胰高血糖素样肽1类似物对前列腺癌LNCaP细胞增殖的影响

目的 探讨胰高血糖素样肽1(GLP-1)类似物对前列腺癌细胞(LNCaP)增殖的影响.方法 分别用浓度为0、1、10和100 nmol/L的GLP-1类似物利拉鲁肽、艾塞那肽处理LNCaP后,采用CCK-8法检测LNCaP细胞的增殖率;Hoechst/PI凋亡试剂盒检测LNCaP细胞的凋亡.结果 艾塞那肽作用LNCaP细胞24 h后,LNCaP细胞增殖率随艾塞那肽浓度的增加而降低(P＜0.01).利拉鲁肽作用细胞24 h后,细胞增殖率显著低于空白对照(P＜0.01),对细胞增殖抑制作用无明显剂量依赖性.1 nmol/L和10 nmol/L的利拉鲁肽作用后的细胞增殖率显著低于相同浓度的艾塞那肽.结论 艾塞那肽、利拉鲁肽均能抑制LNCaP细胞增殖并促进细胞的凋亡.     

胰高血糖素样肽-1受体激动剂的研究进展

在健康人中,肠降血糖素胰高血糖素样肽-1(GLP-1)是在进食后分泌,并通过增加胰岛素分泌和抑制胰高血糖素释放而降低葡萄糖浓度。天然GLP-1在体内降解时间约为2~3 min,因此需要开发各种GLP-1受体激动剂以延长其体内作用时间。已开发出的GLP-1受体激动剂分为短期受体激活的化合物(例如艾塞那肽)和GLP-1受体的长效化合物(例如阿必鲁肽和利拉鲁肽等),以及小分子非肽类药物。这些GLP-1受体激动剂的个体性质可能使基于肠降血糖素的2型糖尿病治疗满足每个患者的需要。本文对当前GLP-1激动剂类药物的研究进行了综述。     

艾塞那肽对人舌鳞癌SCC-25细胞增殖、侵袭及凋亡的影响

摘要： 目的 探讨艾塞那肽对人舌鳞癌 SCC-25 细胞增殖、 侵袭能力以及凋亡相关指标的影响。方法 体外培养 SCC-25 细胞, Western blot 检测 SCC-25 细胞中胰高血糖素样肽 1 受体（GLP-1R）表达。实验分 4 组： 对照组、 1、 10 和 100 nmol/L 艾塞那肽处理组。培养 24 h、 48 h 和 72 h 后 MTT 法检测各组细胞增殖能力, Transwell 实验检测各组细胞侵袭能力。Western blot 检测基质金属蛋白酶（MMP） -2、 Caspase-3 和 p38 丝裂原活化蛋白激酶（Phosphop38 MAPK）表达。结果 SCC-25 细胞表达 GLP-1R。与对照组相比, 艾塞那肽处理组细胞存活率及侵袭率明显降低（P < 0.05）, MMP-2 蛋白表达降低（P < 0.05）, Caspase-3 蛋白表达明显升高（P < 0.05）; 各指标变化呈现艾塞那肽浓度和时间依赖性。10 nmol/L 艾塞那肽处理组 24 h 后 Phospho-p38 MAPK 表达升高（P < 0.05）。结论 艾塞那肽可抑制 SCC-25 细胞增殖和侵袭, 且可能通过促进 Phospho-p38 MAPK 和 Caspase-3 的表达诱导细胞凋亡。     

RV5疫苗与严重轮状病毒性腹泻的关联

背景：和大多数降糖药物不同,高血糖素样肽1（GLP-1）受体激动剂是葡萄糖依赖性的,并能促进体重减轻。该研究比较了利拉鲁肽（liraglutide,人GLP—1类似物）和艾塞那肽（exenatide,GLP-1受体激动剂）的有效性和安全性。方法：在这项为期26周的开放性多国平行试验中,纳入了给予最大剂量二甲双胍或（和）磺脲类药物治疗后血糖控制仍不理想的2型糖尿病患者,并按照先前的治疗进行分组,     

已上市胰高血糖素样肽-1受体激动剂的研究进展

胰高血糖素样肽-1受体激动剂（GLP-1RAs）治疗2型糖尿病受到广泛关注,其不仅具有优异的降糖优势,还有控制体质量,调节血脂,改善胰岛β细胞功能等特点,同时低血糖或体质量增加的不良反应发生率较低。自2005年至今,已经有7个GLP-1RAs经美国食品药品监督管理局批准上市,即艾塞那肽、利拉鲁肽、艾塞那肽长效制剂、阿必鲁肽、度拉糖肽、利西拉来和索马鲁肽;在中国上市的有贝那鲁肽和洛塞那肽。对已经上市的9个GLP-1Ras治疗2型糖尿病的临床研究进展进行综述。     

基因多态性与胰高血糖素样肽1受体激动剂疗效的相关性研究进展

目的:了解基因多态性与胰高血糖素样肽1(GLP-1)受体激动剂疗效的相关性,为GLP-1受体激动剂疗效相关基因多态性的研究和临床个体化用药提供参考。方法:以"胰高血糖素样肽1受体激动剂""基因多态性""艾塞那肽""利拉鲁肽""液泡蛋白分选受体1""大麻素受体1""GLP-1受体""Glucagon-like peptide-1 receptor agonist""Exenatide""Liraglutide""SORCS1""Cannabinoid type 1 receptor""GLP-1 receptor""Genetic polymorphism""Type 2 diabetes""Insulin resistance"等为中英文关键词,在中国知网、万方、维普、Pub Med、Springer Link等数据库中组合查询1991年1月-2019年3月发表的相关文献,对GLP-1受体激动剂相关的遗传因素和基因多态性的研究进展进行总结。结果与结论:共检索到相关文献307篇,其中有效文献33篇。GLP-1受体激动剂与液泡蛋白分选受体1(SORCS1)基因、GLP-1受体(GLP-1R)基因和大麻素受体1(CNR1)基因相关。目前研究表明,基因多态性与GLP-1受体激动剂改善胰岛功能、改善胰岛素抵抗和控制体质量效果相关。但此类研究多为小样本研究,需要更大的样本来确认SORCS1、GLP-1R、CNR1基因多态性与GLP-1受体激动剂疗效的关系,且其他GLP-1受体激动剂(如利司那肽、阿必鲁泰、度拉鲁肽和索玛鲁肽等)和已发现的基因位点多态性的相关性还未知,而与GLP-1受体激动剂疗效相关的新的基因位点还未发现,这可为今后开展相关研究提供方向。     

长效胰高血糖素样肽-1受体激动剂研究进展

新型2型糖尿病治疗药物胰高血糖素样肽-1(GLP-1)受体激动剂与传统降糖药物相比,具有促β细胞增生、稳定患者血糖水平和减轻体重等特点.通过对GLP-1及其类似物exendin-4进行结构修饰已获得一系列长效GLP-1受体激动剂.本文基于对GLP-1受体及其受体结构和功能的认识,对长效GLP-1受体激动剂的研究进展进行综述.     

胰升糖素样肽-1对胰岛β细胞胰岛素基因表达的调节作用

目的 研究不同浓度胰升糖素样肽-1（GLP-1）对大鼠胰岛β细胞胰岛素基因表达的影响,探讨GLP-1在2型糖尿病治疗中的作用。方法 不同刺激浓度的GLP-1（0nmol／L、1nmol／L、10nmol／L、10^2nmol／L、10^3nmol／L）与葡萄糖浓度分别为2．2mmol／L、5．5mmol／L、11.1mmol／L的RPMI1640营养液共培养24h后,提取细胞总RNA,运用半定量RT-PCR技术检测胰岛素基因表达的变化。结果 葡萄糖浓度为2．2mmol／L和5．5mmol／L时,随GLP-1浓度升高,胰岛素基因表达量呈钟型方式升高;葡萄糖浓度为11．1mmol／L时,随GLP-1浓度升高,胰岛素基因表达量呈浓度依赖性升高。结论 GLP-1以葡萄糖依赖和浓度依赖方式促进胰岛素基因的表达。     

以GLP-1受体为靶点的药物筛选模型的建立及功能鉴定

目的以GLP-1受体为靶点,建立GLP-1类似物活性检测的细胞模型,为GLP-1类似物以及GLP-1受体激动剂的药物筛选提供一种简单可靠的评价方法。方法首先将人源GLP-1受体基因插入pEGFP-N3,构建真核表达载体pEGFP-GLP-1R,并转染至HEK293A细胞中,经G418压力筛选后获得稳定表达GLP-1R-GFP的293A细胞株,然后通过GFP荧光信号和Western blot检测GLP-1R-GFP融合蛋白在该细胞中的表达与分布;最后利用GLP-1类似物利拉鲁肽刺激细胞,均相时间分辨荧光法检测细胞内cAMP含量变化。结果成功构建了GLP-1R-GFP-293A稳转细胞株,GLP-1RGFP蛋白主要分布在细胞膜表面,该细胞对GLP-1类似物利拉鲁肽具有高灵敏度和产生cAMP的特异性反应。结论利用所构建的细胞模型,可对小分子和GLP-1类似物进行体外活性分析,为筛选GLP-1受体激动剂奠定了模型基础。     

利拉鲁肽对2型糖尿病患者血脂影响的系统评价

<正>糖尿病(diabetes mellitus,DM)是以胰岛素抵抗和胰岛β细胞功能减退为主要机制、慢性血糖水平增高为特征的代谢疾病群[1,2]。糖尿病患者在全球范围内日益剧增,其中,2型糖尿病患者(type 2 diabetes mellitus,T2DM)占本病群体的95%[3]。利拉鲁肽是胰高血糖素样肽-1(GLP-1)受体激动剂的一种类型,它通过激动GLP-1受体,刺激葡萄糖依赖的胰岛     

A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists are a valuable addition to the type 2 diabetes armamentarium. They increase insulin secretion and reduce glucagon secretion in a glucose-dependent manner, posing a relatively low hypoglycemia risk. GLP-1 receptor agonists also offer weight-loss benefits. Because GLP-1 receptor agonists are relatively new agents, there is limited direction on their use. AREAS COVERED: This article aims to provide guidance to physicians when considering GLP-1 receptor agonist use in individual patients. It examines the clinical profiles of the currently available GLP-1 receptor agonists: exenatide twice-daily (BID), liraglutide once daily and exenatide extended release (ER) once weekly. Phase III clinical trial data on efficacy, safety and patient satisfaction are compared, with a primary focus on head-to-head trials. EXPERT OPINION: Liraglutide seems to be the most effective GLP-1 receptor agonist in terms of HbA(1c) reduction and weight loss. Exenatide BID may offer an advantage where postprandial glucose control is a primary concern. Exenatide ER generally outperforms exenatide BID and is a good option for patients who struggle to adhere to more frequent regimens. The future may hold interesting developments in terms of reduced dosing frequency, oral formulations and alternative therapeutic uses.     

A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists are a valuable addition to the type 2 diabetes armamentarium. They increase insulin secretion and reduce glucagon secretion in a glucose-dependent manner, posing a relatively low hypoglycemia risk. GLP-1 receptor agonists also offer weight-loss benefits. Because GLP-1 receptor agonists are relatively new agents, there is limited direction on their use.

Areas covered: This article aims to provide guidance to physicians when considering GLP-1 receptor agonist use in individual patients. It examines the clinical profiles of the currently available GLP-1 receptor agonists: exenatide twice-daily (BID), liraglutide once daily and exenatide extended release (ER) once weekly. Phase III clinical trial data on efficacy, safety and patient satisfaction are compared, with a primary focus on head-to-head trials.

Expert opinion: Liraglutide seems to be the most effective GLP-1 receptor agonist in terms of HbA_1c reduction and weight loss. Exenatide BID may offer an advantage where postprandial glucose control is a primary concern. Exenatide ER generally outperforms exenatide BID and is a good option for patients who struggle to adhere to more frequent regimens. The future may hold interesting developments in terms of reduced dosing frequency, oral formulations and alternative therapeutic uses.     

Effect of exendin (exenatide)-GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model

Exenatide or Exendin-4 is a 39-amino acid agonist of the glucagon like peptide (GLP-1) receptor approved for the adjunctive treatment for type 2 diabetes. Recent reports suggest that GLP-1 agonists may also have distant effects including C-cell thyroid hyperplasia. The aim of this study was to evaluate the effect of exendin-4 on the thyroid and parathyroid cells in a rat model. Rat thyroids were stained for calcitonin, H&E and for carcinoembryonic antigen (CEA). Thyroid C-cell hyperplasia was graded on H&E stained slides using cell size and secretory granule numbers, morphological features of the parathyroid glands and the serum calcium concentrations of the rats were also evaluated. Counts of stained cells/high power field and intensity of staining were recorded by two pathologists. Data were analyzed by ANOVA/post-tests. C cell hypertrophy was elevated in exenatide-treated vs. untreated animals (22.5±8.7 vs. 10.5±2.7cells/HPF). CEA staining failed to show effects by exendin. Calcitonin staining was significantly elevated in exenatide treated controls (P<0.001). Parathyroid glands were histologically normal in both groups, and serum calcium levels were within normal range in all animals. In summary, exenatide was associated with C cell hyperplasia and increased calcitonin staining of thyroids, but was unrelated to CEA levels. These data raise important concerns about the effects of exenatide which, given its wide clinical use, should be clarified with urgency.     

艾塞那肽联合二甲双胍对初诊成人2型糖尿病患者血糖控制效果观察

目的：观察胰高血糖素样肽-1（GLP-1）受体激动剂———艾塞那肽联合二甲双胍在初诊成人2型糖尿病（ T2DM）患者中的应用效果。方法对北京军区总医院内分泌科2013年11月—2015年6月诊治的78例 T2DM 的临床资料进行回顾性分析,依据治疗方法不同将78例分为二甲双胍单药组和艾塞那肽联合二甲双胍组,每组39例。二甲双胍单药组在饮食控制及运动锻炼的同时给予盐酸二甲双胍0.5 g 口服、3/ d;艾塞那肽联合二甲双胍组在二甲双胍单药组的基础上加用艾塞那肽注射液5μg 皮下注射、2/ d,1周后调整为10μg 皮下注射、2/ d。疗程为12周。观察比较两组治疗前后体重指数（BMI）、体重、空腹血糖（ FBG）、餐后2h 血糖（2 hBG）、糖化血红蛋白（ HbAlc）、血脂、血压、空腹胰岛素（FINS）的变化。结果两组体重、BMI 及 FBG、2 hBG、HbA1c 与治疗前比较显著下降,差异有统计学意义（P ﹤0.05）;艾塞那肽联合二甲双胍组甘油三酯（ TG）、收缩压较治疗前显著下降,FINS 较治疗前显著升高,差异均有统计学意义（P ﹤0.05）。与二甲双胍单药治疗组比较,治疗后艾塞那肽联合二甲双胍组体重、BMI、FBG、2 hBG、HbA1c、TG、收缩压显著下降,FINS 显著升高,差异均有统计学意义（P ﹤0.05）。两组均未发生明显不良反应。结论艾塞那肽联合二甲双胍可有效改善初诊成人 T2DM 患者的体重和糖代谢状态,且安全性较高。     

Glucagon and glucagon-like peptide receptors as drug targets

Glucagon and the glucagon-like peptides are derived from a common proglucagon precursor, and regulate energy homeostasis through interaction with a family of distinct G protein coupled receptors. Three proglucagon-derived peptides, glucagon, GLP-1, and GLP-2, play important roles in energy intake, absorption, and disposal, as elucidated through studies utilizing peptide antagonists and receptor knockout mice. The essential role of glucagon in the control of hepatic glucose production, taken together with data from studies employing glucagon antagonists, glucagon receptor antisense oligonucleotides, and glucagon receptor knockout mice, suggest that reducing glucagon action may be a useful strategy for the treatment of type 2 diabetes. GLP-1 secreted from gut endocrine cells controls glucose homeostasis through glucose-dependent enhancement of beta-cell function and reduction of glucagon secretion and gastric emptying. GLP-1 administration is also associated with reduction of food intake, prevention of weight gain, and expansion of beta-cell mass through stimulation of beta-cell proliferation, and prevention of apoptosis. GLP-1R agonists, as well as enzyme inhibitors that prevent GLP-1 degradation, are in late stage clinical trials for the treatment of type 2 diabetes. Exenatide (Exendin-4) has been approved for the treatment of type 2 diabetes in the United States in April 2005. GLP-2 promotes energy absorption, inhibits gastric acid secretion and gut motility, and preserves mucosal epithelial integrity through enhancement of crypt cell proliferation and reduction of epithelial apoptosis. A GLP-2R agonist is being evaluated in clinical trials for the treatment of inflammatory bowel disease and short bowel syndrome. Taken together, the separate receptors for glucagon, GLP-1, and GLP-2 represent important targets for developing novel therapeutic agents for the treatment of disorders of energy homeostasis.     

MAPK信号通路对蟾蜍灵抑制Jurkat细胞增殖及诱导其凋亡的影响

目的研究丝裂原活化蛋白激酶(MAPK)信号通路对蟾蜍灵(Bufalin)抑制急性淋巴细胞白血病Jurkat细胞增殖及诱导细胞凋亡的影响,初步探讨MAPK在蟾蜍灵治疗急性淋巴细胞白血病中的作用。方法WST-1法检测细胞的增殖活力,流式细胞术分析细胞凋亡。结果蟾蜍灵作用Jurkat细胞48 h,抑制细胞增殖50%的药物浓度(IC50)为44 nmol/L;5 nmol/L及以上蟾蜍灵以剂量依赖方式抑制Jurkat细胞增殖;20 nmol/L蟾蜍灵分别联合PD98059、SP600125,可显著增加对Jurkat细胞增殖的抑制,促进细胞凋亡;20 nmol/L蟾蜍灵联合SB203580作用于Jurkat细胞,可显著减少对Jurkat细胞增殖的抑制但对其凋亡无显著影响。结论 MAPK信号通路与蟾蜍灵抑制急性淋巴白血病Jurkat细胞增殖及诱导凋亡有相关性,表现为ERK和JNK促进增殖、抑制细胞凋亡;p38MAPK抑制增殖,但对凋亡无明显影响。     

Naturally occurring glucagon-like peptide-2 (GLP-2) receptors in human intestinal cell lines

Although clinical trials with GLP-2 receptor agonists are currently ongoing, the mechanisms behind GLP-2-induced intestinal epithelial growth remain to be understood. To approach the GLP-2 mechanism of action this study aimed to identify intestinal cell lines endogenously expressing the GLP-2 receptor. Here we report the first identification of a cell line endogenously expressing functional GLP-2 receptors. The human intestinal epithelial cell line, FHC, expressed GLP-2 receptor encoding mRNA (RT-PCR) and GLP-2 receptor protein (Western blot). In cultured FHC cells, GLP-2 induced concentration dependent cAMP accumulation (pEC(50)=9.7+/-0.04 (mean+/-S.E.M., n=4)). In addition, a naturally occurring human intestinal fibroblast cell line, 18Co, endogenously expressing GLP-2 receptor encoding mRNA (RT-PCR) and protein (Western blot) was identified. No receptor functionality (binding or G-protein signalling) could be demonstrated in 18Co cells. The identified gut-relevant cell lines provide tools for future clarification of the mechanisms underlying GLP-2-induced epithelial growth.     

胰高血糖素样肽1及其受体激动剂研究进展

胰高血糖素样肽1 (Glucagon-like Peptide-1,GLP-1) 是一种由肠道Ｌ细胞分泌的多肽激素,其与GLP-1受体结合后具有促进胰岛素分泌和生物合成,抑制胰高血糖素的分泌,促进胰岛?细胞增殖,抑制胰岛?细胞凋亡,保存?细胞对血糖的敏感性等多种生理功能,但是其在体内的半衰期很短 (<2 min),在临床应用上很受限制。根据GLP-1及其受体设计GLP-1类似物是目前开发糖尿病新药的前沿靶点之一,旨在寻找能够耐受二肽基肽酶4(DPP4)降解并具有GLP-1生理活性的长效肽类及非肽类化合物。本文对GLP-1及其受体激动剂的研究成果综述如下。     

腺苷受体A1亚型对视网膜色素上皮细胞 免疫调节功能的影响

目的 研究视网膜色素上皮细胞（RPE）主要是通过何种亚型的腺苷受体（ARs）来结合腺苷,及其对 RPE 功能的影响。方法 体外培养人 ARPE-19 细胞系,定量 PCR 检测 4 种腺苷受体（ARA1、ARA2A、ARA2B、ARA3）基 因的表达;提取细胞膜蛋白,Western blot 检测 4 种腺苷受体在 RPE 细胞膜上的存在。体外培养 ARPE-19 细胞至 80% 融合后随机分为 A~E 组。其中,A 组为无干预对照组,B～E 组分别给予 ARA1 拮抗剂 DPCPX（50 nmol/L）、 ARA2A 拮抗剂 SCH58261（100 nmol/L）、ARA2B 拮抗剂 MRS1754（100 nmol/L）及 ARA3 拮抗剂 MRS1220（5 μmol/L） 干预。利用 H3-腺苷进行放射性配体结合实验,计算各组细胞对腺苷的最大结合容量（Bmax）。以肿瘤坏死因子 α （TNF-α）10 μg/L 及 γ 干扰素（IFN-γ）1 000 U/mL 联合干预体外培养的 ARPE-19 细胞,给予或不予 ARA1 激动剂 （CCPA）,酶联免疫吸附试验（ELISA）测定培养上清中白细胞介素（IL）-6、IL-10、转化生长因子 β（TGF-β）、单核细胞 趋化因子（MCP）-1、趋化因子 C-X-C 配体 10（CXCL10,IP-10）的含量。结果 在 ARPE-19 细胞中即可检测到 4 种 腺苷受体基因的表达,也可探测到其分子在细胞膜上的存在。A~E 组 ARPE-19 细胞结合腺苷的 Bmax （单位：fmol）分 别为 2.04±0.31、0.44±0.06、1.82±0.28、2.01±0.42 及 2.06±0.44,其中 B 组较其他各组 Bmax均降低（P＜0.01）。以 TNF- α 及 IFN-γ 激活 ARPE-19 细胞,与对照 RPE 组比较,CCPA 干预 RPE 组 IL-6、MCP-1 及 IP-10 的含量降低、IL-10 的含量增加（P＜0.01）。2 组 TGF-β 的含量差异无统计学意义。结论 ARA1 对 ARPE-19 细胞结合腺苷的能力具 有重要的调控作用,ARA1 受体介导的信号可抑制 ARPE-19 细胞分泌促炎因子及驱化因子,具有潜在的免疫抑制 作用。