治疗总有效率(90.91%)高于二甲双胍组(72.72%),而不良反应发生率(7.27%)低于二甲双胍组(16.36%),差异均有统计学意义(均P0.05)。结论酪酸梭菌活菌胶囊联合二甲双胍能有效降低2型糖尿病患者FINS、FBG、2hPG、HBA1c水平及炎症因子水平,患者不良反应发生率低。     

瑞格列奈联合二甲双胍对西宁地区2 型糖尿病患者PAI-1水平的影响

目的:研究瑞格列奈联合二甲双胍对西宁地区2型糖尿病患者纤维蛋白溶酶原激活抑制因子-1(PAI-1)水平的影响。方法:选择2012年2月~2015年9月在我院进行诊治的2型糖尿病患者98例,随机分为三组,分别用瑞格列奈、二甲双胍单独治疗和两药联合治疗。在治疗前后分别检测空腹血糖、糖化血红蛋白和PAI-1水平。结果:联合用药组的治疗总有效率为94.12%,明显高于瑞格列奈组(71.87%)和二甲双胍组(75.00%)(P0.05);瑞格列奈组和二甲双胍组治疗6周后,空腹血糖、糖化血红蛋白和PAI-1水平均明显降低(P0.05),但两单独用药组间相比无显著性差异;联合治疗组上述指标均较单独用药明显降低(P0.05)。联合治疗期间低血糖和胃肠不适的发生率较单独用药无明显升高。结论:瑞格列奈和二甲双胍可较单药治疗进一步降低2型糖尿病患者的PAI-1水平,这可能有助于改善患者的血液凝固程度,减少血管相关并发症,且无明显不良反应,值得临床应用推广。     

二甲双胍调控糖尿病大鼠骨髓间充质干细胞的增殖和分化

虽然二甲双胍广泛用于治疗2型糖尿病,但是其对骨骼的潜在影响知之甚少。因此,本研究评估了二甲双胍对培养的大鼠骨髓间充质干细胞(MSCs)和脂肪细胞两者的分化以及增殖的影响。首先随机组形成对照实验,其中对照组为在不经二甲双胍处理培养基中培养MSCs细胞21 d,而二甲双胍组则在用100μmol/L二甲双胍处理培养基中培养MSCs 21 d。结果表明,二甲双胍增强了大鼠MSCs的成骨细胞分化细胞中ALP的活性,抑制了培养中MSCs脂肪形成分化的过程,但是增强了MSCs细胞的增殖能力。     

JAMA:二甲双胍或无法改善过重1型糖尿病青少年患者机体的血糖控制

正近日,一项发表在国际杂志JAMA上的研究论文中,来自Jaeb健康研究中心的科学家进行了一项临床试验,包括对患1型糖尿病的过重和肥胖青少年进行研究,结果发现,将二甲双胍加入到胰岛素中或许在6个月后并不会改善患者的血糖控制情况。对于1型糖尿病青少年而言,过重或者肥胖会潜在的引发严重的代谢障碍,尤其是处于青春期期间;在所研究的青少年中,需要高剂量的胰岛素才可以克服肥胖的胰岛素耐受性,同时还会引发青春期个体血糖控制困难,同时引发个体未来体重增加;而二甲双胍是一种口服的降血糖制     

Metformin Suppresses Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-+Leprdb/+Leprdb Mice

Obesity and related metabolic disorders, such as diabetes mellitus, raise the risk of liver carcinogenesis. Metformin, which is widely used in the treatment of diabetes, ameliorates insulin sensitivity. Metformin is also thought to have antineoplastic activities and to reduce cancer risk. The present study examined the preventive effect of metformin on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-+Lepr^db/+Lepr^db (db/db) obese and diabetic mice. The mice were given a single injection of DEN at 2 weeks of age and subsequently received drinking water containing metformin for 20 weeks. Metformin administration significantly reduced the multiplicity of hepatic premalignant lesions and inhibited liver cell neoplasms. Metformin also markedly decreased serum levels of insulin and reduced insulin resistance, and inhibited phosphorylation of Akt, mammalian target of rapamycin (mTOR), and p70S6 in the liver. Furthermore, serum levels of leptin were decreased, while those of adiponectin were increased by metformin. These findings suggest that metformin prevents liver tumorigenesis by ameliorating insulin sensitivity, inhibiting the activation of Akt/mTOR/p70S6 signaling, and improving adipokine imbalance. Therefore, metformin may be a potent candidate for chemoprevention of liver tumorigenesis in patients with obesity or diabetes.     

Metformin selectively affects human glioblastoma tumor-initiating cell viability

Cancer stem cell theory postulates that a small population of tumor-initiating cells is responsible for the development, progression and recurrence of several malignancies, including glioblastoma. In this perspective, tumor-initiating cells represent the most relevant target to obtain effective cancer treatment. Metformin, a first-line drug for type II diabetes, was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models. We report that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomas. Metformin also impairs tumor-initiating cell spherogenesis, indicating a direct effect on self-renewal mechanisms. Interestingly, analyzing by FACS the antiproliferative effects of metformin on CD133-expressing subpopulation, a component of glioblastoma cancer stem cells, a higher reduction of proliferation was observed as compared with CD133-negative cells, suggesting a certain degree of cancer stem cell selectivity in its effects. In fact, glioblastoma cell differentiation strongly reduced sensitivity to metformin treatment. Metformin effects in tumor-initiating cell-enriched cultures were associated with a powerful inhibition of Akt-dependent cell survival pathway, while this pathway was not affected in differentiated cells. The specificity of metformin antiproliferative effects toward glioblastoma tumor-initiating cells was confirmed by the lack of significant inhibition of normal human stem cells (umbilical cord-derived mesenchymal stem cells) in vitro proliferation after metformin exposure. Altogether, these data clearly suggest that metformin exerts antiproliferative activity on glioblastoma cells, showing a higher specificity toward tumor-initiating cells, and that the inhibition of Akt pathway may represent a possible intracellular target of this effect.     

Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner

Metformin is a commonly-used treatment for type 2 diabetes, whose mechanism of action has been linked, in part, to activation of AMP-activated protein kinase (AMPK). However, little is known regarding its effect on circadian rhythms. Our aim was to evaluate the effect of metformin administration on metabolism, locomotor activity and circadian rhythms. We tested the effect of metformin treatment in the liver and muscle of young lean, healthy mice, as obesity and diabetes disrupt circadian rhythms. Metformin led to increased leptin and decreased glucagon levels. The effect of metformin on liver and muscle metabolism was similar leading to AMPK activation either by liver kinase B1 (LKB1) and/or other kinases in the muscle. AMPK activation resulted in the inhibition of acetyl CoA carboxylase (ACC), the rate limiting enzyme in fatty acid synthesis. Metformin also led to the activation of liver casein kinase I α (CKIα) and muscle CKIε, known modulators of the positive loop of the circadian clock. This effect was mainly of phase advances in the liver and phase delays in the muscle in clock and metabolic genes and/or protein expression. In conclusion, our results demonstrate the differential effects of metformin in the liver and muscle and the critical role the circadian clock has in orchestrating metabolic processes.     

Use of Metformin Alone Is Not Associated with Survival Outcomes of Colorectal Cancer Cell but AMPK Activator AICAR Sensitizes Anticancer Effect of 5-Fluorouracil through AMPK Activation

Colorectal cancer (CRC) is still the third most common cancer and the second most common causes of cancer-related death around the world. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been shown to have a suppressive effect on CRC risk and mortality, but not all laboratory studies suggest that metformin has antineoplastic activity. Here, we investigated the effect of metformin and AMPK activator AICAR on CRC cells proliferation. As a result, metformin did not inhibit cell proliferation or induce apoptosis for CRC cell lines in vitro and in vivo. Different from metformin, AICAR emerged antitumor activity and sensitized anticancer effect of 5-FU on CRC cells in vitro and in vivo. In further analysis, we show that AMPK activation may be a key molecular mechanism for the additive effect of AICAR. Taken together, our results suggest that metformin has not antineoplastic activity for CRC cells as a single agent but AMPK activator AICAR can induce apoptosis and enhance the cytotoxic effect of 5-FU through AMPK activation.     

Effect of metformin on stem cells: Molecular mechanism and clinical prospect

Metformin is a first-line medication for type II diabetes. Numerous studies have shown that metformin not only has hypoglycemic effects, but also modulates many physiological and pathological processes ranging from aging and cancer to fracture healing. During these different physiological activities and pathological changes, stem cells usually play a core role. Thus, many studies have investigated the effects of metformin on stem cells. Metformin affects cell differentiation and has promising applications in stem cell medicine. It exerts anti-aging effects and can be applied to gerontology and regenerative medicine. The potential anti-cancer stem cell effect of metformin indicates that it can be an adjuvant therapy for cancers. Furthermore, metformin has beneficial effects against many other diseases including cardiovascular and autoimmune diseases. In this review, we summarize the effects of metformin on stem cells and provide an overview of its molecular mechanisms and clinical prospects.     

Is it time to test biguanide metformin in the treatment of melanoma?

Metformin is the most widely used antidiabetic drug that belongs to the biguanide class. It is very well tolerated and has the major clinical advantage of not inducing hypoglycemia. Metformin decreases hepatic glucose production via a mechanism requiring liver kinase B1, which controls the metabolic checkpoint, AMP‐activated protein kinase‐mammalian target of rapamycin and neoglucogenic genes. The effects of metformin on this pathway results in reduced protein synthesis and cell proliferation. These observations have given the impetus for many investigations on the role of metformin in the regulation of tumor cell proliferation, cell‐cycle regulation, apoptosis, and autophagy. Encouraging results from these studies have shown that metformin could potentially be used as an efficient anticancer drug in various neoplasms such as prostate, breast, lung, pancreas cancers, and melanoma. These findings are strengthened by retrospective epidemiological studies that have found a decrease in cancer risk in diabetic patients treated with metformin. In this review, we have focused our discussion on recent molecular mechanisms of metformin that have been described in various solid tumors in general and in melanoma in particular.